CN101367794B

CN101367794B - Preparation method for quinazoline derivants and medical uses thereof

Info

Publication number: CN101367794B
Application number: CN 200810127622
Authority: CN
Inventors: 邓炳初; 冯君; 冯锋; 张蕾; 叶景泉; 王林; 宋志承; 张前锋; 党雅贤; 陆叶营; 宗令; 金池琼; 臧捷; 周颖
Original assignee: Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2007-07-20
Filing date: 2008-06-30
Publication date: 2013-07-10
Anticipated expiration: 2028-06-30
Also published as: CN101367794A

Abstract

The present invention relates to a preparation method of quinazoline derivatives and an application thereof in medicine. In other words, the present invention relates to novel quinazoline compounds as shown in general formulas (I), (II) and (III), a tautomer thereof, an enantiomer thereof, a non-enantiomer thereof, a despinner thereof and a salt thereof acceptable in pharmacy, a metabolite and a metabolism precursor or prodrug, and an application thereof as a treating agent, in particular as a protein kinase inhibitor, wherein, all substituted groups in general formulas (I), (II) and (III) are identical to the definitions in the specification.

Description

The preparation method of quinazoline derivative and in pharmaceutically application

Technical field

The pharmaceutical composition that the present invention relates to a kind of new Pyrrolopyridazine analog derivative, its preparation method and contain this derivative with and as therapeutical agent particularly as the purposes of tyrosine kinase inhibitor.

Background technology

The signal conduction of cell is a kind of mechanism of action of basis, in the signal conductive process, is passed to cell interior from extracellular stimulation, and then regulates the process of different cells.These signals can be regulated multiple physiological responses, comprise cell proliferation, differentiation, apoptosis and motion etc., and they exist with different sorts dissolution factor form, comprise the somatomedin based on paracrine factor, the autocrine factor and endocrine factor.By being combined with specific transmembrane receptor, the somatomedin part is delivered to signal pathway in the cell with the extracellular signal, thereby causes that individual cells is to the reaction of extracellular signal.A lot of signal transduction process are reversing processes of utilizing protein phosphorylation, relate to specific protein kinases and phosphorylated enzyme.

Protein kinase (PKs) is the enzyme that the phosphorylation of the hydroxyl on the tyrosine, Serine, threonine residues to protein plays katalysis.In the signal conductive process, the reverse mechanism of protein kinase and phosphorylated enzyme can balance and conditioning signal stream.A protein phosphorylation state can influence activity, the cellular localization of its conformation, enzyme; the respective action of protein kinase and Phosphoric acid esterase is modified; phosphorylated is an important regulation mechanism in the signal conduction, improper differentiation, conversion and the growth that can cause cell unusually in the signal conductive process.For example, cell can become cancer cells, the growth factor receptor protein that the oncogene that Tyrosylprotein kinase comes to this is coded by its a part of DNA is converted into oncogene; Tyrosylprotein kinase can also sport activated form and cause multiple human cell's variation, we can say that also the normal Tyrosylprotein kinase of overexpression can cause abnormal cellular proliferation.

Tyrosylprotein kinase (PKs) can be divided into two classes easily: protein tyrosine kinase (PTKs) and serine-threonine kinase (STKs).PTKs makes the tyrosine residues phosphorylation on the protein, and STKs makes Serine, the threonine residues phosphorylation on the protein.Tyrosylprotein kinase not only can be that receptor type (comprise cell foreign lands, cell internal area and stride the theca cell territory) can also be non-receptor type (comprising whole cell internal areas).A main aspect of PTK activity is that they relate to as the cell surface protein growth factor receptors.Growth factor receptors with PTK activity is called as receptor tyrosine kinase (" RTKs "), 90 kinds of Tyrosylprotein kinases are identified in Human genome, wherein about 60 kinds is receptor type, about 30 kinds is non-receptor type, these growth factor receptors families can be further divided into 20 kinds of receptor tyrosine kinase subtribes and 10 kinds of nonreceptor tyrosine kinase subtribe (Robinson etc. Oncogene, 2000, 19, 5548-5557).

The RTKs subtribe comprises following several: (1) EGF family, and as EGF, TGF α, Neu and erbB etc.; (2) Regular Insulin family comprises insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor dependency acceptor (IRR)); (3) III type family, as platelet derived growth factor receptor (PDGF, comprise PDGF α and PDGF beta receptor), relevant Tyrosylprotein kinase 3 (Flt3) receptor tyrosine kinase of STEM CELL FACTOR RTKs (SCF RTK, so-called c-Kit), fms-and colony-stimulating factor 1 acceptor (CSF-1R) Tyrosylprotein kinase etc.They are playing a part crucially aspect control cell growth and the differentiation, also be the crucial transmitter (referring to Schlessinger and Ullrich, Neuron 1992,9,383) who causes producing the cell signal of somatomedin and cytokine.The non-limiting kinases of a part comprises Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRaf1, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1, Plh-1, IGF-IR, IKK, IKK1, IKK2, IKK3, INS-R, Integrin-linked kinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie ₁, tie ₂, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70 etc.It is believed that PKs and central nervous system disease such as senile dementia (referring to Mandelkow .FEBS Lett.1992 such as E. M., 314,315; Sengupta .Mol.Cell.Biochem.1997 such as A., 167,99), pain (referring to Yashpal, K.J.Neurosci.1995,15,3263-72), inflammation for example sacroiliitis (referring to Badger, J.Pharmn Exp.Ther.1996,279,1453), psoriasis (referring to Dvir, etc., J.Cell Biol.1991,113,857), skeletal diseases for example osteoporosis (referring to Tanaka etc., Nature, 1996,383,528), (referring to Hunter and Pines, Cell 1994,79 for cancer, 573), arteriosclerosis is (referring to Hajjar andPomerantz, FASEB J.1992,6,2933), thrombosis is (referring to Salari, FEBS1990,263,104), metabolism disorder such as diabetes (referring to Borthwick .Biochem.Biophys.Res.Commun.1995 such as A.C., 210,738), vascular proliferative disease such as vasculogenesis (referring to CancerRes.1996 such as Strawn, 56,3540; J.Pharm.Exp.Ther.1998 such as Jackson, 284,687), autoimmune disease and graft-rejection are (referring to Bolen and Brugge, Ann.Rev.Immunol.1997,15,371), transmissible disease as virus (referring to Littler, E.Nature 1992,358,160) and fungi infestation (referring to Lum, R.T.PCT Int Appl., WO 9805335 A1 980212) etc. the target spot of disease has close contact.

In the PTKs signal conductive process, interact in the extracellular between the particular growth factor (part), receptor dimerization subsequently, the intrinsic activity of activated protein kinase in moment, and carry out phosphorylated.The binding site of internal signal transduction molecule produces, and has generated the mixture with cytoplasmic signal molecule, promotes for example cell fission of various cell responses (propagation), to born of the same parents' metabolic expression of microenvironment outward etc.

The binding site of receptor tyrosine kinase phosphorylated also is to have the binding site of high affinity with signal transduction molecule SH2 (with the src homology) territory.Substrate protein is determined in a lot of cells relevant with receptor tyrosine kinase, and can be divided into two classes: (1) has the no catalytic domain substrate of catalytic domain substrate (2), but can be used as combination, and has the molecule of catalytic activity relevant with some.The interactional specificity of acceptor or albumen and substrate SH2 territory is by determining near the aminoacid sequence of phosphorylated tyrosine residues, and the otherness that SH2 territory and phosphorylated tyrosine sequence aminoacid sequence on every side are combined with special receptor and the otherness of substrate phosphorylated are consistent.The protein tyrosine kinase function can be determined by expression pattern and part operability, also can be determined by the catchment signal conducting path that special receptor activates.Therefore, phosphorylated provides an important adjustable step, and this step can be determined selectivity and the differentiation factor receptors by the signal conduction of special receptor activation.The improper expression of receptor tyrosine kinase or sudden change may cause the disappearance of uncontrollable cell proliferation (as malignant growth) or crucial evolution etc.

Tyrosylprotein kinase, in the human tumour of major part, in cancers such as leukemia, mammary cancer, prostate cancer, nonsmall-cell lung cancer (comprising gland cancer, lung squamous cell cancer), gastrointestinal cancer (comprising colorectal carcinoma, the rectum cancer and cancer of the stomach), bladder cancer, the esophageal carcinoma, ovarian cancer, carcinoma of the pancreas, sudden change or overexpression all can appear.By the human tumor cell is detected, Tyrosylprotein kinase popularity and cognation have further obtained affirmation.For example: comprise that at human cancer the EGFR Tyrosylprotein kinase can be undergone mutation and overexpression in lung cancer, the cancer of the brain, neck cancer, gastrointestinal cancer, mammary cancer, the esophageal carcinoma, ovarian cancer, uterus carcinoma, bladder cancer and the thyroid carcinoma.

" HER " or " Erb " receptor tyrosine kinase subtribe comprises EGFR, HER2, HER3 and HER4.These subtribes are made up of born of the same parents outer glycosylation ligand binding domain, membrane-spanning domain and born of the same parents' inner cell matter catalytic domain that the tyrosine sequence on the protein can be carried out phosphorylated.The receptor tyrosine kinase catalytic activity can be activated by acceptor overexpression or ligand-mediated two polymerizations.HER2 family polymer has homodimer and two kinds of forms of heterodimer.An example of homotype dimerization is that HER1 (EGFR) (comprises EGF with EGF family part, transforming growth factor-alpha, betacellulin, the EGF of being combined with Vitrum AB, epiregulin) abnormal shape two polymerizations between the polymerization, four kinds of HER Tyrosylprotein kinases can be accelerated by the combination with heregulin (also being neuregulin) family's part.Though one of acceptor of HER3 does not have enzymic activity, HER2 and HER3, or the special-shaped dimerization of HER3 and HER4 also can stimulate tyrosine kinase receptor two polymerizations significantly.In all kinds cell, the acceptor overexpression can activate the kinase whose activity of HER2.The activation of acceptor homodimer and heterodimer can be carried out phosphorylated with acceptor and other intracellular protein tyrosine sequences; signal pathway such as microtubule-associated protein kinases (map kinase) and phosphatidylinositols (3) kinases (PI3 kinases) also are activated in the cell subsequently; the activation of these signal pathways impels cell proliferation, suppresses natural death of cerebral cells.

Another subtribe of RTK comprises insulin receptor (IR), IGF-1R (IGF-1R), insulin receptor associated receptor (IRR).IR, IGF-1R and Regular Insulin, IGF-I and IGF-II interact, and have generated by the outer glycosylation α subunit of two kinds of complete born of the same parents and two to pass cytolemma and contain the different tetramer that tyrosine kinase domain β subunit constitutes.

The 3rd subtribe of RTK refers to platelet derived growth factor acceptor (PDGFR) family, comprising PDGFR α, and PDGFR β, CSFIR, c-Kit and c-fms.These acceptors are formed by containing various immunoglobulin-like ring glycosylation extracellular domains and an extracellular domain, and wherein the Tyrosylprotein kinase district is blocked by incoherent aminoacid sequence in born of the same parents' internal area.

The platelet derived growth factor acceptor also is to stride the film tyrosine kinase receptor as PDGFR α and PDGFR β etc.When they combine with part, or formation homotype dipolymer (PDGF-AA, PDGF-BB), or special-shaped dipolymer (PDGF-AB).Receptor dimerization subsequently, Tyrosylprotein kinase is activated, and signal and promote tumor growth in the district downstream.Transgenation is that acceptor does not rely on the reason of being combined with part and being activated, and also is the motivating force that tumour generates.In multiple different tumor cell line, particularly in the cell of mastocarcinoma, colorectal carcinoma, ovarian cancer, prostatitis acyl cancer, sarcoma and glioma, all find to activate the expression of PDGFR somatomedin-PDGF, brain tumor wherein, the pernicious gliosis data of prostate cancer (comprising gland cancer and metastatic carcinoma of bone) has researching value.

C-Kit is the member of pdgf receptor family, and when itself and ligand SCF (STEM CELL FACTOR) when combining, activity is activated.In various solid tumor, the c-Kit expression pattern is studied, in sarcoma, gi tract glioma (GIST), in spermocytoma and the carcinoid tumor, c-Kit has overexpression.[referring to Weber etc., J.Clin.Oncol.22 (14S), 9642 (2004)].GIST is a kind of non-epithelial tumor, and great majority are present in stomach, and minority is distributed in small intestine, exists seldom in esophagus, also is distributed in positions such as liver, peritoneal cavity.GIST comes from Cajal mesenchymal cell (ICC), and ICC can partly form the intestines autonomic nervous system, participates in the control gastric motility.It is because the c-Kit gene is undergone mutation that great majority (50～80%) GIST produces, in digestive tube, the c-Kit/CD117 stained positive generally all be GIST, c-Kit sudden change can make it not rely on SCF and activate and just have the c-Kit function, thereby the cell fission rate is increased, cause genomic instability.In diseases such as distortion mastocytoma, mastocytosis, myeloproliferative syndrome, urticaria, also can detect the expression of c-Kit, the expression of c-Kit is also arranged in acute AML and malignant lymphoma, there is c-Kit to express (referring to Sch ǔ tte et al., innovartis 3/2001) in SCBC, spermocytoma, dysgerminoma, testis, intraepithelial neoplasias, melanoma, mastocarcinoma, neuroblastoma, Ewing sarcoma.As everyone knows, RET (rearranged duringtransfection).Proto-oncogene point genetic mutation is tumorigenesis, suffering from multiple endocrine adenomas 2 (MEN2) patient may cause suffering from pheochromocytoma, medullary thyroid carcinoma and illnesss such as parathyroid adenoma and hyperplasia and (see Huang et al., Cancer Res.60,6223-6 (2000)).

Very similar to the PDGFR subtribe because of tire liver kinases (Flk) acceptor subtribe, be attributed to this family sometimes.This subtribe is inserted territory-acceptor tire liver kinases-1 (KDR/FLK-1, VEGFR2), Flk-1R, Flk-4 and fms sample Tyrosylprotein kinase 1 (Flt-1) is formed by containing kinases.

The another one member of Tyrosylprotein kinase growth factor receptors family is fibroblast growth factor (FGF) acceptor subtribe.This subtribe is by four acceptors, and FGFR1-4, seven parts and FGF1-7 form.Though determine as yet at present, these acceptors by comprise the glycosylated extracellular domain of various immunoglobulin-like rings and one wherein the cell internal area blocked by incoherent aminoacid sequence of tyrosine-kinase enzyme sequence form.

The another one member of Tyrosylprotein kinase growth factor receptors family is vascular endothelial growth factor (VEGF) acceptor subtribe.Similar to PDGF, VEGF is biglycan albumen, but biological function is different with target cell specificity in the body.Particularly, VEGFR and associated angiogenesis suppress vasculogenesis by suppressing VEGFRs, just are being applied to clinical treatment tumour, and are obtaining better curative effect.VEGF is in various malignant entity tumors, as lung cancer, mammary cancer, non-Hodgkin malignant lymphoma, ovarian cancer, carcinoma of the pancreas, malignant pleural mesothelioma and melanoma strong expression is arranged, and relevant with the canceration process, expression is also arranged in leukocytosis and lymphoma.Except its angiogenic activity, VEGFR, VEGF part also can be by directly promoting tumor growth by pro-survival character in tumour cell, and PDGF also has angiogenic action.The process that new vessel generates continues growth for tumour and plays keying action, and under the normal circumstances, the physiological process that is created on the people of new vessel such as embryo growth, wound healing and female genital each process all are very important.Yet the vasculogenesis on non-expectation or the pathology but a series of states with disease is relevant, as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Ka Boji (family name) sarcoma and vascular tumor etc.The generation of vascular endothelial cell activates vasculogenesis, have stimulate in the body in the vascular endothelial cell the more active polypeptide of generation be identified, comprise fibroblast growth factor (aFGF and bFGF) and the vascular endothelial growth factor of acidity, alkalescence.Because the limiting expression of vegf receptor, the activity of its somatomedin is compared with aFGF and bFGF activity, and endotheliocyte is had specificity comparatively speaking.Nearest evidence shows, in the vasculogenesis and blood vessel process of osmosis of VEGF under normal circumstances and pathology situation, all is very important stimulant.VEGF can induction of vascular rudiment phenotype, and the expression of its inducing endothelial cell propagation, proteolytic enzyme and migration promote capillary vessel to generate, thereby forms super infiltration, jejune blood vessel network, and this is the characteristic feature of typical pathology vasculogenesis.People expect that antagonism VEGF activity particularly suppresses the value that tumor growth can have application in treatment disease such as the tumour relevant with angiogenic action or vascular permeability.

FLT3 (Fms sample Tyrosylprotein kinase) is Tyrosylprotein kinase (PTK) III type family member, in leukocytosiss such as adult and child's acute myeloid leukemia (AML), acute myeloid leukemia, myelodysplastic syndrome, the improper expression of FLT3 gene.35% acute myeloid leukemia patient's FLT3 sudden change is activated and prognosis mala, most sudden change has the phenomenon that copies in the structure in nearly film territory, patient's N 835 origination points sudden change of 5-10%, the tyrosine kinase activity of FLT3 is activated, and causing also has signal to exist under the situation of part disappearance and breed.According to the study, there is the probability of patient's healing of mutant form expression of receptor to reduce.In a word, in people's leukocytosis and myelodysplastic syndrome, all the generation with tumour is relevant in the FLT3 sudden change.

Verified pHGF (HGF) acceptor (c-MET or HGFR) Tyrosylprotein kinase and tumour generate, strengthen cell mobility, invasion and attack and transfer closely related (referring to Ma, P.C etc. (2003b) .CancerMetastasis Rev, 22,309-25; Maulik, G. etc. (2002b) .Cytokine Growth Factor Rev, 13,41-59).Various tumours comprise in the small cell lung cancer (SCLC) overexpression or the sudden change can activate c-MET (HGFR) (referring to Ma, P.C. etc. (2003a) .Cancer Res, 63,6272-6281).

The proto-oncogene c-Met hepatocyte growth factor receptor of encoding, be the cytolemma glycoprotein with tyrosine kinase activity, various kinds of cell propagation, differentiation are had important physical regulating effect .c-met gene in many malignant tumours, cross expression, be the important factor of follicular epithelial cell canceration, and with pathological staging, the invasion and attack of thyroid carcinoma and shift closely related.

About the PKT subtribe, Plowman etc. are at DN﹠amp; P 7 (6): have among the 334-339 (1994) more and describe in detail, the document is attached to herein by reference as an integral body.

Except PTKs, also there is other cellular enzymes family, be called receptor tyrosine kinase inhibitors, and use back one title at this, be abbreviated as " CTK ".CTKs itself lacks cell foreign lands and membrane-spanning domain.At present, in 11 subtribes (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK), identified above 24 kinds of CTKs.As if so far, Src subtribe CTKs number at most, comprises Src, Yes, and Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, and Src subtribe enzyme generates relevant with tumour.About the more detailed description of CTKs, can be referring to iBolen, 1993, Oncogen 8:2025-2031, it comprises that in full any accompanying drawing as whole a proposition, is attached to herein by reference.

Similar with CTKs, serine-threonine kinase or STKs, dominate in cell is though only there are several STK receptor kinases.STKs is the most general cytosol kinases, and namely it brings into play its function in the parts of fine kytoplasm, rather than in cytoplasmic organelles.Cytosol is zone in the cell, in this most cells intermediary metabolism and the active generation of biosynthesizing; Be to synthesize at the cytosol rrna as protein.

With one of feature of hyper-proliferative relative disease such as cancer etc. be that the cell pathway is destroyed, the cell pathway is by cell cycle control process.In eukaryotic cell, the orderly cascade reaction of the phosphorylated of cell cycle and protein is closely related, and in the mechanism of signal conduction, as if a lot of families of PKs all play a part key in the cell division cycle cascade.

About cancer, propose two main hypothesis and explain excessive cell proliferation, this propagation drives the tumor development relevant with known function of being regulated by PK.That is, people think that malignant growth is because machine-processed destroyed the causing of control cell fission or propagation.Proto-oncogene protein matter product can the interference adjustments cell signal transduction path of growth and propagation, the protein of these proto-oncogenes comprises extracellular discussed above somatomedin, transmembrane growth factor PTK acceptor (RTKs), tenuigenin PTKs (CTKs) and cytosol STKs.People wait in expectation and can synthesize the inhibitor with anti-tumour cell proliferative activity, wish to suppress among PTKs, CTKs or the STKs one or more, treat effectively and improve super propagation physiologic derangement by PTKs, CTKs or STKs and angiogenic action mediation.

Summary of the invention

In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide a kind of general formula I, new quinazoline compounds shown in II and the III, and their tautomer, enantiomorph, diastereomer, raceme and pharmacy acceptable salt, and meta-bolites and metabolic precursor thereof or prodrug.

Wherein:

R ¹Be selected from alkyl, Heterocyclylalkyl, aryl or heteroaryl, wherein alkyl, Heterocyclylalkyl, aryl or heteroaryl can further be replaced by one or more substituting groups that are selected from alkyl, halogen, aryl, hydroxyl, amino, alkynyl, thiazolinyl, cyano group, nitro, trifluoromethyl, halogeno-benzyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters; Wherein aryl or heteroaryl can and become dicyclo, and this dicyclo can further be replaced by benzyl or halogeno-benzyl; Perhaps R ¹Be structural formula:

Wherein:

B is selected from aryl or heteroaryl, and wherein aryl or heteroaryl can further be replaced by one or more substituting groups that are selected from alkyl, halogen, aryl, hydroxyl, amino, alkynyl, thiazolinyl, cyano group, nitro, trifluoromethyl, halogeno-benzyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;

T is selected from-O (CH ₂) r-,-N (CH ₂) r-or-S (CH ₂) r;

L is selected from aryl or heteroaryl, and wherein aryl or heteroaryl can further be replaced by one or more halogens or alkyl;

R ²Be selected from hydrogen atom, alkyl, cycloalkyl, trifluoromethyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl further by one or more be selected from alkyl, aryl, hydroxyl, halogen, amino, cyano group, alkoxyl group, carboxylic acid, carboxylicesters or-NR ⁶R ⁷Substituting group replace;

R ³And R ⁴Be selected from independently of one another hydrogen atom, alkyl, trifluoromethyl, cycloalkyl, Heterocyclylalkyl, aryl, carboxylicesters ,-SO ₂R ⁶,-CH ₂C (=O) NR ⁶R ⁷,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷Or-NC (=O) R ⁶, wherein alkyl, cycloalkyl, Heterocyclylalkyl further by one or more be selected from alkyl, halogen, trifluoromethyl, aryl, hydroxyl, alkoxyl group, aryloxy, cycloalkyl, Heterocyclylalkyl, heteroaryl, heterocycle alkoxyl group, cyano group, carboxylic acid, carboxylicesters ,-SO ₂R ⁶, or-(CH ₂) nNR ⁶R ⁷Substituting group replace;

Simultaneously, R ³And R ⁴Form 4～8 yuan of cyclic groups together; Wherein 5～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more be selected from alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, alkoxyl group, aryloxy, carbonyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters ,=N-OR ⁶Or-NR ⁶R ⁷Substituting group replace;

R ⁵Be selected from hydrogen atom, alkyl, cycloalkyl ,-C (=O) OR ⁶, wherein alkyl or cycloalkyl further by one or more be selected from alkyl, hydroxyl, alkoxyl group, cyano group ,-NR ⁶R ⁷, carboxylic acid or carboxylicesters replace;

R ⁶And R ⁷Be selected from hydrogen atom, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl respectively, wherein alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl further by one or more be selected from alkyl, cycloalkyl, halogen, aryl, hydroxyl, amino, alkoxyl group, thiazolinyl, Heterocyclylalkyl, hydroxyalkyl ,-SO ₂R ⁶,-C (=O) R ⁶, carboxylic acid, carboxylicesters or-NR ⁶R ⁷Substituting group replace;

Simultaneously, R ⁶And R ⁷Form 4～8 yuan of heterocyclic radicals together; Wherein 5～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more be selected from alkyl, halogen, aryl, heteroaryl, halogenated aryl, halogenated alkoxy, amino, hydroxyl, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, cycloalkyl, Heterocyclylalkyl, carbonyl, carboxylic acid, carboxylicesters ,-C (=O) NR ⁶R ⁷,-NC (=O) R ⁶,-SO ₂R ⁶, or-NR ⁶R ⁷Substituting group replace;

N is 0～6;

R is 0～2.

Particularly, the present invention includes the compound or its salt of following general formula (I) expression:

Wherein:

R ¹Be selected from alkyl, Heterocyclylalkyl, aryl or heteroaryl, wherein alkyl, Heterocyclylalkyl, aryl or heteroaryl can further be replaced by one or more substituting groups that are selected from alkyl, halogen, aryl, hydroxyl, amino, alkynyl, thiazolinyl, cyano group, nitro, trifluoromethyl, halogeno-benzyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters; Wherein aryl or heteroaryl can and become dicyclo, and this dicyclo can further be replaced by a benzyl or halogeno-benzyl;

Perhaps R ¹Be structural formula:

Wherein:

T is selected from-O (CH ₂) r-,-N (CH ₂) r-or-S (CH ₂) r;

N is 0～6;

R is 0～2.

Further, the present invention includes the compound or its salt of following general formula (II) expression:

Wherein:

Wherein:

T is selected from-O (CH ₂) r-,-N (CH ₂) r-or-S (CH ₂) r;

R ³Be selected from hydrogen atom, alkyl, trifluoromethyl, cycloalkyl, Heterocyclylalkyl, aryl, carboxylicesters ,-SO ₂R ⁶,-CH ₂C (=O) NR ⁶R ⁷,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷Or-NC (=O) R ⁶, wherein alkyl, cycloalkyl, Heterocyclylalkyl further by one or more be selected from alkyl, halogen, trifluoromethyl, aryl, hydroxyl, alkoxyl group, aryloxy, cycloalkyl, Heterocyclylalkyl, heteroaryl, heterocycle alkoxyl group, cyano group, carboxylic acid, carboxylicesters ,-SO ₂R ⁶, or-(CH ₂) nNR ⁶R ⁷Substituting group replace;

R ⁵Be selected from hydrogen atom, alkyl, cycloalkyl or-C (=O) OR ⁶, wherein alkyl or cycloalkyl further by one or more be selected from alkyl, hydroxyl, alkoxyl group, cyano group ,-NR ⁶R ⁷, carboxylic acid or carboxylicesters substituting group replace;

N is 0～6;

R is 0～2.

Further, the present invention includes the compound or its salt of following general formula (III) expression:

Wherein:

R ¹Be selected from alkyl, Heterocyclylalkyl, aryl or heteroaryl, wherein alkyl, Heterocyclylalkyl, aryl or heteroaryl can further be replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkynyl, thiazolinyl, cyano group, nitro, trifluoromethyl, halogeno-benzyl, Heterocyclylalkyl, carboxylic acid or carboxylicesterss of being selected from; Wherein aryl or heteroaryl can and become dicyclo, and this dicyclo can further be replaced by benzyl or halogeno-benzyl;

Perhaps R ¹Be structural formula:

Wherein:

B is selected from aryl or heteroaryl, and wherein aryl or heteroaryl can further be replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkynyl, thiazolinyl, cyano group, nitro, trifluoromethyl, halogeno-benzyl, Heterocyclylalkyl, carboxylic acid or carboxylicesterss of being selected from;

T is selected from-O (CH ₂) r-,-N (CH ₂) r-or-S (CH ₂) r;

N is 0～6;

R is 0～2.

Typical compound of the present invention comprises following compound or their pharmacy acceptable salts, but is not limited to these:

Wherein, described salt is above-claimed cpd and the salt that is selected from following acid formation: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, tosic acid, sulfuric acid, phosphoric acid, citric acid, tartrate, acetic acid or trifluoroacetic acid.

Be a kind of pharmaceutical composition in another aspect of the present invention, contain general formula (I), (II) or (III) shown in compound, its salt or its prodrug and pharmaceutically acceptable carrier or vehicle.

Be the control method of protein kinase catalytic activity in another aspect of the present invention, comprise protein kinase is contacted with general formula (I), (II) or compound (III) or salt.This protein kinase is selected from receptor tyrosine kinase, nonreceptor tyrosine kinase and serine-threonine kinase.

Be the preparation method of general formula (I), (II) or compound (III) or salt in another aspect of the present invention, may further comprise the steps:

The preparation method of a kind of general formula (I) compound, this method may further comprise the steps:

(1)

(2)

(3)

(4)

(5)

The preparation method of a kind of general formula (II) compound, this method may further comprise the steps:

(1)

(2)

The preparation method of a kind of general formula (III) compound, this method may further comprise the steps:

Detailed description of the invention

Unless the phase counter-statement is arranged, the following term that is used in specification sheets and claims has following implication.

" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, heteroaryl, heterocycle alkoxyl group, cyano group, nitro ,-C (=O) R ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶

" cycloalkyl " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan or 6 yuan/6 yuan fused rings of carbon or encircles fused rings (" condensing " ring system mean that each ring in the system share a pair of carbon atom that adjoins with other rings in the system) group more, wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.The example of cycloalkyl has cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenes, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.Cycloalkyl can be replacement or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from low alkyl group, halogen, three alkylhalide groups, hydroxyl, lower alkoxy, hydroxyalkyl, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, heterocycle alkoxyl group, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶

" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.Representative example includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from into halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl, cyano group, nitro, heterocycle alkoxyl group, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶

" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are formed.Representative example includes but not limited to ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl, heterocycle alkoxyl group, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶

" aryl " refers to have the group of at least one aromatic ring structure, namely has the aromatic ring of the πDian Zi system of conjugation, comprises isocyclic aryl, heteroaryl and dibenzyl.Alkynyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, nitro, cyano group, lower alkoxy, hydroxyalkyl, alkyl, heteroaryl, Heterocyclylalkyl, carboxyl, carboxylicesters, heterocycle alkoxyl group, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶" heteroaryl " refers to have 1 to 3 heteroatoms as annular atoms, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur and nitrogen.Described ring can be 5 yuan or 6 yuan of rings.The heterocyclic aryl examples of groups comprises furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl etc.Heteroaryl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, nitro, cyano group, lower alkoxy, hydroxyalkyl, alkyl, aryl, Heterocyclylalkyl, carboxyl, carboxylicesters, heterocycle alkoxyl group, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶" Heterocyclylalkyl " refers to monocycle or condensed ring group, in ring, has 5 to 9 annular atomses, and one of them or two annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) n (wherein n is integer 0 to 2), and all the other annular atomses are carbon.These rings can also have one or more pairs of keys.But, these rings do not have the πDian Zi system of total conjugated.Unsubstituted Heterocyclylalkyl include but not limited to pyrrolidyl, piperidino-(1-position only), Piperazino, morpholinyl, thio-morpholinyl, high piperazine its etc., Heterocyclylalkyl can be that replace or unsubstituted.Alkynyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from halogen, low alkyl group, hydroxyalkyl, three alkylhalide groups, hydroxyl, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, carboxyl, carboxylicesters, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶

" hydroxyl " refers to-the OH group.

" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl).Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from into alkyl, halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl, cyano group, nitro ,-C (=O) R ⁶,-C (=O) OR ⁶,-C (=O) NR ⁶R ⁷,-(CH ₂) nNR ⁶R ⁷,-NC (=O) R ⁶R ⁷Or-SO ₂R ⁶

" aryloxy " refer to-the O-aryl and-the O-heteroaryl, aryl and heteroaryl definition are the same.Representative example includes but not limited to phenoxy group, pyridyloxy, furans oxygen base, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygen base etc. and derivative thereof.

" benzyl " refers to-CH ₂-(aryl).

" halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine or chlorine.

" haloalkyl " refers to that alkyl is replaced by halogen.Representative example includes but not limited to trifluoromethyl, trisbromomethyl etc.

" hydroxyalkyl " refers to that alkyl is replaced by hydroxyl.

" amine alkyl " refers to that alkyl is replaced by amino.

" halogenated alkoxy " refers to-O-(haloalkyl).Representative example includes but not limited to trifluoromethoxy, tribromo methoxyl group etc.

" heterocycle alkoxyl group " refers to-O-(Heterocyclylalkyl).

" halogeno-benzyl " refers to-CH ₂-(halogenated aryl).

" trifluoromethyl " refers to-CF ₃

" nitro " refers to-NO ₂

" cyano group " refers to-CN.

" amino " refers to-NH ₂

" carbonyl " refer to-C (=O)-

" carboxylic acid " refers to (alkyl) C (=O) OH

" carboxylicesters " refers to (alkyl) C (=O) O (alkyl)

" optional " or " alternatively " mean describe subsequently ground event or environment can but needn't take place, this explanation comprises that this event or environment take place or spot occasion not.For example, " optional replaced the ground heterocyclic group by alkyl " mean alkyl can but needn't exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.

" pharmaceutical composition " represent on one or more compounds described herein or its physiology/mixture of pharmacy acceptable salt or prodrug and other chemical compositions, and other components are physiology/pharmaceutically acceptable carrier and vehicle for example.The purpose of pharmaceutical composition is to promote compound to the administration of organism.

The synthetic method of The compounds of this invention

In order to finish purpose of the present invention, the present invention adopts following technical scheme:

The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:

(1)

(2)

(3)

(4)

(5)

The preparation method of the described compound or its salt of general formula of the present invention (II) may further comprise the steps:

(1)

(2)

The preparation method of the described compound or its salt of general formula of the present invention (III) may further comprise the steps:

Embodiment

The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is that measuring solvent is deuterochloroform (CDCl with Bruker AVANCE-400 nuclear magnetic resonance spectrometer ₃), deuterated dimethyl sulfoxide (DMSO-D ₆), in be designated as tetramethylsilane (TMS), chemical shift is with 10 ^-6(ppm) provide as unit.

The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph.

The mensuration of the average inhibiting rate of kinases VEGFR is used HTScan microplate reader (Cell Signaling company).

The mensuration of the average inhibiting rate of kinases EGFR/HER-2 is with NovoStar microplate reader (German BMG company).

Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate.

Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.

DMSO-D ₆: deuterated dimethyl sulfoxide;

CDCl ₃: deuterochloroform;

Preparation embodiment:

Embodiment 1

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine

The first step

2-chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene

In 250 mL eggplant-shape bottles, add 2-chloro-4-nitro-phenol 1a (20.0 g under the room temperature, 115 mmol), use 120 mLN, the dinethylformamide dissolving raw material, stir down and add Anhydrous potassium carbonate (32.0 g, 230 mmol), fluorobenzyl chloride (24 g between adding after 10 minutes, 126 mmol), be heated to 90 ℃ of reactions 1.5 hours.Tlc analysis tracks to raw material and disappears, and reaction solution is cooled to room temperature, pours in the 1000 mL water and stirs 30 minutes, decompress filter is with a small amount of washing solid, vacuum-drying, obtain title product 2-chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene 1b (32.3 g, faint yellow solid).Productive rate: 99.5%.

MS m/z(ESI)：282[M+1]

Second step

3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride

In 1000 mL there-necked flasks, add 2-chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene 1b (38.6 g, 136.9mmol), with 300 mL dissolve with methanol raw materials, stir and add 100 mL water down, add iron powder (32.2 g again, 575 mmol) and ammonium chloride (62.4 g, 1.15 mol), reflux 6 hours.Tlc analysis tracks to raw material and disappears, reaction solution is cooled to room temperature, use the diatomite decompress filter, concentrating under reduced pressure is with methylene dichloride (100mL * 3) extraction, merge organic phase, with the washing of 50 mL saturated nacl aqueous solutions, dichloromethane layer anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain title product 3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride 1c (33.2 g, white solid).Productive rate: 84.3%.

MS m/z(ESI)：252[M+1]

The 3rd step

2-amino-5-iodo-methyl benzoate

In 500 mL eggplant-shape bottles, add 2-amino-methyl benzoate 1d (23.3 g, 154 mmol), with hydrochloric acid soln (concentrated hydrochloric acid 16 mL, water 200 mL) dissolving raw material, under 10 ℃ of stirrings, drip iodine chloride (25 g, 154 mmol) hydrochloric acid soln (concentrated hydrochloric acid 28 mL, water 100 mL), stirring at room 1 hour, decompress filter, solid vacuum-drying obtains title product 2-amino-5-iodo-methyl benzoate 1e (29 g, faint yellow solid).Productive rate: 69.0%.

MS m/z(ESI)：278[M+1]

The 4th step

6-iodo-3H-quinazoline-4-one

(13.5 g 48.7mmol) and ammonium formiate (3.5 g, 55 mmol), are dissolved in the 75 mL methane amides, are heated to 180 ℃ under stirring and react 1.2 hours to add 2-amino-5-iodo-methyl benzoate 1e under the nitrogen atmosphere in 250 mL eggplant-shape bottles.TLC tracks to raw material and disappears, and reaction solution is cooled to room temperature, and it is freezing to put into refrigerator, decompress filter, and with 15 mL methane amides and the washing of 50 mL normal hexanes, vacuum-drying obtains title product 6-iodo-3H-quinazoline-4-one 1f (12 g, white solid) respectively.Productive rate: 90.9%.

MS m/z(ESI)：273[M+1]

The 5th step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine

Add 6-iodo-3H-quinazoline-4-one 1f (25 g, 91.9 mmol) under the nitrogen atmosphere in 500 mL eggplant-shape bottles, be dissolved in 300 mL thionyl chlorides and 5 mLN, in the mixed solvent of dinethylformamide, reflux is transparent to reaction solution.TLC tracks to raw material and disappears, and steams thionyl chloride, and is standby.

Under the nitrogen atmosphere standby intermediate is dissolved in the 400 mL Virahols, adds 3-chloro-4-(3-fluoro-benzyl)-anilinechloride 1c (12 g, 50.4 mmol), reflux 3 hours.Tlc analysis tracks to raw material and disappears, reaction solution is cooled to room temperature, decompress filter, with the mixed solvent dissolving of gained solid with 100 mL ethyl acetate and 30 mL ammoniacal liquor, stirring at room 30 minutes, decompress filter, vacuum-drying, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (12 g, off-white color solid).Productive rate: 51.7%.MS m/z(ESI)：506[M+1]

The 6th step

In 250 mL eggplant-shape bottles, add [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (600 mg, 1.12 mmol), Anhydrous potassium carbonate (650 mg under the nitrogen atmosphere, 4.7 mmol), cuprous iodide (100mg, 0.5 mmol) and pyrroles (3 g, 44 mmol), dissolve with 25 mL toluene, stir and drip N, N '-dimethyl-1 (140 mg down, 1.6 mmol), reflux stirs and spends the night.Tlc analysis tracks to raw material and disappears, add 20 mL water and 100 mL ethyl acetate, diatomite filtration is transferred pH to 7 with the 2N hydrochloric acid soln, separatory, organic phase water (50 mL * 2) washing is successively used anhydrous magnesium sulfate drying, decompress filter again, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 1 (500 mg, faint yellow solid).Productive rate: 95.0%.MS m/z(ESI)：445[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.73(s，1H)，8.59(t，2H)，8.14(dd，1H，J＝9.2)，8.03(d，1H，J＝2.4)，7.87(d，1H，J＝8.8)，7.76(dd，1H，J＝8.8)，7.56(t，2H)，7.48(q，1H)，7.32(q，3H)，7.18(m，1H)，6.39(t，2H)，5.27(s，2H)

Embodiment 2

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-methylsulfonyl-ethylamino)-methyl]-pyrroles-1-yl }-quinoline Azoles quinoline-4-yl)-amine

The first step

2-methylsulfonyl-ethylamine hydrochloride

In 100 mL there-necked flasks, add borine (40 mL, 1.0 mol/L) under the nitrogen atmosphere, drip methylsulfonyl acetonitrile 2a under the stirring at room, stirred overnight at room temperature.Tlc analysis tracks to raw material and disappears, and drips methyl alcohol in the reaction solution till do not have bubble and produce, and concentrating under reduced pressure is removed methyl alcohol.Add the saturated hydrogen chloride methanol solution of 30 mL, reflux 1 hour, with the dilution of 30 mL methylene dichloride, decompress filter, solid vacuum-drying obtains title product 2-methylsulfonyl-ethylamine hydrochloride 2b (1.53 g, white solid).Productive rate: 67.4%.

MS m/z(ESI)：124[M+1]

Second step

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole-2-aldehyde

Under the nitrogen atmosphere, resulting compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (1.6 g during the adding embodiment of the invention 1 the 5th goes on foot in 500 mL there-necked flasks, 3.17 mmol), add Anhydrous potassium carbonate (1.7 g again, 13 mmol), cuprous iodide (910 mg, 4.76 mmol), pyrrole-2-aldehyde (1g, 10.5 mmol), dissolve with 200 mL toluene, stir and drip N, N '-dimethyl-1 (560 mg down, 6.34 mmol), reflux stirred 24 hours.Tlc analysis tracks to raw material and disappears, reaction solution is cooled to room temperature, diatomite filtration, wash organic phase with less water, concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates, obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 2c (500 mg, faint yellow solid).Productive rate: 33.4%.

MS m/z(ESI)：472[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，9.60(s，1H)，8.74(s，1H)，8.63(m，1H)，8.05(m，1H)，7.93(dd，1H，J＝8.8)，7.88(m，1H)，7.76(d，1H，J＝8.8)，7.60(m，1H)，7.50(m，1H)，7.35(m，4H)，7.21(m，1H)，6.57(m，1H)，5.26(s，2H)

The 3rd step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-methylsulfonyl-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine

In 50 mL eggplant-shape bottles, add resulting compound 2-methylsulfonyl-ethylamine hydrochloride 2b (70 mg in the embodiment of the invention 2 the first steps under the nitrogen atmosphere, 0.4 mmol), the mixed solvent that adds 5 mL tetrahydrofuran (THF)s and 5 mL methyl alcohol, stir and add triethylamine (0.2 mL down, 0.6 mmol), add 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino again]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 2c (120 mg, 0.25 mmol), stirring at room 30 minutes.Tlc analysis tracks to raw material and disappears, and adds sodium borohydride (40 mg, 1 mmol), stirring at room 30 minutes in batches.Tlc analysis tracks to raw material and disappears; with the reaction solution concentrating under reduced pressure; pour in the 50 mL water, with 100 mL ethyl acetate extractions, organic phase washes with water; anhydrous magnesium sulfate drying; filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates; obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-methylsulfonyl-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine 2 (120 mg, faint yellow solid).Productive rate: 50%.

MS m/z(ESI)：580[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，8.64(s，1H)，8.57(d，1H，J＝1.6)，8.06(m，2H)，7.88(d，1H，J＝8.8)，7.76(dd，1H，J＝9.0)，7.48(q，1H)，7.32(m，3H)，7.18(m，1H)，7.08(s，1H)，6.26(m，2H)，5.27(s，2H)，3.75(s，2H)，3.17(t，2H)，2.89(d，5H)

Embodiment 3

N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-Ji Jia Base)-and N ', N '-diethyl-1

Repeat the embodiment of the invention reaction in 2 second steps, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 2c makes raw material, carry out this raw material and N according to described same way as of the 3rd step of the embodiment of the invention 2, N-diethyl-1, the reaction of 2-quadrol, with silica gel column chromatography purifying gained resistates, then obtain title product N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy) phenylamino]-quinazoline-6-yl-1H-pyrroles-2-ylmethyl)-N ', N '-diethyl-1,2-quadrol 3 (50 mg, light yellow solid).Productive rate: 16.5%.

MS m/z(ESI)：573[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，8.64(s，1H)，8.60(d，1H，J＝1.6)，8.08(m，2H)，7.88(d，1H，J＝9.2)，7.77(dd，1H，J＝9.0)，7.48(q，1H)，7.31(m，3H)，7.18(m，1H)，7.06(t，1H)，6.22(d，2H，J＝2.0)，5.26(s，2H)，3.71(s，2H)，2.46(m，2H)，2.31(m，5H)，1.91(s，1H)，1.24(t，6H)

Embodiment 4

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-morpholine-4-base-ethylamino)-methyl]-pyrroles-1-yl }-quinoline Azoles quinoline-4-yl)-amine

Repeat the embodiment of the invention reaction in 2 second steps, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 2c makes raw material, carry out the reaction of this raw material and 2-morpholine-4-base-ethamine according to described same way as of the 3rd step of the embodiment of the invention 2, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-morpholine-4-base-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine 4 (50 mg, light yellow solid).Productive rate: 23.8%.

MS m/z(ESI)：586[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.86(s，1H)，8.65(s，2H)，8.05(m，2H)，7.87(m，1H)，7.75(dd，1H，J＝8.8)，7.45(q，1H)，7.30(m，3H)，7.18(m，1H)，7.13(s，1H)，6.38(s，1H)，6.27(s，1H)，5.27(s，2H)，3.93(m，2H)，3.40(m，4H)，2.87(m，2H)，2.35(t，2H，J＝2.0)，2.23(s，4H)

Embodiment 5

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methylsulfonyl-ethylamino)-methyl]-pyrroles-1-yl }-quinoline Azoles quinoline-4-yl)-amine

The first step

1H-pyrroles-3-formaldehyde

In 250 mL eggplant-shape bottles, add sodium hydride (1.51 g under 0 ℃ of the nitrogen atmosphere, 57 mmol), be dissolved in the 80 mL tetrahydrofuran (THF)s, stir and drip pyrroles 5a (4 g down, 59 mmol), stirred 30 minutes under the room temperature, drip tri isopropyl chlorosilane (10 g under 0 ℃ of stirring, 52 mmol), reaction is 45 minutes.Tlc analysis tracks to raw material and disappears, and with the reaction solution concentrating under reduced pressure, adds 100 mL water and 100 mL ethyl acetate, and ethyl acetate layer is washed with 50 mL.Concentrating under reduced pressure, standby.

Under 0 ℃ of the nitrogen atmosphere oxalyl chloride (7.24 g, 46.7 mmol) is dissolved in the 240 mL methylene dichloride, stirs and drip N down, 5 mL dichloromethane solutions of dinethylformamide (4.6 g, 63 mmol), 0 ℃ was stirred 20 minutes down.Standby intermediate is dissolved in the 10 mL methylene dichloride, splashes into fast in the reaction solution, 60 ℃ were refluxed 30 minutes down, were cooled to 0 ℃, filtered under the nitrogen atmosphere, and solid washs with ether, and vacuum-drying is standby.

Above-mentioned standby intermediate is dissolved in the sodium hydroxide solution (50 mL, 5%), stirred 4 hours under the room temperature.Tlc analysis tracks to raw material and disappears, and with dichloromethane extraction (100 mL * 3), merges organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, then obtain title product 1H-pyrroles-3-formaldehyde 5b (1.20 g, brown solid).Productive rate: 31.6%.

Second step

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde

Resulting compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g made raw material during the use embodiment of the invention 1 the 5th went on foot, carry out the reaction of this raw material and 1H-pyrroles-3-formaldehyde 5b according to described same way as of the 6th step of the embodiment of the invention 1, with silica gel column chromatography purifying gained resistates, then obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c (250 mg, light yellow solid).Productive rate: 47.0%.

MS m/z(ESI)：473[M+1]

The 3rd step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methylsulfonyl-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine

In 100 mL eggplant-shape bottles, add 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino under the nitrogen atmosphere]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c (50 mg, 0.1 mmol) with 2-methylsulfonyl-ethylamine hydrochloride (40 mg, 0.3 mmol), be dissolved in the mixed solvent of 10 mL tetrahydrofuran (THF)s and 0.2 mL methyl alcohol, add triethylamine (0.2mL, 10 mmol) again, stirring at room 30 minutes, add sodium cyanoborohydride (40 mg, 0.6 mmol), stirring at room 4 hours.Tlc analysis tracks to raw material and disappears; add 30 mL ethyl acetate and 30 mL water; the ethyl acetate layer anhydrous magnesium sulfate drying; filter; filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, then obtains title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methylsulfonyl-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine 5 (20 mg; faint yellow solid), productive rate: 34.5%.

MS m/z(ESI)：580[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.81(s，1H)，8.59(t，2H)，8.12(dd，1H，J＝9.0)，8.30(d，1H，J＝2.8)，7.86(d，1H，J＝9.2)，7.77(dd，1H，J＝8.8)，7.50(m，3H)，7.33(m，3H)，7.19(m，1H)，6.35(s，1H)，5.28(s，2H)，3.68(s，2H)，3.34(m，7H)

Embodiment 6

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid Ethyl ester

The first step

4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester

Under the nitrogen atmosphere; with tolysulfonyl ylmethyl isonitrile (0.975 g; 5 mmol) and (E)-4; 4; 4-trifluoro butenoic acid ethyl (0.84 g, 5 mmol) is dissolved in the mixed solvent of 8 mL methyl-sulphoxides and 16 mL ether, under the stirring at room it is added dropwise to sodium hydride (240 mg; 6 mmol) in the 6 mL ether suspension liquids, stirring at room 15 minutes.Tlc analysis tracks to raw material and disappears, add 30 mL water, with extracted with diethyl ether (30 mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, then obtain title product 4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6b (640 mg, light yellow solid).Productive rate: 61.8%.

MS m/z(ESI)：206[M-1]

Second step

Resulting compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g made raw material during the use embodiment of the invention 1 the 5th went on foot, carry out the reaction of this raw material and 4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6b according to described same way as of the 6th step of the embodiment of the invention 1, obtain title compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6 (30 mg, light yellow solid).Productive rate: 51.4%.

MS m/z(ESI)：585[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.77(s，2H)，8.32(s，1H)，8.27(s，1H)，8.19(s，1H)，8.00(d，1H，J＝4.0)，7.90(s，1H)，7.72(dd，1H，J＝8.8)，7.48(q，1H)，7.31(m，3H)，7.18(t，1H)，5.26(s，2H)，4.28(q，2H)，1.31(t，3H)

Embodiment 7

2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester

The first step

Pyrroles-1-carboxylic acid tert-butyl ester

Add pyrroles (6.71 g, 100 mmol) in 100 mL eggplant-shape bottles, tert-Butyl dicarbonate (26.20 g, 130 mmol) and 4-dimethylamino pyridine (4.89 g, 40 mmol) are with the dissolving of 50 mL acetonitriles, stirred overnight at room temperature.Tlc analysis tracks to raw material and disappears, and concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, then obtains title product pyrroles-1-carboxylic acid tert-butyl ester 7a (12.5 g, colourless liquid).Productive rate: 85.7%.

Second step

1-carboxylic acid tert-butyl ester-2-pyrroles's boric acid

Under the argon atmospher, (10.47 g 62.6mmol), are dissolved in the 100 mL tetrahydrofuran (THF)s to add pyrroles-1-carboxylic acid tert-butyl ester 7a in 250 mL there-necked flasks, drip lithium diisopropylamine (34 mL under-78 ℃ of stirrings, tetrahydrofuran solution, 2.0 mol/L) ,-78 ℃ were reacted 2 hours, drip trimethyl borate (9 mL, 81.4 mmol) ,-78 ℃ were reacted 1 hour, were warming up to-40 ℃ of reactions 30 minutes.Tlc analysis tracks to raw material and disappears, and reaction solution is poured in the 100 mL frozen water, transfers pH to 1 with 1N hydrochloric acid, with ethyl acetate extraction (100 mL * 3), merge organic phase, organic phase is washed with 200 mL saturated nacl aqueous solutions, the ethyl acetate layer anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates, add 50 mL normal hexanes, it is freezing to put into refrigerator, decompress filter, vacuum-drying, then obtain title product 1-carboxylic acid tert-butyl ester-2-pyrroles's boric acid 7b (6.94 g, faint yellow solid).Productive rate: 52.6%.

¹HNMR(400MHz，DMSO-d ₆)：δ8.02(s，2H)，7.33(dd，1H，J＝2.8)，6.43(dd，1H，J＝3.2)，6.22(t，1H)，1.55(s，9H)

The 3rd step

Repeat the embodiment reaction in five steps of 1 the first step to the, with compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (2.02 g that obtain, 4 mmol), 1-(tert-butoxycarbonyl)-1H-pyrroles-2-boric acid (1.1g, 5.2mmol), four triphenylphosphine palladium (0.23g, 0.2mmol), salt of wormwood (1.38g, 10mmol) be dissolved in 25 mL N, in the mixed solvent of dinethylformamide and 6 mL water, the mixture heating up to 70 that obtains ℃, afterreaction finished in 2 hours.Reaction solution is cooled to room temperature, pour in the 300mL frozen water, separate out white solid, stir after ten minutes, suction filtration, product are dry under vacuum, and the solid that obtains further passes through column chromatography, obtain title product 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester 7 (1.86 g, light yellow solid).Productive rate: 85.7%.

MS m/z(ESI)：545[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.78(s，1H)，8.61(s，1H)，8.58(s，1H)，8.07(d，1H，J＝2.0)，7.85(dd，1H，J＝8.6)，7.78(s，，1H)，7.76(d，1H)，7.46(m，2H)，7.31(m，3H)，7.18(t，1H)，6.45(m，1H)，6.38(t，1H)，5.26(s，2H)，1.30(s，9H)

Embodiment 8

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine

In the 100mL eggplant-shape bottle, the adding embodiment of the invention 7 is resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in the 3rd step]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester 7 (1.18 g, 2.17mmol), be dissolved in the 50 mL tetrahydrofuran (THF)s, add sodium methylate (936 mg, 8.66 mmol), stirred overnight at room temperature.Tlc analysis tracks to raw material and disappears, and reaction solution is poured in the 100 mL frozen water, with ethyl acetate extraction (50mL * 3), merge organic phase, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, add 20 mL normal hexanes, it is freezing to put into refrigerator, decompress filter, vacuum-drying, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 8 (0.65 g, light green solid).Productive rate: 80.0%.

MS m/z(ESI)：445[M+1]

¹HNMR(400MHz，DMSO-d ₆)：8.64(d，1H，J＝2.0)，8.53(s，1H)，8.14(dd，1H，J＝8.4)，8.05(d，1H，J＝2.8)，7.77(dd，2H，J＝9.0)，7.49(q，1H)，7.33(m，4H)，7.19(m，1H)，6.97(s，1H)，6.78(s，1H)，6.22(s，1H)，5.27(s，2H)

Embodiment 9

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-methyl isophthalic acid H-pyrroles-2-yl)-quinazoline-4-yl]-amine

Under the argon atmospher, compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 8 that in 10 mL eggplant-shape bottles, adds the embodiment of the invention 8 gained, be dissolved in 2 mLN, dinethylformamide stirs adding sodium hydride (8 mg, 0.337 mmol) down, stirring at room 1 hour, add methyl iodide (32 mg, 0.225 mmol), stirred overnight at room temperature.Tlc analysis tracks to raw material and disappears, and reaction solution is poured in the 20 mL water, with ethyl acetate extraction (25 mL * 3), merges organic phase, with the washing of 25 mL saturated nacl aqueous solutions, ethyl acetate layer anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, then obtains title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-methyl isophthalic acid H-pyrroles-2-yl)-quinazoline-4-yl]-amine 9 (35 mg, faint yellow solid).Productive rate: 34.0%.

MS m/z(ESI)：459[M+1]

¹HNMR(400MHz，DMSO-d ₆)：9.78(s，1H)，8.59(s，1H)，8.53(s，1H)，8.04(d，1H，J＝2.4)，7.94(dd，1H，J＝8.4)，7.81(d，1H，J＝8.4)，7.76(dd，1H，J＝9.0)，7.49(q，1H)，7.31(m，3H)，7.19(t，1H)，6.95(s，1H)，6.35(s，1H)，6.15(s，1H)，5.27(s，2H)，3.75(s，3H)

Embodiment 10

2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrrole Cough up-4-ketone

The first step

6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone

In 100 mL there-necked flasks; add tolysulfonyl ylmethyl isonitrile (5.48 g; 28.05 mmol), be dissolved in the 20 mL tetrahydrofuran (THF)s, drip 1 under 0 ℃ of stirring; 8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene (4.2 mL; 28.05 mmol), add 5,6-dihydro pyrone 10a (2.5 g after 15 minutes; 25.5 20 mL tetrahydrofuran solutions mmol), stirring at room 2 hours.Tlc analysis tracks to raw material and disappears, and pours in the 150 mL saturated nacl aqueous solutions stirred overnight at room temperature into.Concentrating under reduced pressure is removed tetrahydrofuran (THF), with ethyl acetate extraction (50 mL * 5), merges organic phase, uses anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates, and with 15 mL re-crystallizing in ethyl acetate, obtains title product 6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10b (2.20 g, yellow solid).Productive rate: 76.3%.

¹HNMR(400MHz，DMSO-d ₆)：δ11.70(s，1H)，7.16(dd，1H，J＝2.8)，6.64(d，1H，J＝0.8)，2.80(t，2H)，2.71(t，2H)

Second step

Compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (4.31 g that in 250 mL eggplant-shape bottles, add the 5th step of the embodiment of the invention 1 gained under the argon atmospher, 8.53 mmol), add 6 again, 7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10b (1.52 g, 11.68 mmol), and cuprous iodide (840 mg, 4.26mmol) and potassiumphosphate (5.43 g, 25.58 mmol), be dissolved in 80 mL N, in the dinethylformamide, stir adding N down, N '-dimethyl-1,2-quadrol (0.5 mL, 4.26 mmol) is heated to 68 ℃ of stirrings and spends the night.Tlc analysis tracks to raw material and disappears, reaction solution is poured in the 800 mL water, separate out solid under stirring, decompress filter, solid wash (50 mL * 2), vacuum-drying with water, then obtain title product 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 (3.57 g, yellow-green colour solid).Productive rate: 81.3%.

MS m/z(ESI)：515[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.81(s，1H)，8.74(d，1H，J＝2.0)，8.61(s，1H)，8.26(d，1H，J＝2.0)，8.23(dd，1H，J＝9.0)，8.02(d，1H，J＝2.8)，7.90(d，1H，J＝8.8)，7.74(dd，1H，J＝8.8)，7.53(s，1H)，7.48(q，1H)，7.34(m，3H)，7.19(t，1H)，5.28(s，2H)，4.49(t，2H，J＝5.8)，2.91(t，2H，J＝5.8)

Embodiment 11

N-(5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-Ji Jia Base)-and N ', N '-diethyl-1

The first step

5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole-2-aldehyde

Compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 8 (1.02 g that in 50 mL eggplant-shape bottles, add the embodiment of the invention 8 gained under the argon atmospher, 2.30 mmol), be dissolved in 10 mLN, in the dinethylformamide, under-15 ℃ of stirrings, add phosphorus oxychloride (0.3 mL, 3.45 mmol), stirred overnight at room temperature.Tlc analysis tracks to raw material and disappears, add 10 mL frozen water, transfer pH to 11 with the 1N sodium hydroxide solution, filter, solid vacuum-drying, then obtain title product 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-the thick product of 1H-pyrrole-2-aldehyde 11a (0.686 g, blackish green solid).Productive rate: 63.1%.

MS m/z(ESI)：473[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ12.44(s，1H)，9.76(s，1H)，9.56(s，1H)，8.90(s，1H)，8.59(s，1H)，8.40(d，1H，J＝9.2)，8.04(s，1H)，7.81(d，1H，J＝8.8)，7.75(dd，1H，J＝8.8)，7.46(m，1H)，7.33(m，3H)，7.20(m，2H)，7.02(s，1H)，5.28(s，2H)

Second step

N-(5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-N ', N '-diethyl-1

Add 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in the 100 mL eggplant-shape bottles]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 11a (294 mg, 0.62 mmol) and N, N-diethyl-1,2-quadrol (139 mg, 1.2 mmol) is dissolved in the mixed solvent of 10 mL tetrahydrofuran (THF)s and 0.2 mL methyl alcohol, stirring at room 30 minutes, add sodium cyanoborohydride (80 mg, 1.2 mmol), stirring at room 4 hours.Tlc analysis tracks to raw material and disappears, add 50 mL water, with ethyl acetate extraction (50 * 3), merge organic phase, the ethyl acetate layer anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, then obtain title product N-(5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-1H-pyrroles-2-ylmethyl)-N ', N '-diethyl-1 11 (35 mg, yellow solid).Productive rate: 1 0.2%.

MS m/z(ESI)：573[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.82(s，1H)，9.84(s，1H)，9.10(s，1H)，8.55(s，1H)，8.26(s，1H)，8.14(d，1H，J＝8.4)，7.98(d，1H，J＝8.4)，7.75(d，1H，J＝8.4)，7.47(m，1H)，7.33(m，3H)，7.19(t，1H)，6.73(s，1H)，6.19(s，1H)，5.26(s，2H)，2.84(dd，4H，J＝13.8)，2.73(d，4H，J＝6.8)，1.36(s，1H)，1.26(s，1H)，1.06(t，6H，J＝6.6)

Embodiment 12

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-2-yl }- Quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 11 the first steps to the second; use resulting compound 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in the above-mentioned the first step]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 11a makes raw material; carry out the reaction of this raw material and 2-methylsulfonyl-ethylamine hydrochloride 2b according to described same way as of 11 second step of the embodiment of the invention; with silica gel column chromatography purifying gained resistates; then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-2-yl }-quinazoline-4-yl)-amine 12 (21 mg, yellow solid).Productive rate: 9.1%.

MS m/z(ESI)：580[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.90(s，1H)，9.86(s，1H)，8.93(s，1H)，8.57(s，1H)，8.14(d，2H)，7.83(m，2H)，7.48(q，1H)，7.32(q，3H)，7.20(t，1H)，6.82(s，1H)，6.40(s，1H)，5.28(s，2H)，4.27(s，2H)，3.57(m，2H)，3.39(m，2H)，3.15(s，3H)

Embodiment 13

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Carboxylic acid-(2-diethylin-ethyl)-amine

Compound 2-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino that in 25 mL eggplant-shape bottles, adds 10 second step of embodiment of the invention gained under the argon atmospher]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 (500 mg, 0.971 mmol), be dissolved in 2 mLN, in N-diethyl-1, be heated to 85 ℃ of stirrings and spend the night.Tlc analysis tracks to raw material and disappears, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates, use 2 mL re-crystallizing in ethyl acetate again, then obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-amine 13 (274 mg, faint yellow solid).Productive rate: 44.7%.

MS m/z(ESI)：631[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.85(s，1H)，8.62(d，1H，J＝2.0)，8.59(s，1H)，8.09(dd，1H，J＝9.0)，8.00(dd，2H，J＝9.0)，7.89(m，2H)，7.74(dd，1H，J＝9.0)，7.48(q，1H)，7.39(d，1H，J＝2.0)，7.33(q，3H)，7.19(t，1H)，5.27(s，2H)，4.82(s，1H)，3.66(s，2H)，3.30(m，3H)，2.90(t，2H，J＝6.8)，2.53(m，5H)，0.99(t，6H，J＝7.2)

Embodiment 14

N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-Ji Jia Base)-and N ', N '-diethyl-1

Repeat the reaction in step of the embodiment of the invention 5 the first steps to the second, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, carry out this raw material and N according to described same way as of the 3rd step of the embodiment of the invention 5, N-diethyl-1, the reaction of 2-quadrol, with ethyl acetate and normal hexane recrystallization, then obtain title product N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-1H-pyrroles-3-ylmethyl)-N ', N '-diethyl-1,2-quadrol 14 (60 mg, yellow solid).Productive rate: 43.8%.

MS m/z(ESI)：573[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.60(s，1H)，8.58(s，1H)，8.10(dd，1H，J＝2.2)，8.19(d，1H，J＝2.4)，7.89(d，1H，J＝8.8)，7.60(dd，1H，J＝2.4)，7.62(s，1H)，7.56(s，1H)，7.48(q，1H)，7.32(m，3H)，7.18(t，1H)，6.51(s，1H)，5.27(s，2H)，3.88(s，2H)，2.85(s，2H)，2.68(s，4H)，2.51(s，2H)，1.00(t，6H)

Implement 15

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-morpholine-4-base-ethylamino)-methyl]-pyrroles-1-yl }- Quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 5 the first steps to the second, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, carry out the reaction of this raw material and 2-morpholine-4-base-ethylamine hydrochloride according to described same way as of the 3rd step of the embodiment of the invention 5, with re-crystallizing in ethyl acetate gained solid, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-morpholine-4-base-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine 15 (20 mg, yellow solid).Productive rate: 50%.

MS m/z(ESI)：587[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.60(d，1H，J＝1.6)，8.55(s，1H)，8.09(dd，1H，J＝9.2)，8.02(d，1H，J＝2.0)，7.84(d，1H，J＝9.2)，7.76(dd，1H，J＝8.8)，7.56(d，2H)，7.46(q，1H)，7.30(m，3H)，7.18(t，1H)，6.39(s，1H)，5.24(s，2H)，3.56(s，4H)，2.77(t，2H)，2.46(t，2H)，2.35(s，4H)，1.82(s，2H)

Embodiment 16

2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene [c] pyrroles -4-ketone

The first step

5,6-dihydro-2H-pentamethylene [c] pyrroles-4-ketone

In 50 mL there-necked flasks, adding the different acetonitrile of p-toluenesulfonyl (2.56 g, 13.1 mmol) under 0 ℃, be dissolved in 12 mL tetrahydrofuran (THF)s, (2.0 g, 13.4mmol), 0 ℃ was stirred 15 minutes to be added dropwise to 1,8-diazabicylo [5,4,0], 11 carbon-7-alkene.Be added dropwise to cyclopentenes-2-ketone 16a (1.0 g, 11.9 mmol), stirring at room 2 hours.Tlc analysis tracks to raw material and disappears, and pours in the 50 mL water, and stirring is spent the night, concentrating under reduced pressure steams except tetrahydrofuran (THF), with ethyl acetate extraction (50 * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, then obtains title product 5,6-dihydro-2H-pentamethylene [c] pyrroles-4-ketone 16b (749 mg, white solid).Productive rate: 52%.

MS m/z(ESI)：122[M+1]

Second step

2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene [c] pyrroles 4-ketone

Repeat the embodiment of the invention reaction in five steps of 1 the first step to the, use above-mentioned the 5th the step in resulting compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g make raw material, carry out this raw material and 5 according to described same way as of the 6th step of the embodiment of the invention 1, the reaction of 6-dihydro-2H-pentamethylene [c] pyrroles-4-ketone 16b, use the methylene dichloride recrystallization, then obtain title product 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene [c] pyrroles-4-ketone 16 (211 mg, white solid).Productive rate: 42.3%.

MS m/z(ESI)：499[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.79(s，1H)，8.75(d，1H，J＝2.4)，8.62(s，1H)，8.22(dd，1H，J＝9.0)，8.02(d，2H)，7.90(d，1H)，7.75(dd，1H，J＝8.8)，7.50(m，2H)，7.35(m，3H)，7.18(t，1H)，5.28(s，2H)，2.97(t，2H)，2.83(q，2H)

Embodiment 17

[1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Base]-(4-methyl-piperazine-1-yl)-ketone

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and 1-methyl-piperazine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, obtain title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-(4-methyl-piperazine-1-yl)-ketone 17 (366 mg, light yellow solid).Productive rate: 77.7%.

MS m/z(ESI)：615[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.58(s，2H)，8.16(dd，1H，J＝9.0)，8.01(d，1H，J＝2.8)，7.86(d，1H，J＝8.8)，7.73(dd，1H，J＝9.0)，7.66(d，1H，J＝2.0)，7.48(q，2H)，7.34(q，3H)，7.19(t，1H)，5.28(s，2H)，4.69(t，1H，J＝1.2)，3.58(t，6H)，2.69(t，2H，J＝3.2)，2.33(s，4H)，2.21(s，3H)

Embodiment 18

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Carboxylic acid-(2-morpholine-4-base-ethyl)-amine

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and 2-morpholine-4-base-ethamine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-base-ethyl)-amine 18 (50 mg, faint yellow solid).Productive rate: 13.3%.

MS m/z(ESI)：645[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.87(s，1H)，8.64(d，1H，J＝1.6)，8.59(s，1H)，8.10(d，1H)，8.02(d，2H)，7.92(m，2H)，7.75(dd，1H，J＝8.8)，7.48(q，1H)，7.41(s，1H)，7.33(q，3H)，7.19(t，1H)，5.27(s，2H)，4.83(s，1H)，3.65(t，2H)，3.60(t，4H)，3.38(m，2H)，2.90(t，2H)，2.45(m，6H)

Embodiment 19

[6-(3-[1,4 '] two piperidyls-1 '-ylmethyl-pyrroles-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)- Phenyl]-amine

Repeat the reaction in step of the embodiment of the invention 5 the first steps to the second, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, carry out the reaction of this raw material and 4-piperidinyl piperidine according to described same way as of the 3rd step of the embodiment of the invention 5, with re-crystallizing in ethyl acetate gained solid, then obtain title product [6-(3-[1,4 '] two piperidyls-1 '-ylmethyl-pyrroles-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 19 (60 mg, light brown solid).Productive rate: 60.1%.

MS m/z(ESI)：625[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.61(d，1H，J＝2.0)，8.55(s，1H)，8.12(dd，1H，J＝8.8)，8.03(d，1H，J＝2.8)，7.85(d，1H，J＝9.2)，7.76(dd，1H，J＝8.8)，7.50(m，3H)，7.32(q，3H)，7.18(t，1H)，6.31(s，1H)，5.26(s，2H)，3.43(s，2H)，2.50(m，5H)，1.70(m，4H)，1.40(m，10H)

Embodiment 20

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidines-1-base-ethylamino)-methyl]-pyrroles-1-yl }- Quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 5 the first steps to the second, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, carry out the reaction of this raw material and 2-piperidines-1-base-ethamine according to described same way as of the 3rd step of the embodiment of the invention 5, with re-crystallizing in ethyl acetate gained solid, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidines-1-base-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine 20 (48 mg, yellow solid).Productive rate: 46.7%.

MS m/z(ESI)：585[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.58(t，2H)，8.11(dd，1H，J＝8.8)，8.02(d，1H，J＝2.4)，7.86(d，1H，J＝9.2)，7.76(dd，1H，J＝8.8)，7.52(m，2H)，7.46(t，1H)，7.32(q，3H)，7.18(t，1H)，6.36(s，1H)，5.26(s，2H)，3.70(s，2H)，2.70(t，2H)，2.35(m，6H)，1.50(m，6H)

Embodiment 21

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(3-diethylamino methyl-pyrroles-1-yl)-quinazoline-4-yl]- Amine

Repeat the reaction in step of the embodiment of the invention 5 the first steps to the second, use resulting compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, carry out the reaction of this raw material and diethylamide according to described same way as of the 3rd step of the embodiment of the invention 5, with re-crystallizing in ethyl acetate gained solid, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidines-1-base-ethylamino)-methyl]-pyrroles-1-yl }-quinazoline-4-yl)-amine 21 (50 mg, yellow solid).Productive rate: 63.1%.

MS m/z(ESI)：630[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.63(s，1H)，8.58(s，1H)，8.14(dd，1H，J＝9.2)，8.04(d，1H)，7.88(d，1H，J＝8.8)，7.77(dd，1H，J＝8.8)，7.64(s，1H)，7.57(s，1H)，7.48(q，1H)，7.32(m，3H)，7.18(t，1H)，6.42(s，1H)，5.27(s，2H)，3.84(s，2H)，2.79(d，3H，J＝5.2)，1.92(s，1H)，1.12(m，6H)

Embodiment 22

2-[1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(4-methyl-piperazine-1-Ji Jia Base)-1H-pyrroles-3-yl]-ethanol

In 50 mL eggplant-shape bottles, add Lithium Aluminium Hydride (26 mg, 0.68 mmol), be dissolved in the 6 mL tetrahydrofuran (THF)s, stir and drip [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl down-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-(4-methyl-piperazine-1-yl)-ketone 17 (166 mg, 0.27 5 mL tetrahydrofuran solutions mmol), reflux 4 hours.Tlc analysis tracks to raw material and disappears, reaction solution is cooled to room temperature, add 1 mL anhydrous methanol, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, then obtain title product 2-[1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(4-methyl-piperazine-1-ylmethyl)-1H-pyrroles-3-yl]-ethanol 22 (72 mg, yellow solid).Productive rate: 45%.

MS m/z(ESI)：601[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.76(s，1H)，8.52(d，2H)，8.11(d，1H，J＝8.4)，8.01(s，1H)，7.83(d，1H，J＝8.8)，7.74(d，1H，J＝8.0)，7.40(m，6H)，7.19(t，1H)，5.27(s，2H)，5.03(s，1H)，3.61(s，2H)，3.32(m，2H)，2.67(s，2H)，2.35(m，8H)，2.21(s，3H)

Embodiment 23

N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3- Ylmethyl)-and N ', N '-diethyl-1

The first step

(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-yl)-

Methyl alcohol

Add 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino at 50 mL eggplant-shape bottles]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6 (250 mg, 0.40 mmol), be dissolved in the 15 mL tetrahydrofuran (THF)s, be added dropwise to Lithium Aluminium Hydride (40 mg under stirring, 1 mmol) 5 mL tetrahydrofuran solutions, 40 ℃ of stirrings are spent the night.Tlc analysis tracks to raw material and disappears, add 1 mL anhydrous methanol, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, then obtain title product (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-methyl alcohol 23a (177 mg, yellow solid).Productive rate: 76.3%.

MS m/z(ESI)：543[M+1]

Second step

Formaldehyde

Add adjacent iodoxybenzene formic acid (185 mg at 100 mL eggplant-shape bottles, 0.66 mmol), be dissolved in the 10 mL methyl-sulphoxides, be added dropwise to (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-yl)-methyl alcohol 23a (177 mg, 0.33 5 mL dimethyl sulfoxide solutions mmol), stirred overnight at room temperature.Tlc analysis tracks to raw material and disappears, reaction solution is poured in the 30 mL frozen water, decompress filter, solid methylene dichloride recrystallization, then obtain title product (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b (119 mg, yellow solid).Productive rate: 70.0%.

MS m/z(ESI)：541[M+1]

The 3rd step

N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-ylmethyl)-N ', N '-diethyl-1

Add at 25 mL eggplant-shape bottles (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b (40 mg, 0.075 mmol) and N, N-diethyl-1,2-quadrol (10mg, 0.08 mmol), be dissolved in the 5 mL methylene dichloride, react after 3 hours, add sodium triacetoxy borohydride (32 mg, 0.15 mmol).Stirring at room 3 days.Tlc analysis tracks to raw material and disappears, add 20 mL saturated nacl aqueous solutions, with dichloromethane extraction (20 mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, then obtain title product N-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-ylmethyl)-N ', N '-diethyl-1 23 (22 mg, yellow solid).Productive rate: 51.2%.

MS m/z(ESI)：641[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.85(s，1H)，8.70(s，1H)，8.60(s，1H)，8.20(d，1H，J＝8.8)，8.03(d，2H，J＝15.2)，7.89(d，1H，J＝8.0)，7.75(d，1H，J＝7.2)，7.65(s，1H)，7.49(m，1H)，7.30(m，3H)，7.19(t，1H)，5.27(s，2H)，3.74(s，2H)，2.67(d，2H，J＝5.6)，2.55(s，4H)，1.23(s，2H)，0.95(t，6H)

Embodiment 24

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Carboxylic acid-[2-(4-methyl-piperazine-1-yl)-ethyl]-amine

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and 2-(4-methyl-piperazine-1-yl)-ethamine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid-[2-(4-methyl-piperazine-1-yl)-ethyl]-amine 24 (512 mg, faint yellow solid).Productive rate: 50.4%.

MS m/z(ESI)：658[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.86(s，1H)，8.63(s，1H)，8.59(s，1H)，8.10(dd，1H，J＝9.2)，8.01(dd，2H，J＝8.0)，7.89(m，2H)，7.75(dd，1H，J＝9.0)，7.48(q，1H)，7.40(d，1H)，7.33(q，3H)，7.19(t，1H)，5.28(s，2H)，4.82(s，1H)，3.66(t，2H)，3.35(2H)，2.90(t，2H)，2.40(m，10H)，2.16(s，3H)

Embodiment 25

[1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Base]-piperidines-1-base-ketone

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and piperidines according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-piperidines-1-base-ketone 25 (150 mg, faint yellow solid).Productive rate: 16.3%.

MS m/z(ESI)：600[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.57(s，2H)，8.15(dd，1H，J＝9.2)，8.01(d，1H，J＝2.8)，7.86(d，1H，J＝9.2)，7.73(dd，1H，J＝9.0)，7.63(d，1H，J＝2.4)，7.46(m，2H)，7.32(m，3H)，7.18(t，1H)，5.27(s，2H)，3.58(m，6H)，2.67(t，2H)，1.64(d，2H)，1.51(s，4H)

Embodiment 26

[1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Base]-tetramethyleneimine-1-base-ketone

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and tetramethyleneimine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-tetramethyleneimine-1-base-ketone 26 (596mg, faint yellow solid).Productive rate: 52.4%.

MS m/z(ESI)：586[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.76(s，1H)，8.58(s，2H)，8.18(dd，1H，J＝9.2)，8.01(d，1H，J＝2.4)，7.87(d，1H，J＝8.8)，7.81(d，1H，J＝2.0)，7.73(dd，1H，J＝6.4)，7.48(q，1H)，7.43(s，1H)，7.33(q，3H)，7.1 8(t，1H)，5.28(s，2H)，4.79(t，1H)，3.62(m，4H)，3.47(m，2H)，2.80(t，2H)，1.88(s，4H)

Embodiment 27

[1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Base]-morpholine-4-base-ketone

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and morpholine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-morpholine-4-base-ketone 27 (695 mg, faint yellow solid).Productive rate: 59.5%.

MS m/z(ESI)：602[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.66(s，2H)，8.17(s，1H)，8.02(d，2H，J＝2.4)，7.74(dd，1H，J＝8.8)，7.69(d，1H，J＝2.4)，7.48(m，2H)，7.33(q，3H)，7.20(t，1H)，5.28(s，2H)，4.69(t，2H)，3.59(s，4H)，2.70(t，4H)，1.99(s，2H)

Embodiment 28

2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-piperidines-1-ylmethyl-1H-pyrroles -3-yl)-ethanol

Argon gas divides and add 2 mL tetrahydrofuran (THF)s down in the 10mL eggplant-shape bottle, add Lithium Aluminium Hydride (16 mg again, 0.42 mmol), be added dropwise to [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl under the stirring at room }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-piperidines-1-base-ketone 25 (50 mg, 0.08 2 mL tetrahydrofuran solutions mmol), reflux stirred 3 hours.Tlc analysis tracks to raw material and disappears, add water-containing tetrahydrofuran quencher reaction, concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates, then obtain title product 2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-piperidines-1-ylmethyl-1H-pyrroles-3-yl)-ethanol 28 (32 mg, faint yellow solid).Productive rate: 65.6%.

MS m/z(ESI)：586[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.12(s，1H)，8.81(s，1H)，8.57(s，1H)，8.11(d，2H)，7.86(t，2H)，7.76(s，1H)，7.55(s，1H)，7.47(q，1H)，7.33(m，3H)，7.19(t，1H)，5.27(s，2H)，3.97(s，2H)，3.68(t，2H)，2.73(t，2H)，1.71(s，4H)，1.52(s，2H)，1.24(s，4H)

Embodiment 29

2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-tetramethyleneimine-1-ylmethyl-1H-pyrrole Cough up-the 3-yl)-ethanol

Use the embodiment of the invention 26 gained compounds [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-tetramethyleneimine-1-base-ketone 26 carries out the reaction of this raw material and Lithium Aluminium Hydride according to the embodiment of the invention 28 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product 2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-tetramethyleneimine-1-ylmethyl-1H-pyrroles-3-yl)-ethanol 29 (55 mg, faint yellow solid).Productive rate: 28.2%.

MS m/z(ESI)：572[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.09(s，1H)，8.75(s，1H)，8.56(s，1H)，8.10(m，2H)，7.84(m，2H)，7.67(s，1H)，7.48(m，2H)，7.32(m，3H)，7.18(t，1H)，5.27(s，2H)，3.80(s，2H)，3.64(t，2H)，2.89(s，4H)，2.71(q，2H)，1.82(s，4H)

Embodiment 30

2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-morpholine-4-ylmethyl-1H-pyrroles -3-yl)-ethanol

Use the embodiment of the invention 27 gained compounds [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-morpholine-4-base-ketone 27 carries out the reaction of this raw material and Lithium Aluminium Hydride according to the embodiment of the invention 28 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product 2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-morpholine-4-ylmethyl-1H-pyrroles-3-yl)-ethanol 30 (115 mg, faint yellow solid).Productive rate: 58.9%.

MS m/z(ESI)：588[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.93(s，1H)，8.63(s，1H)，8.55(s，1H)，8.09(d，1H，J＝9.2)，8.05(d，1H，J＝2.4)，7.83(d，1H，J＝8.8)，7.79(dd，1H，J＝9.0)，7.53(s，1H)，7.46(m，2H)，7.32(m，3H)，7.19(t，1H)，5.26(s，2H)，3.65(m，6H)，3.53(s，2H)，2.70(t，2H，J＝2.6)，2.59(s，4H)

Embodiment 31

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Carboxylic acid-(2-tetramethyleneimine-1-base-ethyl)-amine

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and 2-tetramethyleneimine-1-base-ethamine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid-(2-tetramethyleneimine-1-base-ethyl)-amine 31 (420 mg, tawny solid).Productive rate: 38.5%.

MS m/z(ESI)：629[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.75(s，1H)，8.63(s，1H)，8.56(s，1H)，8.09(dd，1H，J＝9.2)，8.02(d，2H，J＝1.6)，7.91(m，2H)，7.74(dd，1H，J＝8.8)，7.48(q，1H)，7.40(d，1H，J＝2.0)，7.33(q，3H)，7.19(t，1H)，5.28(s，2H)，4.70(s，1H)，3.64(m，2H)，3.35(m，2H)，2.90(t，2H)，2.55(m，6H)，1.68(m，4H)

Embodiment 32

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3- Carboxylic acid-(2-piperidines-1-base-ethyl)-amine

Repeat the reaction in step of the embodiment of the invention 10 the first steps to the second, use resulting compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino in above-mentioned second step]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 10 makes raw material, carry out the reaction of this raw material and 2-piperidines-1-base-ethamine according to the embodiment of the invention 13 described same way as, with silica gel column chromatography purifying gained resistates, then obtain title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-amine 32 (546 mg, tawny solid).Productive rate: 43.4%.

MS m/z(ESI)：643[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.85(s，1H)，8.63(d，1H，J＝2.0)，8.59(s，1H)，8.10(dd，1H，J＝9.2)，8.01(m，2H)，7.89(m，2H)，7.74(dd，1H，J＝8.8)，7.48(q，1H)，7.40(d，1H，J＝1.6)，7.33(q，3H)，7.20(t，1H)，5.27(s，2H)，4.83(s，1H)，3.66(t，2H，J＝2.4)，3.35(t，2H)，2.90(t，2H，J＝2.8)，2.42(m，6H)，1.52(m，6H)

Embodiment 33

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-morpholine-4-base-ethylamino)-methyl]-4-trifluoromethyl-pyrrole Cough up-the 1-yl-quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 2-morpholine-4-base-ethamine according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-morpholine-4-base-ethylamino)-methyl]-4-trifluoromethyl-pyrroles-1-yl }-quinazoline-4-yl)-amine 33 (86 mg, faint yellow solid).Productive rate: 71.0%.

MS m/z(ESI)：655[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.85(s，1H)，8.70(s，1H)，8.61(s，1H)，8.19(d，1H，J＝9.6)，8.07(s，1H)，8.02(s，1H)，7.91(d，1H，J＝8.8)，7.74(d，1H，J＝6.8)，7.68(s，1H)，7.49(q，1H)，7.33(m，3H)，7.19(t，1H)，5.28(s，2H)，3.80(s，2H)，3.58(s，4H)，3.31(s，4H)，2.77(s，2H)，2.39(s，2H)

Embodiment 34

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(3-{[2-(4-methyl-piperazine-1-yl)-ethylamino]-methyl }-4-three Methyl fluoride-pyrroles-1-yl)-quinazoline-4-yl]-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 2-(4-methyl-piperazine-1-yl)-ethamine according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(3-{[2-(4-methyl-piperazine-1-yl)-ethylamino]-methyl }-4-trifluoromethyl-pyrroles-1-yl)-quinazoline-4-yl]-amine 34 (88 mg, faint yellow solid).Productive rate: 71.5%.

MS m/z(ESI)：668[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.87(s，1H)，8.73(s，1H)，8.61(s，1H)，8.18(dd，1H，J＝8.8)，8.07(s，1H)，8.03(s，1H)，7.91(d，1H，J＝8.8)，7.77(d，1H，J＝2.8)，7.71(s，1H)，7.48(m，1H)，7.31(m，3H)，7.18(t，1H)，5.28(s，2H)，3.83(s，2H)，3.83(s，2H)，2.44(m，6H)，2.20(s，3H)，2.09(s，4H)

Embodiment 35

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidines-1-base-ethylamino)-methyl]-4-trifluoromethyl-pyrrole Cough up-the 1-yl-quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 2-piperidines-1-base-ethamine according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidines-1-base-ethylamino)-methyl]-4-trifluoromethyl-pyrroles-1-yl }-quinazoline-4-yl)-amine 35 (86 mg, faint yellow solid).Productive rate: 71.7%.

MS m/z(ESI)：653[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.86(s，1H)，8.74(s，1H)，8.62(s，1H)，8.17(dd，1H，J＝8.4)，8.08(s，1H)，8.04(m，1H)，7.92(d，1H，J＝9.2)，7.76(m，2H)，7.47(q，1H)，7.32(q，3H)，7.19(t，1H)，5.28(s，2H)，3.84(s，2H)，2.87(s，2H)，2.66(m，6H)，1.61(s，4H)，1.44(s，2H)

Embodiment 36

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methoxyl group-ethylamino)-methyl]-4-trifluoromethyl-pyrroles -1-yl }-quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 2-methoxyl group-ethamine according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methoxyl group-ethylamino)-methyl]-4-trifluoromethyl-pyrroles-1-yl }-quinazoline-4-yl)-amine 36 (78 mg, faint yellow solid).Productive rate: 70.3%.

MS m/z(ESI)：600[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 8.66(d，1H)，8.59(s，1H)，8.17(dd，1H，J＝9.0)，8.03(s，1H)，8.00(d，1H，J＝2.8)，7.89(d，1H，J＝8.8)，7.73(dd，1H，J＝8.8)，7.64(s，1H)，7.46(q，1H)，7.31(q，3H)，7.18(t，1H)，5.26(s，2H)，3.76(s，2H)，3.45(s，2H)，3.25(s，3H)，2.78(t，2H)

Embodiment 37

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methylsulfonyl-ethylamino)-methyl]-4-trifluoromethyl 1-pyrrole Cough up-the 1-yl-quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second; use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material; carry out the reaction of this raw material and 2-methylsulfonyl-ethamine according to described same way as of the 3rd step of the embodiment of the invention 23; with silica gel column chromatography purifying gained resistates; then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methylsulfonyl-ethylamino)-methyl]-4-trifluoromethyl 1-pyrroles-1-yl }-quinazoline-4-yl)-amine 37 (50 mg, faint yellow solid).Productive rate: 41.7%.

MS m/z(ESI)：648[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 8.66(d，1H)，8.60(s，1H)，8.17(dd，1H，J＝8.8)，8.04(s，1H)，8.01(d，1H，J＝2.4)，7.90(d，1H，J＝8.8)，7.73(dd，1H，J＝9.0)，7.63(s，1H)，7.47(q，1H)，7.31(m，3H)，7.18(t，1H)，5.26(s，2H)，3.74(s，2H)，3.42(s，2H)，3.29(t，2H，J＝2.8)，3.01(t，3H)

Embodiment 38

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(3-morpholine-4-base-third amino)-methyl]-4-trifluoromethyl-pyrrole Cough up-the 1-yl-quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 3-morpholine-4-base-propylamine according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(3-morpholine-4-base-third amino)-methyl]-4-trifluoromethyl-pyrroles-1-yl }-quinazoline-4-yl)-amine 38 (70 mg, faint yellow solid).Productive rate: 56.9%.

MS m/z(ESI)：669[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.94(s，1H)，8.78(s，1H)，8.62(s，1H)，8.17(dd，1H，J＝8.8)，8.13(s，1H)，8.05(m，1H)，7.92(d，1H，J＝9.2)，7.84(s，1H)，7.77(m，1H)，7.48(q，1H)，7.32(q，3H)，7.19(t，1H)，5.26(s，2H)，3.92(s，2H)，3.54(t，4H)，2.84(s，2H)，2.37(t，6H)，1.72(t，2H)

Embodiment 39

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-tetramethyleneimine-1-base-ethylamino)-methyl]-the 4-trifluoromethyl- Pyrroles-1-yl }-quinazoline-4-yl)-amine

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 2-tetramethyleneimine-1-base-ethamine according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-tetramethyleneimine-1-base-ethylamino)-methyl]-4-trifluoromethyl-pyrroles-1-yl }-quinazoline-4-yl)-amine 39 (60 mg, faint yellow solid).Productive rate: 50.4%.

MS m/z(ESI)：639[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.01(s，1H)，8.84(s，1H)，8.61(s，1H)，8.21(d，1H，J＝8.8)，8.10(m，2H)，7.87(m，3H)，7.47(q，1H)，7.32(m，3H)，7.21(t，1H)，5.27(s，2H)，3.80(s，2H)，2.89(m，8H)，1.84(m，4H)

Embodiment 40

1-[(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3- Ylmethyl)-amino]-3-morpholine-4-base-propan-2-ol

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out the reaction of this raw material and 1-amino-3-morpholine-4-base-propan-2-ol according to described same way as of the 3rd step of the embodiment of the invention 23, with silica gel column chromatography purifying gained resistates, then obtain title product 1-[(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-ylmethyl)-amino]-3-morpholine-4-base-propan-2-ol 40 (70 mg, faint yellow solid).Productive rate: 55.1%.

MS m/z(ESI)：685[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.98(s，1H)，8.80(s，1H)，8.61(s，1H)，8.17(m，2H)，8.06(s，1H)，7.91(d，1H，J＝8.8)，7.79(m，2H)，7.48(q，1H)，7.32(m，3H)，7.19(t，1H)，5.27(s，2H)，4.80(s，1H)，3.87(s，3H)，3.53(m，4H)，2.84(m，1H)，2.67(m，1H)，2.33-2.42(m，6H)

Embodiment 41

4-{[(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3- Ylmethyl)-amino]-methyl }-1,1-dioxy-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

Repeat the reaction in step of the embodiment of the invention 23 the first steps to the second, use resulting compound in above-mentioned second step (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-formaldehyde 23b makes raw material, carry out this raw material and 4-aminomethyl-1,2,1-dioxy-six hydrogen-1 λ according to described same way as of the 3rd step of the embodiment of the invention 23 ^*6 ^*The reaction of-thiapyran-4-alcohol, with silica gel column chromatography purifying gained resistates, then obtain title product 4-{[(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-ylmethyl)-amino]-methyl }-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 41 (107 mg, faint yellow solid).Productive rate: 82.3%.

MS m/z(ESI)：704[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.84(s，1H)，8.69(s，1H)，8.61(s，1H)，8.20(dd，1H，J＝8.8)，8.06(s，1H)，8.02(d，1H，J＝2.8)，7.90(d，1H，J＝9.2)，7.73(dd，1H，J＝8.8)，7.65(s，1H)，7.48(m，1H)，7.33(q，3H)，7.20(t，1H)，5.28(s，2H)，4.78(s，1H)，3.76(s，2H)，3.18(m，2H)，2.95(m，2H)，2.60(s，2H)，1.98(m，4H)

Embodiment 42

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Under the nitrogen atmosphere in 50 mL eggplant-shape bottles, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (255 mg, 0.505 mmol), 1-(triisopropyl silicon)-1H-pyrroles-3-boric acid (269 mg, 1.01mmol), four triphenylphosphine palladiums (2.3 mg, 0.02 mmol), salt of wormwood (138 mg, 1 mmol) is dissolved in 6 mLN, in the mixed solvent of dinethylformamide and 1.5 mL water, the mixture heating up to 70 that obtains ℃, afterreaction finished in 2 hours.Reaction solution is cooled to room temperature, pour in the 100mL frozen water, separate out white solid, stir after ten minutes, suction filtration, product are dry under vacuum, and the solid that obtains further passes through column chromatography, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (138 mg, yellow solid).Productive rate: 61.7%.

MS m/z(ESI)：445[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 11.09(s，1H)，9.68(s，1H)，8.56(d，1H，J＝1.2)，8.50(s，1H)，8.09(dd，1H，J＝7.6)，8.03(d，1H，J＝2.8)，7.77(dd，1H，J＝8.8)，7.70(d，1H，J＝8.8)，7.46(m，2H)，7.33(m，3H)，7.19(t，1H)，6.98(m，1H)，6.70(d，1H，J＝1.6)，5.27(s，2H)

Embodiment 43

[1-(3-luorobenzyl)-1H-indazole-5-yl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine

The first step

[1-(3-luorobenzyl)-1H-indazole-5-yl]-(6-iodine quinazoline-4-yl)-amine

Repeat the embodiment of the invention reaction in four steps of 1 the first step to the, compound 6-iodo-3H-quinazoline-4-one 1f (10 g with the 4th step gained, 36.7 mmol), under nitrogen atmosphere, join in the 500 mL eggplant-shape bottles, be dissolved in 100 mL thionyl chlorides and 3 mL N, in the mixed solvent of dinethylformamide, reflux is transparent to reaction solution.Stir after 6 hours, tlc analysis is followed the tracks of raw material and disappeared, and steams thionyl chloride, and is standby.

Under the nitrogen atmosphere standby intermediate is dissolved in the 250 mL Virahols, adds 1-(3-luorobenzyl)-1H-indazole-5-amine 43a (8.85 g, 36.7 mmol), reflux is spent the night.Tlc analysis tracks to raw material and disappears, reaction solution is cooled to room temperature, decompress filter washs the gained solid with 50 mL ethyl acetate, filter cake is joined ammoniacal liquor (200 mL, 100mL ammoniacal liquor adds 100mL water) and the mixed solvent of ethyl acetate in dissolve, stirring at room 10 minutes, decompress filter, vacuum-drying, obtain title product [1-(3-luorobenzyl)-1H-indazole-5-yl]-(6-iodine quinazoline-4-yl)-amine 43b (13 g, off-white color solid).Productive rate: 71.8%.

MS m/z(ESI)：496[M+1]

Second step

[3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine

In 100 mL eggplant-shape bottles, add [1-(3-luorobenzyl)-1H-indazole-5-yl]-(6-iodine quinazoline-4-yl)-amine 43b (100 mg, 0.2 mmol), potassiumphosphate (127 mg under the nitrogen atmosphere, 0.6 mmol), and cuprous iodide (57 mg, 0.3mmol) and pyrroles (20 mg, 0.3 mmol), with 5 mL N, the dinethylformamide dissolving is stirred and is dripped N down, N '-dimethyl-1,2-quadrol (26 mg, 0.29 mmol), reflux stir and spend the night.Tlc analysis tracks to raw material and disappears, pour in the 50 mL frozen water, filter, obtain blackish green solid and further obtain title product [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 43 (30 mg, faint yellow solid) by column chromatographic isolation and purification.Productive rate: 30%.

MS m/z(ESI)：435[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.98(s，1H)，8.71(s，1H)，8.53(s，1H)，8.25(s，1H)，8.18(s，1H)，8.17(dd，1H，J＝9.2)，7.87(d，1H，J＝9.2)，7.79(d，1H，J＝8.8)，7.74(m，1H)，7.61(m，2H)，7.38(m，1H)，7.11(m，3H)，6.38(m，2H)

Embodiment 44

The first step

3-chloro-4-(pyridine-2-methoxyl group)-aniline

In the 250mL eggplant-shape bottle, add 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine 44a (9.5g, 35.9mmol), 100mL methyl alcohol, (19.17g, 359mmol) and 50 mL water, the mixture heating up of the gained 3 hours afterreactions that reflux finish ammonium chloride.The cooling reaction solution is to room temperature, filter, the mother liquor decompression concentrates down, the residue that obtains adds 80 mL water, with dichloromethane extraction gained mixed solution (100 mL * 3), and the organic phase anhydrous sodium sulfate drying, filter, filtrate obtains this title product 3-chloro-4-(pyridine-2-methoxyl group)-aniline 44b (8.7 g, yellow solid), 100% after concentrating.Purity: 98.13%.

Second step

[3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-iodine quinazoline-4-base l)-amine

Repeat the embodiment of the invention reaction in four steps of 1 the first step to the, compound 6-iodo-3H-quinazoline-4-one 1f (5 g with the 4th step gained, 18.3 mmol) be dissolved in 50 mL thionyl chlorides and 0.5 mLN, in the mixed solvent of dinethylformamide, reflux is transparent to reaction solution.Stir after 6 hours, tlc analysis is followed the tracks of raw material and disappeared, and steams thionyl chloride, and is standby.

Under the nitrogen atmosphere standby intermediate is dissolved in the 160 mL Virahols, adds 3-chloro-4-(pyridine-2-methoxyl group)-aniline 44b (4.25 g, 18.2 mmol), reflux is spent the night.Tlc analysis tracks to raw material and disappears, reaction solution is cooled to room temperature, decompress filter, the gained solid is added ammoniacal liquor (200mL with 5 mL dissolve with methanol dilution back, volume ratio is 1: 1), regulate the pH value to 8-9, ice-water bath cooling back suction filtration obtains title product [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-iodine quinazoline-4-base l)-amine 44c (8 g, off-white color solid).Productive rate: 89.6%.

MS m/z(ESI)：489[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.78(s，1H)，8.60(d，3H)，8.16(d，1H，J＝9.2)，8.04(m，1H)，7.89(m，2H)，7.76(d，1H，J＝9.2)，7.59(m，3H)，7.38(t，1H)，7.31(d，1H，J＝8.8)，6.38(s，2H)，5.31(s，2H)

The 3rd step

[3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-2-yl)-amine

In 100 mL eggplant-shape bottles, add [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-iodine quinazoline-4-base l)-amine 44c (1.95 g, 4 mmol) potassiumphosphate (2.55 g under the nitrogen atmosphere, 12 mmol), cuprous iodide (2.28 g, 12 mmol) and pyrroles (11 mL, 160 mmol), use 25 mLN, the dinethylformamide dissolving is stirred and is dripped N down, N '-dimethyl-1,2-quadrol (1.3 mL, 12 mmol), reflux stir 4 hours afterreactions and finish.Reaction solution is cooled to room temperature, pours in the 100 mL frozen water, filter, obtain black solid, further by column chromatographic isolation and purification, obtain title product [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-2-yl)-amine 44 (1.3 g, white solid).Productive rate: 76%.

MS m/z(ESI)：428[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.78(s，1H)，8.60(d，3H)，8.16(d，1H，J＝9.2)，8.04(m，1H)，7.89(m，2H)，7.76(d，1H，J＝9.2)，7.59(m，3H)，7.38(t，1H)，7.31(d，1H，J＝8.8)，6.38(s，2H)，5.31(s，2H)

Embodiment 45

The first step

2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester

Repeat the reaction in step of embodiment 44 the first steps to the second, with compound [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-iodine quinazoline-4-base l)-amine 44c (1.95 g that obtain, 4 mmol), 1-(tert-butoxycarbonyl)-1H-pyrroles-2-boric acid 7b (1.1 g, 5.2 mmol), four triphenylphosphine palladium (0.23 g, 0.2 mmol), salt of wormwood (1.38g, 10 mmol) be dissolved in 25 mLN, in the mixed solvent of dinethylformamide and 6 mL water, the mixture heating up to 70 that obtains ℃, afterreaction finished in 2 hours.Reaction solution is cooled to room temperature, pour in the 300 mL frozen water, separate out white solid, stir after ten minutes, suction filtration, product are dry under vacuum, the solid that obtains further passes through column chromatography, obtain title product 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester 45a (2.0g, yellow solid), productive rate: 95%.

MS m/z(ESI)：529[M+1]

Second step

Compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that above-mentioned steps is obtained]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester 45a is dissolved in the 55 mL anhydrous tetrahydro furans, the yellow solution that obtains is cooled to 0 ℃ with ice-water bath, add sodium methylate (1.728 g, 16 mmol), reaction solution is risen to room temperature gradually, afterreaction finished in 3 hours, and reaction solution is scarlet.The reaction solution that obtains is poured in the saturated sodium-chloride water solution, separate out solid, filter, the yellow solid that obtains is under vacuum after the drying, further pass through column chromatographic isolation and purification, obtain title product [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-2-yl)-amine 45 (1.15 g, yellow solid), productive rate 68%.

MS m/z(ESI)：428[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.38(s，1H)，9.67(s，1H)，8.65(s，1H)，8.61(d，1H)，8.53(s，1H)，8.14(d，1H，J＝9.2)，8.06(m，1H)，7.88(t，1H)，7.76(m，2H)，7.60(d，1H，J＝7.6)，7.38(t，1H)，7.3 1(d，1H，J＝9.2)，6.97(s，1H)，6.77(s，1H)，6.22(s，1H)，5.31(s，2H)

Embodiment 46

[3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-2- Base }-quinazoline-4-yl)-amine

The first step

5-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole-2-aldehyde

Under the nitrogen atmosphere, with 10 mL N, dinethylformamide is cooled to 0 ℃ with ice bath, and (0.085mL, 0.98mmol), mixed solution rises to room temperature, stirs half an hour to add the trichlorine phosphine oxide.The solution that obtains is cooled to 0 ℃, add embodiment 45 resulting compounds [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-2-yl)-amine 45, mixed solution at room temperature stir 4 hours the reaction finish after, add the 10mL frozen water, and regulate pH=11 with the 1N sodium hydroxide solution.Extract with methylene dichloride and methanol mixed solvent (60 mL * 5).Organic phase under reduced pressure concentrates, and the residue of gained is at room temperature placed and spent the night, and has yellow solid to separate out, filter, obtain title product 5-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 46a (120 mg, yellow solid), productive rate 40%.

MS m/z(ESI)：456[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ12.59(s，1H)，11.20(s，1H)，9.60(s，1H)，9.25(s，1H)，8.86(s，1H)，8.62(d，1H，J＝4.4)，8.58(d，1H，J＝8.8)，8.00(s，1H)，7.91(m，2H)，7.72(d，1H，J＝8.8)，7.61(d，1H，J＝7.6)，7.38(m，2H)，7.20(s，1H)，7.14(s，1H)，5.36(s，2H)

Second step

[3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-2-yl }-quinazoline-4-yl)-amine

With 2-methylsulfonyl-ethylamine hydrochloride 2b (30 mg, 0.186 mmol), triethylamine (0.038 mL, 0.275mmol) be dissolved in the 5mL methylene dichloride, the dissolving back adds compound 5-{4-[3-chloro-4-(pyridine-2-the methoxyl group)-phenylamino of above-mentioned steps gained fully]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 46a (50 mg, 0.11 mmol), stir after 6 hours, add sodium triacetoxy borohydride (61 mg, 0.286 mmol).The mixed solution of gained at room temperature stirs and spends the night, and reaction finishes.With TLC chromatographic separation product, obtain title product [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-2-yl }-quinazoline-4-yl)-amine 46 (46 mg, yellow solid), productive rate 74.0%.

MS m/z(ESI)：564[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.92(s，1H)，9.84(s，1H)，9.04(s，1H)，8.61(s，1H)，8.55(s，1H)，8.23(s，1H)，8.15(d，1H，J＝8.8)，7.90(m，2H)，7.77(d，1H，J＝8.4)，7.61(d，1H，J＝7.6)，7.38(t，1H)，7.30(d，1H，J＝9.2)，6.77(s，1H)，6.29(s，1H)，5.36(s，2H)，4.12(s，2H)，3.51(t，2H)，3.11(s，3H)，3.06(t，2H)

Embodiment 47

2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] Pyrroles-4-ketone

In the 100mL eggplant-shape bottle, add successively [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-iodine quinazoline-4-base l)-amine 44c (1.95 g, 4 mmol), 6,7-dihydro-2H-pyrans is [3,4-c] pyrroles-4-ketone 10b (713mg also, 5.2 mmol), potassiumphosphate (2.55 g, 12 mmol), cuprous iodide (0.76 g, 4 mmol) and 25 mLN, dinethylformamide, mixture under agitation add N, N '-dimethyl-1,2-quadrol (0.44 mL, 4mmol), reacting by heating liquid to 70 ℃, stirring is spent the night.The cooling reaction solution, pour in the 100 ml frozen water, there is blackish green solid to separate out, suction filtration, the solid that obtains is purified by column chromatography for separation, the title product 2-{4-[3-chloro-4-that obtains (pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 (0.9 g, off-white color solid), productive rate 45.2%.

MS m/z(ESI)：498[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.83(s，1H)，8.75(s，1H)，8.61(m，2H)，8.24(t，2H)，8.03(s，1H)，7.89(m，2H)，7.73(d，1H，J＝8.8)，7.60(d，1H，J＝7.6)，7.54(s，1H)，7.38(t，1H)，7.32(d，1H，J＝8.8)，5.32(s，2H)，4.48(t，2H)，2.91(t，2H)

Embodiment 48

(3-chloro-4-fluorophenyl)-(6-pyrroles-1-quinazoline-4-yl)-amine

The first step

(3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-yl)-amine

Repeat the embodiment of the invention 1 the 5th described experimental procedure, different is to make raw material with the compound 6-iodo-3H-quinazoline-4-one 1f that embodiment 1 the 4th goes on foot gained, make the reaction of this raw material and 3-chloro-4-fluoro-aniline according to described same way as of the embodiment of the invention 1 the 5th step, obtain title compound (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-yl)-amine 48a (15 mg, yellow solid), productive rate 56%.

MS m/z(ESI)：400[M+1]

Second step

(3-chloro-4-fluorophenyl)-(6-pyrroles-1-quinazoline-4-yl)-amine

In 100 mL eggplant-shape bottles, with compound (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-the yl)-amine 48a (2 g, 5 mmol) of above-mentioned steps gained, potassiumphosphate (3.18 g, 15mmol), cuprous iodide (0.95g, 5mmol) be dissolved in 40 mL N, in the dinethylformamide, mixture under agitation adds N, N '-dimethyl-1,2-quadrol (0.55 mL, 5 mmol), reacting by heating liquid to 65 ℃, stirring is spent the night.Reaction solution is poured in the 600 mL water, there is the yellow-green colour solid to separate out, suction filtration, the solid that obtains is purified by column chromatography for separation, the title product that obtains (3-chloro-4-fluorophenyl)-(6-pyrroles-1-quinazoline-4-yl)-amine 48 (0.9 g yellow solid), productive rate 53%.

MS m/z(ESI)：339[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.89(s，1H)，8.64(d，2H)，8.19(m，2H)，7.91(d，1H，J＝9.2)，7.85(m，1H)，7.59(t，2H)，7.50(m，1H)，6.39(t，2H)

Embodiment 49

(3-chloro-4-fluoro-phenyl)-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine

The first step

2-{4-[3-chloro-4-fluoro-phenylamino]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester

Repeat the reaction of embodiment 48 the first steps, with compound (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-the yl)-amine 48a (1.60 g, 4 mmol) that obtains, 1-(tert-butoxycarbonyl)-1H-pyrroles-2-boric acid 7b (1.1 g, 5.2mmol), four triphenylphosphine palladiums (0.23 g, 0.2 mmol), salt of wormwood (1.38 g, 10 mmol) be dissolved in 25 mL N, in the mixed solvent of dinethylformamide and 6 mL water, the mixture heating up to 70 that obtains ℃, afterreaction finished in 2 hours.Reaction solution is cooled to room temperature, pour in the 300 mL frozen water, separate out white solid, stir after ten minutes, suction filtration, product are dry under vacuum, and the solid that obtains further passes through column chromatography, obtain title product 2-{4-[3-chloro-4-fluoro-phenylamino]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester 49a (1.49g, yellow solid) productive rate: 85%.

MS m/z(ESI)：439[M+1]

Second step

[(3-chloro-4-fluoro-phenyl)-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine

The compound 2-{4-[3-chloro-4-fluoro-phenylamino that above-mentioned steps is obtained]-quinazoline-6-yl }-pyrroles-1-carboxylic acid tert-butyl ester 49a is dissolved in the 55 mL anhydrous tetrahydro furans, the yellow solution that obtains is cooled to 0 ℃ with ice-water bath, add sodium methylate (1.46 g, 13 mmol), reaction solution is risen to room temperature gradually, afterreaction finished in 3 hours, and reaction solution is scarlet.The reaction solution that obtains is poured in the saturated sodium-chloride water solution, separate out solid, filter, the yellow solid that obtains is under vacuum after the drying, further pass through column chromatographic isolation and purification, obtain title compound (3-chloro-4-fluoro-phenyl)-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 49 (767 mg, faint yellow solid), productive rate 67%.

MS m/z(ESI)：339[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.41(s，1H)，9.79(s，1H)，8.65(s，1H)，8.58(s，1H)，8.21(d，1H，J＝6.8)，8.15(d，1H，J＝8.0)，7.86(m，1H)，7.80(d，1H，J＝8.8)，7.48(t，1H)，6.98(s，1H)，6.78(t，1H)，6.24(q，1H)

Embodiment 50

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{4-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-2-yl }-quinoline Azoles quinoline-4-yl)-amine

The first step

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-triisopropylsilyl-1H-pyrroles-2-yl)-quinazoline-4-yl]-amine

Compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 8 (225 mg with the invention process 8 gained, 0.5 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, the dissolving back is cooled to-78 ℃ at the dry ice bath, add diisopropylamine lithium (0.5 mL, 0.5 mol), stir and rise to room temperature reaction after 10 minutes after 20 minutes, continue ice bath and be cooled to-78 ℃, add triisopropyl silicon chlorine (195 mg, 1 mmol), afterreaction finished in 1 hour.In reaction solution, add water quencher reaction, steam tetrahydrofuran (THF) under the decompression, residue ethyl acetate (100mL * 3) extractive reaction liquid, the organic phase anhydrous sodium sulfate drying that merges filters, and concentrates under the filtrate decompression, residue further passes through column chromatographic isolation and purification, obtain this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-tri isopropyl silane base-1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 50a (145 mg, yellow solid), productive rate: 48.3%.

MS m/z(ESI)：601[M+1]

Second step

5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1-triisopropylsilyl-1H-pyrroles-3-formaldehyde

With 5 mLN, dinethylformamide is under condition of ice bath, after being cooled to 0 ℃, add phosphorus oxychloride (26mg, 0.17 mmol), be warming up to room temperature, stir and be cooled to 0 ℃ again after 1 hour, add compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-tri isopropyl silane base-1H-pyrroles-2-yl)-quinazoline-4-yl]-amine 50a (67 mg, 0.11 mmol) of above-mentioned steps gained, the mixture of gained at room temperature stirs and spends the night, and reaction finishes.Dropwise 5 % sodium hydroxide solution in the reaction solution, regulate pH=11, with ethyl acetate (100 mL * 3) extractive reaction liquid, the organic phase anhydrous sodium sulfate drying that merges filters, and concentrates under the filtrate decompression, the residue of gained is by the further separation and purification of column chromatography, obtain this title product 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1-triisopropylsilyl-1H-pyrroles-3-formaldehyde 50b (36 mg, yellow solid), productive rate: 68%.

MS m/z(ESI)：473[M+1]

The 3rd step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{4-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-2-yl }-quinazoline-4-yl)-amine

Compound 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino with the above-mentioned steps gained]-quinazoline-6-yl }-1-triisopropylsilyl-1H-pyrroles-3-formaldehyde 50b (36 mg, 0.076 mmol) be dissolved in the 5 mL tetrahydrofuran (THF)s, stir and drip 2-morpholine-4-base-ethamine (15 mg down, 0.114 mmol), add sodium triacetoxy borohydride (127 mg in batches, 0.6 mmol), 3 hours afterreactions of mixture liquid reflux of gained finish.Reaction solution is evaporate to dryness under reduced pressure, the residue of gained further passes through column chromatographic isolation and purification, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{4-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-2-yl }-quinazoline-4-yl)-amine 50 (37 mg, yellow solid), productive rate: 83.1%.

MS m/z(ESI)：587[M+1]

¹HNMR(400MHz，CDCl ₃)：δ 10.17(s，1H)，8.67(s，1H)，8.09(s，1H)，7.96(d，1H，J＝8.8)，7.89(s，1H)，7.82(m，2H)，7.64(d，1H，J＝8.8)，7.35(m，1H)，7.25(m，2H)，7.02(m，1H)，6.96(d，1H，J＝8.8)，6.13(s，1H)，6.12(s，1H)，5.14(s，2H)，3.91(s，2H)，3.64(t，4H)，2.80(t，2H)，2.50(t，2H)，2.20(t，4H)

Embodiment 51

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-diethyllaminoethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

Compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (70 mg with the invention process 42 gained, 0.157mmol) be dissolved in 5 mLN, in the dinethylformamide, solution is under the ice bath cooling, add sodium hydride (16 mg, 0.4 mmol), mixed solution rises to room temperature, stir after 30 minutes, add (2-bromotrifluoromethane)-diethylamine hydrobromide (62 mg, 0.236 mmol), reacting by heating liquid to 60 ℃, stir 2 hours afterreactions and finish, add water quencher reaction.Reaction solution extracts with ethyl acetate (100 mL * 3), the organic phase anhydrous sodium sulfate drying that merges, filter, the residue that concentrates gained under the filtrate decompression further passes through column chromatographic isolation and purification, obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(2-diethyllaminoethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 51 (40 mg, yellow solid), productive rate: 46.8%.

MS m/z(ESI)：544[M+1]

¹HNMR(400MHz，CD ₃OD)：δ 8.40(s，1H)，7.85(d，1H)，7.70(s，1H)，7.34(d，1H，J＝8.8)，7.27(m，1H)，7.11(m，4H)，7.03(m，3H)，6.70(s，1H)，6.48(s，1H)，4.72(s，2H)，4.02(t，2H)，2.63(t，2H)，2.42(q，4H)，0.79(t，6H)

Embodiment 52

[6-(5-[1,4 '] dipiperidino-1 '-methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy Base)-]-amine

The first step

3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrroles-2-first

Aldehyde

Repeat described experimental procedure of 50 second step of the embodiment of the invention, compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42a that different is with above-mentioned the first step gained is as raw material, in embodiment described mode of 50 second step, carry out this raw material and phosphorus oxychloride and N, the reaction of dinethylformamide, obtain this title product 3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrrole-2-aldehyde 52a (35 mg, yellow solid), productive rate: 56.0%.

MS m/z(ESI)：473[M+1]

Second step

Repeat described experimental procedure of the 3rd step of the embodiment of the invention 50, compound 3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with above-mentioned experiment gained]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrrole-2-aldehyde 52a makes raw material, make this raw material and [1 according to described same way as of the embodiment of the invention 50 the 3rd step, 4 '] reaction of two piperidines, obtain title compound [6-(5-[1,4 '] dipiperidino-1 '-methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-]-amine 52 (100 mg, white solid), productive rate 68.0%.

MS m/z(ESI)：625[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.12(s，1H)，9.91(s，1H)，8.62(s，1H)，8.59(s，1H)，8.18(d，1H，J＝8.8)，8.14(s，1H)，7.86(d，1H，J＝8.8)，7.80(d，1H，J＝8.8)，7.55(m，1H)，7.40(m，2H)，7.25(t，1H)，6.85(s，1H)，6.60(s，1H)，5.33(s，2H)，3.65(s，2H)，2.96(m，2H)，2.74(m，2H)，2.05(m，1H)，2.02(m，2H)，1.82(m，2H)，1.30-1.60(m，10H)

Embodiment 53

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-carboxylic Acid-(2-diethyllaminoethyl)-methane amide

With 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 (100 mg, 0.2 mmol) with 1 mL N, N-diethyl-1 adds in the 10 mL eggplant-shape bottles, mixture heating up to 90 ℃, stirring is spent the night, and reaction finishes.Reaction solution under reduced pressure concentrates, the residue that obtains with acetic acid ethyl dissolution after, add hexanaphthene again, there are a large amount of white solids to separate out, filter, the solid that obtains dissolves with small amount of methanol, further separate purification with the TLC plate, obtain yellow solid, vacuum-drying obtains title product 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-carboxylic acid-(2-diethyllaminoethyl)-methane amide 53 (110 mg, yellow solid), productive rate: 89.5%.

MS m/z(ESI)：615[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.25(s，1H)，8.91(s，1H)，8.61(m，2H)，8.42(s，2H)，8.13(d，2H，J＝7.2)，7.89(m，3H)，7.60(d，1H，J＝7.6)，7.53(s，1H)，7.38(m，1H)，7.30(d，1H，J＝8.8)，5.31(s，2H)，4.70(s，1H)，3.64(m，4H)，3.22(m，6H)，2.91(t，2H)，1.27(t，6H)

Embodiment 54

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3- Carboxylic acid-(2-morpholine-4-ethyl)-methane amide

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 2-morpholine-4-base-ethamine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-ethyl)-methane amide 54 (110 mg, yellow solid), productive rate: 87.3%.

MS m/z(ESI)：629[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.97(s，1H)，8.74(s，1H)，8.60(m，2H)，8.09(m，3H)，7.89(m，3H)，7.79(d，1H，J＝8.8)，7.60(d，1H，J＝8.0)，7.45(s，1H)，7.38(t，1H)，7.30(d，1H，J＝8.8)，5.31(s，2H)，4.81(s，1H)，3.64(m，8H)，3.17(m，6H)，2.89(t，2H)

Embodiment 55

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3- Carboxylic acid-(2-methoxy ethyl)-methane amide

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 2-methoxyethyl amine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-carboxylic acid-(2-methoxy ethyl)-methane amide 55 (110 mg, yellow solid), productive rate: 87.3%.

MS m/z(ESI)：571[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.00(s，1H)，8.72(s，1H)，8.68(d，2H)，8.18(d，1H，J＝9.2)，8.13(s，1H)，8.09(m，2H)，8.00(m，2H)，7.97(d，1H，J＝8.0)，7.67(d，1H，J＝8.0)，7.46(m，2H)，7.39(d，1H，J＝9.2)，5.39(s，2H)，4.85(s，1H)，3.72(t，2H)，3.52(m，2H)，3.47(m，2H)，3.37(s，3H)，2.97(t，2H)

Embodiment 56

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3- Carboxylic acid-[2-(4-methyl-piperazine-1-yl)-ethyl]-acid amides

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 2-(4-methyl-piperazine-1-yl)-ethamine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-carboxylic acid-[2-(4-methyl-piperazine-1-yl)-ethyl]-acid amides 56 (90 mg, yellow solid), productive rate: 88%.

MS m/z(ESI)：643[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.11(s，1H)，8.89(s，1H)，8.06(m，2H)，8.25(s，1H)，8.13(m，2H)，7.90(m，4H)，7.60(d，1H，J＝7.6)，7.49(s，1H)，7.37(t，1H)，7.26(d，1H，J＝9.2)，5.31(s，2H)，4.82(s，1H)，3.65(t，2H)，3.26(m，2H)，2.89(t，2H)，2.67(m，10H)，2.41(s，3H)

Embodiment 57

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3- Carboxylic acid-(3-morpholine-4-propyl group)-acid amides

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 3-morpholine-4-base-propylamine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-carboxylic acid-(3-morpholine-4-propyl group)-acid amides 57 (90 mg, yellow solid), productive rate 88%.

MS m/z(ESI)：640[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.10(s，1H)，8.84(s，1H)，8.59(d，2H)，8.21(s，1H)，8.10(m，2H)，8.02(s，1H)，7.88(m，2H)，7.83(d，1H，J＝8.0)，7.60(d，1H，J＝7.6)，7.49(s，1H)，7.38(t，1H)，7.29(d，1H，J＝8.8)，5.31(s，2H)，4.86(s，1H)，3.62(m，6H)，3.36(m，2H)，3.25(m，2H)，2.89(t，2H)，2.21(m，4H)，1.71(m，2H)

Embodiment 58

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3- Base]-morpholine-4-ketone

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and morpholine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 58 (230 mg, white solid), productive rate: 98.2%.

MS m/z(ESI)：584[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.59(m，3H)，8.17(d，1H，J＝10.4)，8.02(s，1H)，7.88(m，2H)，7.73(d，1H，J＝8.0)，7.68(s，1H)，7.60(d，1H，J＝7.2)，7.45(s，1H)，7.38(t，1H)，7.32(d，1H，J＝9.2)，5.31(s，2H)，4.69(t，1H)，3.57(m，8H)，3.17(m，2H)，2.70(t，2H)

Embodiment 59

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3- Base]-(4-methyl-piperazine-1-yl)-ketone

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 1-methylpiperazine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-yl]-(4-methyl-piperazine-1-yl)-ketone 59 (100 mg, brown oil), productive rate: 95%.

MS m/z(ESI)：599[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.60(m，3H)，8.17(d，1H，J＝8.8)，8.02(s，1H)，7.88(m，2H)，7.73(d，1H，J＝6.4)，7.65(s，1H)，7.60(d，1H，J＝8.0)，7.45(s，1H)，7.38(t，1H)，7.32(d，1H，J＝9.2)，5.31(s，2H)，4.69(s，1H)，3.60(m，6H)，2.69(t，2H)，2.33(t，4H)，2.21(s，3H)

Embodiment 60

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-yl]- Tetramethyleneimine-1-ketone

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and tetramethyleneimine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-yl]-tetramethyleneimine-1-ketone 60 (170 mg, gray solid), productive rate 95%.

MS m/z(ESI)：570[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.78(s，1H)，8.59(m，3H)，8.18(d，1H，J＝8.4)，8.01(s，1H)，7.89(t，2H)，7.81(s，1H)，7.72(d，1H，J＝7.2)，7.60(d，1H，J＝7.6)，7.42(s，1H)，7.36(t，1H)，7.32(d，1H，J＝8.8)，5.31(s，2H)，4.78(s，1H)，3.62(t，4H)，3.52(t，2H)，2.79(t，2H)，1.88(s，4H)

Embodiment 61

2-[1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(4-methyl-piperazine-1-first Base)-1H-pyrroles-3-yl]-ethanol

The first step

In 25 mL eggplant-shape bottles, add lithium aluminum hydride (44 mg, 1.16mmol) and the 4mL tetrahydrofuran (THF), stir under the room temperature, drip compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino gradually]-quinazoline-6-yl }-4-(2-hydroxyl)-1H-pyrroles-3-yl]--(4-methyl-piperazine-1-yl)-ketone 59 (130 mg, 0.385 3 mL tetrahydrofuran solutions mmol), have a large amount of bubbles to produce in the solution, and have thick solid to produce, it is yellow that reaction solution is.Reaction solution is heated to 50 ℃, stirs 2 hours afterreactions and finish, cool off reaction solution with ice bath, slowly drip methyl alcohol, reaction solution is clear.With the flushing of decompression post, concentration of reaction solution, the solid that obtains is further by the separation and purification of TLC plate, obtain title product 2-[1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(4-methyl-piperazine-1-methyl)-1H-pyrroles-3-yl]-ethanol 61 (70 mg, yellow solid), productive rate: 55.6%.

MS m/z(ESI)：585[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.99(s，1H)，8.61(m，3H)，8.05(d，2H)，7.88(t，1H)，7.81(t，2H)，7.59(d，1H，J＝7.6)，7.46(d，2H)，7.39(t，1H)，7.29(d，1H，J＝9.2)，5.30(s，2H)，3.78(m，4H)，2.73(t，2H)，2.23(m，8H)，2.11(s，3H)

Embodiment 62

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }- Quinazoline-4-yl)-amine

Repeat described experimental procedure of 52 second step of the embodiment of the invention; compound 3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with above-mentioned experiment gained]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrrole-2-aldehyde 52a makes raw material; make the reaction of this raw material and 2-methylsulfonyl ethamine according to described same way as of the embodiment of the invention 52 second step; obtain title compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 62 (10 mg; yellow solid), productive rate 8.5%.

MS m/z(ESI)：580[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.15(s，1H)，9.91(s，1H)，8.70(s，1H)，8.49(s，1H)，8.08(d，1H，J＝8.8)，7.83(d，1H，J＝9.2)，7.69(d，1H，J＝8.8)，7.51(s，1H)，7.47(t，1H)，7.32(m，3H)，7.20(t，1H)，6.88(s，1H)，6.74(s，1H)，5.26(s，2H)，3.86(s，2H)，3.24(t，2H)，2.95(s，3H)，2.92(t，2H)

Embodiment 63

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(3-morphine woods-4-third amino)-methyl]-1H-pyrroles-3-yl }- Quinazoline-4-yl)-amine

Repeat described experimental procedure of 52 second step of the embodiment of the invention, compound 3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with above-mentioned experiment gained]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrrole-2-aldehyde 52a makes raw material, make the reaction of this raw material and 3-morpholine-4-base-propylamine according to described same way as of the embodiment of the invention 52 second step, obtain title compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(3-morphine woods-4-third amino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 63 (20 mg, yellow solid), productive rate 35.0%.

MS m/z(ESI)：601[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.10(s，1H)，9.90(s，1H)，8.53(d，2H)，8.08(s，1H)，8.10(d，1H，J＝8.4)，7.81(d，1H)，7.73(d，1H，J＝8.4)，7.47(m，1H)，7.30(m，3H)，7.18(t，1H)，6.80(s，1H)，6.46(s，1H)，5.26(s，2H)，3.86(s，2H)，3.59(t，2H)，3.48(t，2H)，2.33(t，4H)，2.24(t，4H)，1.57(m，2H)

Embodiment 64

[3-chloro-4-(3-fluoro-benzyloxy) phenyl]-6-[1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyrroles-3-yl]-the quinoline azoles Quinoline-4-yl }-amine

Repeat the invention process 51 described experimental procedures, compound [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 42 that different is with embodiment 42 gained is as raw material, according to embodiment 51 described modes, carry out the reaction of this raw material and 1-(2-chloroethyl)-tetramethyleneimine, obtain this title product [3-chloro-4-(3-fluoro-benzyloxy) phenyl]-{ 6-[1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine (30 mg, yellow solid), productive rate: 35.9%.

MS m/z(ESI)：542[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.65(s，1H)，8.02(m，2H)，7.91(d，1H，J＝8.4)，7.81(m，2H)，7.52(d，1H，J＝8.8)，7.32(m，1H)，7.20(m，2H)，7.04(m，2H)，6.90(d，1H，J＝9.2)，6.70(s，1H)，6.49(s，1H)，5.09(s，2H)，4.01(t，2H)，2.86(t，2H)，2.54(m，4H)，1.77(m，4H)

Embodiment 65

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-{3-[4-(3-chloro-phenyl-)-piperazine-1-yl]-propyl group }-1H-pyrroles -3-yl)-quinazoline-4-yl]-amine

Repeat the invention process 51 described experimental procedures, compound [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 42 that different is with embodiment 42 gained is as raw material, according to embodiment 51 described modes, carry out the reaction of this raw material and 1-(3-chloro-phenyl-)-4-(3-chloropropyl)-piperazine, obtain this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-{3-[4-(3-chloro-phenyl-)-piperazine-1-yl]-propyl group }-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine (32 mg, yellow solid), productive rate: 20.9%.

MS m/z(ESI)：681[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.67(s，1H)，8.52(d，2H)，8.03(m，2H)，7.70(d，1H，J＝8.8)，7.46(d，1H，J＝10.8)，7.34(m，2H)，7.29(m，3H)，7.19(m，2H)，6.92(m，3H)，6.77(d，1H，J＝6.4)，6.67(s，1H)，5.21(s，2H)，4.01(t，2H)，3.28(t，4H)，3.20(t，4H)，2.33(t，2H)，1.98(t，2H)

Embodiment 66

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole Cough up-the 3-carboxylic acid-(2-tetramethyleneimine-1-base-ethyl)-acid amides

The first step

(6-iodo-quinazoline-4-yl)-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenyl]-amine

Repeat described experimental procedure of the 5th step of the embodiment of the invention 1, different is to make raw material with the compound 6-iodo-3H-quinazoline-4-one 1f that embodiment 1 the 4th goes on foot gained, make the reaction of this raw material and 3-methyl-4-(6-methyl-pyridine-3-oxo)-aniline according to described same way as of the embodiment of the invention 1 the 5th step, obtain title compound (6-iodo-quinazoline-4-yl)-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenyl]-amine 66a (10 g, pale solid), productive rate 65%.

MS m/z(ESI)：469[M+1]

Second step

2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans

And [3,4-c] pyrroles-4-ketone

In 250 mL eggplant-shape bottles, compound (6-iodo-quinazoline-4-yl)-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenyl]-amine 66a (11.7 g with the above-mentioned steps gained, 25mmol), 6,7-dihydro-2H-pyrans is [3,4-c] pyrroles-4-ketone 47b (3.6g also, 26.25 mmol), potassiumphosphate (15.92 g, 25mmol), cuprous iodide (4.775g, 25mmol) be dissolved in 80 mLN, in the dinethylformamide, mixture under agitation drips N, N '-dimethyl-1,2-quadrol (2.18 g, 25 mmol), reacting by heating liquid to 80 ℃, stirring is spent the night.Reaction solution is poured in the 250 mL frozen water, there is yellow solid to separate out, suction filtration, the solid that obtains is with 300 mL methanol wash, and the solid that obtains is dry under vacuum, obtains this title product 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b (11.59 g, yellow solid), productive rate 97.06%.

MS m/z(ESI)：478[M+1]

The 3rd step

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid (2-tetramethyleneimine-1-base-ethyl)-acid amides

With 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxygen)-phenylamino]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b (120 mg, 0.25 mmol) add in the 10 mL eggplant-shape bottles with 2 mL 2-pyrrolidyl-1-base-ethamine, mixture heating up to 90 ℃, stirring is spent the night, and reaction finishes.Reaction solution under reduced pressure concentrates, the residue that obtains with acetic acid ethyl dissolution after, add hexanaphthene again, there are a large amount of white solids to separate out, filter, the solid that obtains dissolves with small amount of methanol, separate purification with the TLC plate, obtain yellow solid, vacuum-drying obtains title product 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid-(2-tetramethyleneimine-1-base-ethyl)-acid amides 66 (17 mg, light yellow solid), productive rate: 97.0%.

MS m/z(ESI)：592[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.89(s，1H)，8.68(s，1H)，8.58(s，1H)，8.19(s，1H)，8.09(m，3H)，7.91(d，1H，J＝8.8)，7.78(s，1H)，7.73(dd，1H，J＝8.4)，7.42(s，1H)，7.24(m，2H)，6.99(d，1H，J＝8.8)，4.85(s，1H)，3.65(t，2H)，3.41(m，2H)，2.90(t，2H)，2.67(m，6H)，2.45(s，3H)，2.23(s，3H)，1.74(m，4H)

Embodiment 67

N-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3- Base)-2-methyl-acrylamide

The first step

4,4,4-, three fluoro-but-2-ene acid

In 100 mL eggplant-shape bottles, add 4,4,4-, three fluoro-but-2-ene acetoacetic ester 67a (56 g, 0.33 mmol), formic acid (46g, 1 mmol) and the 1 mL vitriol oil, the mixed solution that obtains is heated to 80 ℃, and stirring is spent the night, and reaction finishes.Stop heating, 40～80 ℃ cut is collected in distillation at normal temperatures, obtains this title product 4,4,4-three fluoro-but-2-enes acid 67b (24 g, white solid), productive rate 51.9%.

MS m/z(ESI)：139[M-1]

Second step

4,4,4-, three fluoro-but-2-ene acid benzyl esters

In 1000 mL eggplant-shape bottles, add 4,4,4-, three fluoro-but-2-enes acid 67b (26.5 g, 0.18 mol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (54 g, 0.27 mol), I-hydroxybenzotriazole (3.85 g, 0.27mol), triethylamine (46 g, 0.45mol), with 400 mL tetrahydrofuran (THF)s, the mixture of gained at room temperature stir add after 1 hour benzylalcohol (29.2 g, 0.27mol), stirring is spent the night, and reaction finishes.In reaction solution, add frozen water quencher reaction, extract with ethyl acetate (400 mL * 3), the organic phase anhydrous sodium sulfate drying filters, and filtrate concentrates, the residue that obtains further passes through column chromatographic isolation and purification, obtain this title product 4,4,4-three fluoro-but-2-ene acid benzyl ester 67c (2.95 g, yellow oily liquid), productive rate: 7.7%.

MS m/z(ESI)：579[M-1]

The 3rd step

4-Trifluoromethyl-1 H-pyrroles-3-benzyl formate

(2.73g 14.1mmol) is dissolved in the 25 mL tetrahydrofuran (THF)s, and ice bath is cooled to 0 ℃ with tolysulfonyl methyl isonitrile, under the nitrogen atmosphere, add two rings [5,4,0]-1, and 8-phenodiazine-7-nonene (2.15 g, 14.1mmol), stir and add 4 after 30 minutes, 4,4-, three fluoro-but-2-ene acid benzyl ester 67c (2.95g, 12.7mmol), the mixture that obtains stirs and spends the night, and reaction finishes.In reaction solution, add 40 mL frozen water quenchers reaction, extract with methylene dichloride (100mL * 3), the organic phase anhydrous magnesium sulfate drying that merges, filter, concentrate, the residue that obtains further by column chromatographic isolation and purification, obtains this title product 4-Trifluoromethyl-1 H-pyrroles-3-benzyl formate 67d (1.938 g, yellow solid), productive rate: 56.7%.

MS m/z(ESI)：268[M-1]

The 4th step

4-Trifluoromethyl-1 H-pyrroles-3-formic acid

In 25 mL eggplant-shape bottles, under the condition of ice bath, add compound 4-Trifluoromethyl-1 H-pyrroles-3-benzyl formate 67d (120 mg of above-mentioned steps gained, 0.445mmol) and 3 mL trifluoracetic acids, stir 30 minutes recession deicings and bathe, stir under the room temperature and spend the night, reaction finishes.Reaction solution is poured in the 50 mL frozen water, extract with ethyl acetate (200 ml * 3), the organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and the residue that obtains further by column chromatographic isolation and purification, obtains this title product 4-Trifluoromethyl-1 H-pyrroles-3-formic acid 67e (3.39g, yellow solid), productive rate: 52.6%.

MS m/z(ESI)：180[M+1]

The 5th step

1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-formic acid

Compound 4-Trifluoromethyl-1 H-pyrroles-3-formic acid (2.14 g with the above-mentioned steps gained, 12 mmol), [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (6.07 g, 12 mmol), potassiumphosphate (10.19 g, 48 mmol), cuprous iodide (3.44 g, 18 mmol) and 4-Trifluoromethyl-1 H-pyrroles-3-formic acid (2.14 g, 12 mmol) and 5 mLN, the dinethylformamide dissolving, stir and drip N, N '-dimethyl-1 (1.6 g down, 18 mmol), reflux stirs and spends the night.Reaction solution is joined in the 150 mL frozen water, have yellow solid to separate out, suction filtration, the yellow solid that obtains directly carries out next step reaction (500 mg, faint yellow solid) without separating.

MS m/z(ESI)：445[M+1]

The 6th step

1-{4-[4-(3-fluorine benzyloxy)-3-chlorobenzene amino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-azido--ketone

Compound 1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino with the above-mentioned steps gained]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-formic acid 67f (278 mg, 0.5mmol), triethylamine (76 mg, 0.75mmol) be dissolved in the 2 mL tetrahydrofuran (THF)s, stir and add azido-diphenyl phosphate (151 mg down, 0.55mmol), the mixture of gained at room temperature stirs 7 hours afterreactions and finishes.Reaction solution extracts with ethyl acetate (30mL * 3), the organic phase that merges is used 70 mL water successively, 30 mL saturated common salt water washings, anhydrous sodium sulfate drying filters, and decompression is concentrated organic phase down, the residue of gained further passes through column chromatographic isolation and purification, obtain this title product 1-{4-[4-(3-fluorine benzyloxy)-3-chlorobenzene amino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-azido--ketone 67g (101 mg, yellow solid), productive rate: 35%.

MS m/z(ESI)：581[M+1]

The 7th step

(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-yl)-

T-butyl carbamate

Compound 1-{4-[4-(3-fluorine benzyloxy)-3-chlorobenzene amino with the above-mentioned steps gained]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-azido--ketone 67g (1.37 g, 2.35mmol) be dissolved in 75 mL toluene, bath temperature is under 130 ℃ outside, the yellow suspension of heating gained, add the trimethyl carbinol (15 mL after 3 hours, 159mmol), after continuing to reflux 2 hours, under 45 ℃, stir and spend the night, the evaporate to dryness reaction solution, the residue of gained (1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-yl)-t-butyl carbamate 67h (1.6 g, yellow solid) directly carries out next step reaction without separating.

MS m/z(ESI)：628[M+1]

The 8th step

[6-(3-amino-4-trifluoromethyl-pyrroles-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine

Under the nitrogen atmosphere, in 50 mL eggplant-shape bottles, with the compound of above-mentioned steps gained (1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-t-butyl carbamate 67h (219 mg, 0.35 mmol) be dissolved in 20 mL methylene dichloride, the solution that obtains Dropwise 5 mL trifluoracetic acid gradually under ice bath cooling stirs 1.5 hours afterreactions and finishes under the room temperature.Reaction solution under reduced pressure concentrated boil off solvent, the solid that obtains is dry in drying basin, obtain this title product [6-(3-amino-4-trifluoromethyl-pyrroles-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine 67i (100 mg, yellow solid), productive rate: 54.3%

MS m/z(ESI)：528[M+1]

The 9th step

N-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-Trifluoromethyl-1 H-pyrroles-3-yl)-2-methyl-acrylamide

Compound [6-(3-amino-4-trifluoromethyl-pyrroles-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine 67i (200 mg with the above-mentioned steps gained, 0.379 mmol), triethylamine (0.4 mL, 0.758 mmol) be dissolved in the 15 mL methylene dichloride, mixture adds 2-methyl-Ding-3-alkene acyl chlorides (0.1 mL under the cooling of acetone the dry ice bath, 0.379 mmol), stirring had solid to separate out after 4 hours.The solid of gained carries out separation and purification by the TLC plate, wash with ethyl acetate, obtain this title product N-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-2-methyl-acrylamide (49 mg, yellow solid), productive rate 21.7%.

MS m/z(ESI)：596[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.87(s，1H)，9.25(s，1H)，8.69(s，1H)，8.62(s，1H)，8.24(d，1H，J＝8.8)，8.10(s，1H)，8.01(s，1H)，7.91(d，1H，J＝8.8)，7.85(s，1H)，7.73(d，1H，J＝8.8)，7.48(q，1H)，7.33(m，3H)，7.20(t，1H)，5.82(s，1H)，5.52(s，1H)，5.28(s，2H)，1.97(s，3H)

Embodiment 68

[1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3- Base]-piperidines-1-ketone

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and piperidines according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound [1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-piperidines-1-ketone 68 (100 mg, gray solid), productive rate 95%.

MS m/z(ESI)：584[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.88(s，1H)，8.61(m，3H)，8.17(d，1H，J＝8.8)，8.05(s，1H)，7.88(m，2H)，7.76(d，1H，J＝8.8)，7.67(s，1H)，7.60(d，1H，J＝7.6)，7.48(s，1H)，7.38(t，1H)，7.31(d，1H，J＝8.4)，5.31(s，2H)，4.71(s，1H)，3.56(m，6H)，2.68(t，2H)，1.52-1.64(m，6H)

Embodiment 69

2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-piperidines-1-methyl isophthalic acid H-pyrroles-3-yl)-ethanol

Repeat the described experimental procedure of the embodiment of the invention 61 the first steps, compound [1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl that different is with embodiment 68 gained }-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-piperidines-1-ketone 68 makes raw material, make this raw material and lithium aluminum hydride react according to the described same way as of the embodiment of the invention 61 the first steps, obtain title compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-piperidines-1-methyl isophthalic acid H-pyrroles-3-yl)-ethanol 69 (150 mg, brown solid), productive rate: 40%.

MS m/z(ESI)：570[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.07(s，1H)，8.79(s，1H)，8.60(t，2H)，8.10(q，2H)，7.90(t，2H)，7.80(t，2H)，7.59(t，2H)，7.38(t，1H)，7.30(d，1H，J＝8.8)，5.31(s，2H)，4.14(s，2H)，3.69(t，2H)，3.00(t，4H)，2.75(t，2H)，1.66(m，6H)

Embodiment 70

4-{[(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-methyl)-amino]- Methyl }-1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

Repeat the embodiment of the invention 5 the first steps to the described experimental procedure of three steps, different is with compound 1-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino of embodiment 5 second step gained]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, make this raw material and 4-aminomethyl-1 according to described same way as of the embodiment of the invention 5 the 3rd step, 1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol reaction obtains this title product 4-{[(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-methyl)-amino]-methyl }-1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 70 (90 mg, yellow solid), productive rate: 67.2%.

MS m/z(ESI)：637[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.42(s，1H)，8.99(s，1H)，8.92(s，1H)，8.38(dd，1H，J＝8.8)，8.05(d，1H，J＝9.2)，8.01(d，1H，J＝2.4)，7.94(s，1H)，7.85(t，1H)，7.79(dd，1H，J＝9.2)，7.48(m，1H)，7.35(m，3H)，7.20(t，1H)，6.62(s，1H)，5.25(s，2H)，4.09(s，2H)，3.19(m，2H)，3.07(m，4H)，2.06(m，4H)

Embodiment 71

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole Cough up-the 3-carboxylic acid-(2-methoxy ethyl)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 66 the first steps to the, different is to go on foot the compound of gained with 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenylamino with second]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b makes raw material, make the reaction of this raw material and 2-methoxyethyl amine according to described same way as of the embodiment of the invention 66 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid (2-methoxy ethyl)-acid amides 71 (15 mg, yellow solid), productive rate: 8%.

MS m/z(ESI)：553[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.86(s，1H)，8.69(s，1H)，8.58(s，1H)，8.19(s，1H)，8.08(t，2H)，8.00(s，1H)，7.91(d，1H，J＝8.4)，7.78(s，1H)，7.71(d，1H，J＝8.4)，7.41(s，1H)，7.25(m，2H)，7.00(d，1H，J＝8.4)，4.80(t，1H)，3.66(q，2H)，3.44(t，2H)，3.39(t，2H)，3.29(s，3H)，2.90(t，2H)，2.45(s，3H)，2.24(s，3H)

Embodiment 72

[1,4 '] dipiperidino-1 '-Ji-(5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole Cough up-the 2-yl)-ketone

The first step

5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid

Repeat the experimental procedure of the invention process 11 the first steps, compound 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino with embodiment 11 the first step gained]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 11a (283 mg, 0.6mmol) be dissolved in the 5 mL tetrahydrofuran (THF)s, add 6 mL 1.5N potassium permanganate solutions in batches, stir 5 hours afterreactions and finish.In reaction solution, add saturated sodium bisulfite solution, filter, filtrate extracts with ethyl acetate (100 mL * 3), with the washing of 50 mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying filters the organic phase that merges successively, concentrate under the filtrate decompression, obtain this title product 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid 72a (265 mg, yellow solid), productive rate 90.4%.

MS m/z(ESI)：489[M+1]

Second step

5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6 base }-1H-pyrroles-2-carboxylic acid (2-morpholine-4-ethyl)-acid amides

Compound 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino with above-mentioned experiment gained]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid 72a (49 mg, 0.1mmol), thionyl chloride (60 mg, 0.5 mmol) be dissolved in the 5 mL methylene dichloride, reflux was cooled to room temperature after 1 hour, added [1,4 '] two piperidines (33.6 mg, 0.2 5 mL dichloromethane solutions mmol), the mixed solution of gained at room temperature stir 2 hours afterreactions and finish.Decompression is concentrated solvent down, the residue that obtains is by the separation and purification of TLC plate, obtain this title product 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6 base }-1H-pyrroles-2-carboxylic acid (2-morpholine-4-ethyl)-acid amides 72 (12 mg, white solid), productive rate: 18.8%.

MS m/z(ESI)：639[M+1]

¹HNMR(400MHz，CDCl ₃)：δ 9.20(s，1H)，8.71(s，1H)，7.92(d，3H，J＝9.2)，7.85(m，2H)，7.53(d，1H，J＝8.8)，7.35(m，1H)，7.22(m，2H)，7.02(t，1H)，6.96(d，1H，J＝8.8)，6.88(s，1H)，6.38(s，1H)，5.16(s，2H)，2.53(m，4H)，2.19(m，4H)，2.00(m，1H)，1.48(m，8H)，1.34(m，2H)

Embodiment 73

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole Cough up 3-carboxylic acid (2-piperidines-1-ethyl)-acid amides

Repeat the embodiment of the invention 66 the first steps to the described experimental procedure of three steps, compound 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenylamino that different is with embodiment 66 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b makes raw material, make the reaction of this raw material and 2-piperidines-1-base-ethamine according to described same way as of the embodiment of the invention 66 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid (2-piperidines-1-ethyl)-acid amides 73 (42mg, yellow solid), productive rate: 15.7%.

MS m/z(ESI)：604[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.93(s，1H)，8.73(s，1H)，8.58(s，1H)，8.19(s，1H)，8.11(s，1H)，8.09(m，1H)，7.90(m，2H)，7.76(s，1H)，7.75(dd，1H，J＝8.8)，7.44(s，1H)，7.23(m，2H)，7.00(d，1H，J＝8.8)，3.66(t，2H)，3.58(q，2H)，2.89(t，2H)，2.45(m，6H)，2.34(m，2H)，2.27(m，4H)，1.50(m，6H)

Embodiment 74

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-4-(2-hydroxyethyl)-1H-pyrroles -3-carboxylic acid (2-tetramethyleneimine-1-base-ethyl)-acid amides

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 2-tetramethyleneimine-1-base-ethamine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid (2-tetramethyleneimine-1-base-ethyl)-acid amides 74 (140mg, yellow solid), productive rate 40.0%.

MS m/z(ESI)：611[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.99(d，1H，J＝12.8)，8.85(d，1H，J＝12.8)，8.61(d，2H，J＝6.0)，8.44(m，1H)，8.31(s，1H)，8.13(t，2H)，7.88(t，3H)，7.60(d，1H，J＝8.0)，7.50(d，1H，J＝5.2)，7.38(t，1H)，7.30(d，1H，J＝9.2)，5.31(s，2H)，4.73(s，1H)，3.58(m，6H)，3.09(m，4H)，2.91(t，2H)，1.96(m，4H)

Embodiment 75

1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid (2-piperidines-1-ethyl)-acid amides

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make the reaction of this raw material and 2-piperidines-1-base-ethamine according to the described same way as of the embodiment of the invention 53 the first steps, obtain title compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid (2-piperidines-1-ethyl)-acid amides 75 (70 mg, brown solid), productive rate 56.0%.

MS m/z(ESI)：625[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.07(s，1H)，8.89(s，1H)，8.60(d，1H，J＝7.6)，8.29-8.45(m，2H)，8.14(m，2H)，7.89(t，3H)，7.60(d，1H，J＝8.0)，7.52(d，1H)，7.37(t，1H)，7.30(d，1H，J＝9.2)，5.31(s，2H)，4.74(s，1H)，3.65(m，4H)，2.98-3.16(m，4H)，2.91(t，4H)，2.78(m，6H)

Embodiment 76

2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-tetramethyleneimine-1-methyl isophthalic acid H-pyrrole Cough up-the 3-yl)-ethanol

Repeat the described experimental procedure of the embodiment of the invention 61 the first steps, the compound that different is with embodiment 60 gained-{ 4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3-yl]-tetramethyleneimine-1-ketone 60 makes raw material, make this raw material and lithium aluminum hydride react according to the described same way as of the embodiment of the invention 61 the first steps, obtain title compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-tetramethyleneimine-1-methyl isophthalic acid H-pyrroles-3-yl)-ethanol 76 (30 mg, brown solid), productive rate: 44%.

MS m/z(ESI)：556[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.88(s，1H)，8.58(d，3H)，8.11(d，1H，J＝7.6)，8.04(s，1H)，7.88(m，2H)，7.76(d，1H，J＝6.8)，7.60(d，2H)，7.44(s，1H)，7.37(t，1H)，7.31(d，1H，J＝9.2)，5.31(s，2H)，3.85(s，2H)，3.65(t，2H)，2.90(m，4H)，2.71(t，2H)，1.83(m，4H)

Embodiment 77

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-piperidines-1-ketone

The first step

(6-iodo-quinazoline-4-yl)-(1-styroyl)-amine

Repeat the embodiment of the invention 1 the 5th described experimental procedure, different is to make raw material with the compound 6-iodo-3H-quinazoline-4-one 1f that embodiment 1 the 4th goes on foot gained, make the reaction of this raw material and 1-phenyl-ethyl amine according to described same way as of the embodiment of the invention 1 the 5th step, obtain title compound (6-iodo-quinazoline-4-yl)-(1-styroyl)-amine 77a (9 g, yellow solid), productive rate 66%.

MS m/z(ESI)：376[M+1]

Second step

2-[4-(1-benzene ethylamino)-quinazoline-6-yl]-6,7-dihydro-2H-pyrans is [3,4-c] pyrroles-4-ketone also

In 100 mL eggplant-shape bottles, compound (6-iodo-quinazoline-4-yl)-(1-styroyl)-amine 77a (2.3 g with the above-mentioned steps gained, 6.13 mmol), 6,7-dihydro-2H-pyrans is [3,4-c] pyrroles-4-ketone 10b (1.093g also, 7.97mmol), potassiumphosphate (3.9 g, 18.4mmol), cuprous iodide (2.33 g, 10.26 mmol) be dissolved in 25 mLN, in the dinethylformamide, stir and drip N, N '-dimethyl-1 down, 2-quadrol (0.897 g, 10.26 mmol), reacting by heating liquid to 70 ℃, stirring is spent the night.Reaction solution is poured in the 100 mL frozen water, the adularescent solid is separated out, suction filtration, the solid that obtains is with 300 mL methanol wash, and solid is dry under vacuum, obtains this title product 2-[4-(1-benzene ethylamino)-quinazoline-6-yl]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b (2.2 g, yellow solid), productive rate 95.7%.

MS m/z(ESI)：385[M+1]

The 3rd step

With 2-[4-(1-benzene ethylamino)-quinazoline-6-yl]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b (300 mg, 0.78 mmol) and 3 mL piperidines is added in the 10 mL eggplant-shape bottles, mixture heating up to 65 ℃, stirring is spent the night, and reaction finishes.Reaction solution under reduced pressure concentrates, the residue that obtains with acetic acid ethyl dissolution after, add hexanaphthene again, have a large amount of white solids to separate out, filter, the solid that obtains dissolves with small amount of methanol, separate to purify with the TLC plate, obtain yellow solid, vacuum-drying obtains title product { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-piperidines-1-ketone 77 (360 mg, light yellow solid), productive rate: 98.6%.

MS m/z(ESI)：470[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.56(s，1H)，8.48(d，2H，J＝6.8)，8.07(s，1H)，7.83(s，1H)，7.78(s，1H)，7.44(m，3H)，7.33(t，2H)，7.23(t，1H)，5.64(m，1H)，4.71(s，1H)，3.68(m，6H)，2.67(t，2H)，1.63(d，3H，J＝6.4)，1.24(t，6H)

Embodiment 78

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-tetramethyleneimine-1-ketone

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make the reaction of this raw material and tetramethyleneimine according to described same way as of the embodiment of the invention 77 the 3rd step, obtain title compound { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-tetramethyleneimine-1-ketone 78 (42mg, yellow solid), productive rate: 95%.

MS m/z(ESI)：456[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.65(s，2H)，8.40(s，1H)，8.10(d，1H，J＝8.4)，7.83(s，1H)，7.76(d，1H，J＝8.4)，7.46(m，3H)，7.32(t，2H)，7.21(t，1H)，5.64(m，1H)，4.81(s，1H)，3.61(m，4H)，3.46(m，2H)，2.78(t，2H)，1.86(m，4H)，1.64(d，3H，J＝6.8)

Embodiment 79

4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid (2-diethylin Ethyl)-acid amides

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make this raw material N according to described same way as of the embodiment of the invention 77 the 3rd step, N-diethyl-1, the reaction of 2-quadrol, obtain title compound 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid (2-diethyllaminoethyl)-acid amides 79 (50 mg, yellow solid), productive rate: 26%.

MS m/z(ESI)：501[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.82(s，1H)，8.75(d，1H，J＝7.2)，8.41(m，3H)，8.03(d，1H，J＝8.8)，7.78(d，1H，J＝8.8)，7.50(m，3H)，7.32(t，2H)，7.21(t，1H)，5.64(m，1H)，4.76(s，1H)，3.64(t，2H)，3.58(m，2H)，3.13(m，6H)，2.91(t，2H)，1.66(d，3H，J＝7.2)，1.24(t，6H)

Embodiment 80

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(3-{[(1,1-dioxy-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-methyl)-amino]- Methyl }-pyrroles-1-yl)-quinazoline-4-yl]-amine

Repeat the embodiment of the invention 5 the first steps to the described experimental procedure of three steps, different is with compound 1-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino of embodiment 5 second step gained]-quinazoline-6-yl }-1H-pyrroles-3-formaldehyde 5c makes raw material, make this raw material and C-(1,1-dioxo-six hydrogen-1 λ according to described same way as of the embodiment of the invention 5 the 3rd step ^*6 ^*-thiapyran-4-yl)-and the reaction of methylamine, obtain title compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(3-{[(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-methyl)-amino]-methyl }-pyrroles-1-yl)-quinazoline-4-yl]-amine 80 (53 mg, yellow solid), productive rate 40.7%.

MS m/z(ESI)：621[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.85(s，1H)，8.62(s，1H)，8.57(s，1H)，8.12(dd，1H，J＝8.8)，8.04(d，1H，J＝2.4)，7.86(d，1H，J＝8.8)，7.77(dd，1H，J＝8.8)，7.54(s，2H)，7.47(q，1H)，7.32(m，3H)，7.19(t，1H)，6.39(s，1H)，5.27(s，2H)，3.71(s，2H)，3.08(m，4H)，2.58(m，2H)，2.11(m，2H)，1.80(m，1H)，1.62(m，2H)

Embodiment 81

1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid (2 -tetramethyleneimine-1-ethyl)-acid amides

The first step

2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone

In the 100mL eggplant-shape bottle, add (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-yl)-amine 1g (100mg successively, 0.25mmol), 6,7-dihydro-2H-pyrans is [3,4-c] pyrroles-4-ketone 10b (44.6 mg also, 0.33 mmol), potassiumphosphate (159.2 mg, 0.75 mmol), cuprous iodide (57.1mg, 0.3 mmol) be dissolved in 2 mLN, in the dinethylformamide, stir and drip N, N '-dimethyl-1 down, 2-quadrol (26.3 mg, 0.3 mmol), reacting by heating liquid to 70 ℃, stirring is spent the night.Reaction solution is poured in the 40 mL frozen water, the adularescent solid is separated out, suction filtration, the solid that obtains is with 300 mL methanol wash, and solid is dry under vacuum, obtains this title product 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a (102.2 g, yellow solid), productive rate 100%.

MS m/z(ESI)：409[M+1]

Second step

1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid (2-tetramethyleneimine-1-ethyl)-acid amides

With 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a (110 mg, 0.25 mmol) with 2-tetramethyleneimine-1-base-ethamine (0.6 mL, 0.25 mmol) be added in the 10 mL eggplant-shape bottles, mixture heating up to 90 ℃, stirring is spent the night, and reaction finishes.Reaction solution under reduced pressure concentrates, the residue that obtains with acetic acid ethyl dissolution after, add hexanaphthene again, have a large amount of white solids to separate out, filter, the solid that obtains dissolves with small amount of methanol, separate purification with the TLC plate, obtain yellow solid, vacuum-drying obtains title product 1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-carboxylic acid-(2-tetramethyleneimine-1-ethyl)-acid amides 81 (25 mg, yellow solid), productive rate: 31.87%.

MS m/z(ESI)：524[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.24(s，1H)，8.97(s，1H)，8.64(s，1H)，8.56(s，1H)，8.35(m，2H)，8.15(d，1H，J＝8.8)，8.06(m，1H)，7.92(d，1H，J＝9.2)，7.56(s，1H)，7.47(t，1H)，4.73(s，1H)，3.71(t，2H)，3.63(q，2H)，3.43(m，2H)，2.91(t，2H)，2.50(m，4H)，1.85(m，4H)

Embodiment 82

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-methyl-pyridine-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H- Pyrroles-3-carboxylic acid-(3-morpholine-4-propyl group)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 66 the first steps to the, different is to go on foot the compound of gained with 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenylamino with second]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b makes raw material, make the reaction of this raw material and 3-morpholine-4-propylamine according to described same way as of the embodiment of the invention 66 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid-(3-morpholine-4-propyl group)-acid amides 82 (20 mg, yellow solid), productive rate: 8.6%.

MS m/z(ESI)：621[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.87(s，1H)，8.69(s，1H)，8.58(s，1H)，8.19(s，1H)，8.10(d，1H，J＝8.8)，8.00(m，2H)，7.91(d，1H，J＝8.8)，7.78(s，1H)，7.72(d，1H，J＝8.8)，7.42(s，1H)，7.25(m，2H)，7.00(d，1H，J＝8.8)，4.84(t，1H)，3.58-3.66(m，8H)，2.89(t，2H)，2.45(s，3H)，2.36(s，6H)，2.24(s，3H)，2.14(t，2H)

Embodiment 83

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-methyl-pyridine-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H- Pyrroles-3-carboxylic acid-(2-morpholine-4-ethyl)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 66 the first steps to the, different is to go on foot the compound of gained with 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenylamino with second]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b makes raw material, make the reaction of this raw material and 2-morpholine-4-base-ethamine according to described same way as of the embodiment of the invention 66 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-ethyl)-acid amides 83 (10 mg, yellow solid), productive rate: 5.4%.

MS m/z(ESI)：608[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.85(s，1H)，8.66(s，1H)，8.58(s，1H)，8.19(s，1H)，8.09(d，1H，J＝9.2)，8.00(s，1H)，7.91(m，2H)，7.77(s，1H)，7.72(d，1H，J＝9.2)，7.41(s，1H)，7.25(m，2H)，7.00(d，1H，J＝8.8)，4.82(t，1H)，3.58-3.66(m，8H)，2.90(t，2H)，2.45(m，9H)，2.24(s，3H)

Embodiment 84

4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-methyl-pyridine-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H- Pyrroles-3-carboxylic acid-(2-diethyllaminoethyl)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 66 the first steps to the, different is to go on foot the compound of gained with 2-{4-[3-methyl-4-(6-methyl-pyridine-3-oxygen)-phenylamino with second]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 66b makes raw material, make this raw material and N according to described same way as of the embodiment of the invention 66 the 3rd step, N-diethyl-1, the reaction of 2-quadrol, obtain title compound 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-picoline-3-oxygen base)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3-carboxylic acid-(2-ethylamino ethyl)-acid amides 84 (36 mg, yellow solid), productive rate: 15%.

MS m/z(ESI)：592[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.98(s，1H)，8.81(s，1H)，8.58(s，1H)，8.09-8.19(m，4H)，7.78-7.91(m，3H)，7.48(s，1H)，7.24(s，2H)，6.99(d，1H，J＝8.0)，4.79(s，1H)，3.65(t，2H)，3.40(t，2H)，2.74-2.90(m，8H)，2.45(s，3H)，2.23(s，3H)，1.08(t，6H)

Embodiment 85

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-6-[1-(2-methoxy ethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

Repeat the invention process 51 described experimental procedures, compound [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 42 that different is with embodiment 42 gained is as raw material, according to embodiment 51 described modes, carry out the reaction of this raw material and 1-chloro-2-methyl ethyl ether, obtain this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-{ 6-[1-(2-methoxy ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 85 (100 mg, yellow solid), productive rate: 20%.

MS m/z(ESI)：503[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.87(s，1H)，8.65(s，1H)，8.49(s，1H)，8.07(s，1H)，8.04(d，1H，J＝8.8)，7.80(d，1H)，7.69(d，1H，J＝8.8)，7.48(m，2H)，7.31(m，3H)，7.18(t，1H)，6.89(t，1H)，6.70(s，1H)，5.27(s，2H)，4.10(t，2H)，3.66(t，2H)，3.28(s，3H)

Embodiment 86

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-6-[1-(2-morpholine-4-ethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

Repeat the invention process 51 described experimental procedures, compound [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 42 that different is with embodiment 42 gained is as raw material, according to embodiment 51 described modes, carry out the reaction of this raw material and 1-(2-chloroethyl)-morpholine hydrochloride, obtain this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-{ 6-[1-(2-morpholine-4-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine (6 mg, yellow solid) 86, productive rate: 7.2%.

MS m/z(ESI)：559[M+1]

¹HNMR(400MHz，CDCl3)：δ8.70(s，1H)，7.92(d，1H)，7.83(m，3H)，7.54(m，2H)，7.34(m，1H)，7.23(m，2H)，7.09(s，1H)，6.99(m，2H)，6.77(m，1H)，6.52(m，1H)，5.14(s，2H)，4.03(t，2H)，3.71(t，4H)，2.75(t，2H)，2.49(t，4H)

Embodiment 87

5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6 base }-1H-pyrroles-2-carboxylic acid-(2-morpholine-4- Ethyl)-acid amides

Repeat the embodiment of the invention 72 the first steps to the second experimental procedure in step, compound 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with embodiment 72 the first step gained]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid 72a is as raw material, according to embodiment described mode of 72 second step, carry out the reaction of this raw material and 2-morpholine-4-base-ethamine, obtain this title product 5-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6 base }-1H-pyrroles-2-carboxylic acid-(2-morpholine-4-ethyl)-acid amides 87 (20 mg, white solid), productive rate: 33%.

MS m/z(ESI)：601[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.85(s，1H)，9.91(s，1H)，8.64(s，1H)，8.56(s，1H)，8.04(s，1H)，7.93(d，1H，J＝8.4)，7.78(m，2H)，7.47(q，1H)，7.30(m，3H)，7.18(t，1H)，7.06(s，1H)，6.98(s，1H)，6.36(s，1H)，5.26(s，2H)，3.26(t，2H)，3.20(s，4H)，2.29(t，2H)，2.21(s，4H)

Embodiment 88

2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-morpholine-4-methyl isophthalic acid H-pyrroles -3-yl)-ethanol

Repeat the described experimental procedure of the embodiment of the invention 61 the first steps, compound 1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 58 gained]-quinazoline-6-yl }-4--4-(2-hydroxyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 58 makes raw material, make this raw material and lithium aluminum hydride react according to the described same way as of the embodiment of the invention 61 the first steps, obtain title compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-morpholine-4-methyl isophthalic acid H-pyrroles-3-yl)-ethanol 88 (30 mg, brown solid), productive rate: 44%.

MS m/z(ESI)：556[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.82(s，1H)，8.61(d，1H，J＝4.4)，8.54(s，2H)，8.11(d，1H，J＝8.8)，8.02(s，1H)，7.89(t，1H)，7.83(d，1H，J＝8.8)，7.74(d，1H，J＝8.8)，7.60(d，1H，J＝7.6)，7.44(s，1H)，7.38(m，2H)，7.31(d，1H，J＝8.8)，5.31(s，2H)，3.63(t，2H)，3.58(s，4H)，3.36(s，2H)，2.68(t，3H)，2.42(s，4H)

Embodiment 89

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-morpholine-4-ketone

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make the reaction of this raw material and morpholine according to described same way as of the embodiment of the invention 77 the 3rd step, obtain title compound { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-morpholine-4-ketone 89 (110 mg, yellow solid), productive rate: 30%.

MS m/z(ESI)：472[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.57(s，1H)，8.51(d，1H，J＝7.6)，8.40(s，1H)，8.08(d，1H，J＝8.4)，7.77(d，1H，J＝8.8)，7.67(s，1H)，7.45(m，3H)，7.33(t，2H)，7.23(t，1H)，5.64(m，1H)，4.70(t，1H)，3.60(s，10H)，2.69(t，2H)，1.63(d，3H，J＝6.8)

Embodiment 90

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-(4-methyl-piperazine-1- Base)-ketone

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make the reaction of this raw material and 1-methylpiperazine according to described same way as of the embodiment of the invention 77 the 3rd step, obtain title compound { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-(4-methyl-piperazine-1-yl)-ketone 90 (130 mg, yellow solid), productive rate: 34%.

MS m/z(ESI)：485[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.62(s，1H)，7.89(s，1H)，7.87(d，1H)，7.69(dd，1H，J＝8.8)，7.48(d，2H)，7.35(t，2H)，7.28(d，1H)，7.15(s，1H)，7.03(s，1H)，6.61(s，1H)，5.70(m，1H)，3.78(m，6H)，3.48(s，1H)，2.80(t，2H)，2.48(t，4H)，2.33(s，3H)，1.73(d，3H，J＝6.8)

Embodiment 91

2-{1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-4-piperidines-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol

In 25 mL eggplant-shape bottles, add lithium aluminum hydride (36 mg, 0.957 mmol) with 3 mL tetrahydrofuran (THF)s, stir under the room temperature, drip compound { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-piperidines-1-ketone 77 (150 mg gradually, 0.319 3 mL tetrahydrofuran solutions mmol), have a large amount of bubbles to produce in the solution, and have thick solid to produce, it is yellow that reaction solution is.Reaction solution is heated to 50 ℃, stirs 4 hours afterreactions and finish, cool off reaction solution with ice bath, slowly drip methyl alcohol, reaction solution is clear.With the flushing of decompression post, concentration of reaction solution, the solid that obtains further by the separation and purification of TLC plate, obtain title product 2-{1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-4-piperidines-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol 91 (40mg, yellow solid), productive rate: 27.5%.

MS m/z(ESI)：456[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 8.79(s，1H)，8.75(s，1H)，8.39(s，1H)，8.01(d，1H，J＝8.4)，7.78(d，2H，J＝6.8)，7.50(m，3H)，7.3 1(t，2H)，7.22(t，1H)，5.64(m，1H)，4.07(s，2H)，3.67(q，2H)，3.17(m，4H)，3.11(t，2H)，1.74(s，4H)，1.65(d，3H，J＝6.8)，1.43(m，2H)

Embodiment 92

2-{1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-4-tetramethyleneimine-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol

Repeat the described experimental procedure of the embodiment of the invention 91 the first steps, the compound that different is with embodiment 78 gained { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-tetramethyleneimine-1-ketone 78 is made raw material, make this raw material and lithium aluminum hydride react according to the described same way as of the embodiment of the invention 90 the first steps, obtain title compound 2-{1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-4-tetramethyleneimine-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol 92 (60 mg, yellow solid), productive rate: 31%.

MS m/z(ESI)：442[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.91(s，1H)，8.82(s，1H)，8.34(s，1H)，8.00(dd，1H，J＝8.8)，7.88(s，1H)，7.77(d，1H，J＝8.8)，7.51(m，3H)，7.31(t，2H)，7.21(t，1H)，5.64(m，1H)，4.20(s，2H)，3.66(t，2H)，3.29(m，4H)，2.74(t，2H)，1.94(s，4H)，1.66(d，3H，J＝6.8)

Embodiment 93

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-tetramethyleneimine-1-base- Ethyl)-acid amides

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make the reaction of this raw material and 2-pyrrolidyl-1-base-ethamine according to described same way as of the embodiment of the invention 77 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-tetramethyleneimine-1-base-ethyl)-acid amides 93 (50 mg, yellow solid), productive rate: 32%.

MS m/z(ESI)：490[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.81(m，2H)，8.40(m，3H)，8.04(d，1H，J＝8.8)，7.78(d，1H，J＝8.8)，7.48(m，3H)，7.32(t，2H)，7.22(t，1H)，5.64(m，1H)，4.75(s，1H)，3.64(t，2H)，3.57(q，2H)，3.22(m，6H)，2.90(t，2H)，1.93(s，4H)，1.65(d，3H，J＝7.2)

Embodiment 94

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-piperidines-1-ethyl)- Acid amides

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make the reaction of this raw material and 2-piperidyl-1-base-ethamine according to described same way as of the embodiment of the invention 77 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-piperidines-1-ethyl)-acid amides 94 (50 mg, yellow solid), productive rate: 25%.

MS m/z(ESI)：513[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 8.82(s，1H)，8.76(d，1H，J＝6.0)，8.45(m，3H)，8.04(d，1H，J＝7.6)，7.79(d，1H，J＝8.0)，7.51(m，3H)，7.31(t，2H)，7.22(t，1H)，5.64(m，1H)，4.75(s，1H)，3.64(t，4H)，3.49(m，2H)，3.20(t，2H)，2.90(t，4H)，1.82(m，4H)，1.66(d，3H，J＝6.0)，1.23(m，2H)

Embodiment 95

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-methoxy ethyl)- Acid amides

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, make the reaction of this raw material and 2-methoxyethyl amine according to described same way as of the embodiment of the invention 77 the 3rd step, obtain title compound 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-methoxy ethyl)-acid amides 95 (50 mg, yellow solid), productive rate: 28%.

MS m/z(ESI)：460[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.76(d，1H，J＝7.2)，8.68(s，1H)，8.44(s，1H)，8.09(s，1H)，8.02(t，2H)，7.81(d，1H，J＝8.8)，7.47(d，2H，J＝7.6)，7.40(s，1H)，7.33(t，2H)，7.23(t，1H)，5.66(m，1H)，4.80(s，1H)，3.64(t，2H)，3.45(t，2H)，3.39(t，2H)，3.27(s，3H)，2.89(t，2H)，1.64(d，3H，J＝6.8)

Embodiment 96

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-ethyl)- Acid amides

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, according to described same way as of the embodiment of the invention 77 the 3rd step make this raw material and 2-morpholine-4-base-ethamine reaction, obtain title compound 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-ethyl)-acid amides 96 (85 mg, yellow solid), productive rate: 42.5%.

MS m/z(ESI)：515[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.66(m，2H)，8.41(s，1H)，8.00(m，3H)，7.76(d，1H)，7.47(d，2H，J＝7.6)，7.39(s，1H)，7.33(t，2H)，7.19(t，1H)，5.62(m，1H)，4.70(s，1H)，3.64(m，8H)，2.89(t，2H)，2.54(m，6H)，1.64(d，3H，J＝6.8)

Embodiment 97

4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(3-morpholine-4-propyl group)- Acid amides

Repeat the embodiment of the invention 77 the first steps to the described experimental procedure of three steps, compound 2-[4-(1-benzene ethylamino)-quinazoline-6-yl that different is with embodiment 77 gained]-6,7-dihydro-2H-pyrans also [3,4-c] pyrroles-4-ketone 77b makes raw material, according to described same way as of the embodiment of the invention 77 the 3rd step make this raw material and 2-morpholine-4-base-propylamine reaction, obtain title compound 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-propyl group)-acid amides 97 (86 mg, yellow solid), productive rate: 42%.

MS m/z(ESI)：529[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.88(s，2H)，8.39(s，2H)，8.12(s，1H)，8.04(d，1H，J＝8.4)，7.77(d，1H，J＝8.8)，7.51(m，3H)，7.31(t，2H)，7.21(t，1H)，5.64(m，1H)，4.83(s，1H)，3.70(m，6H)，3.33(m，2H)，2.89(m，6H)，2.54(m，2H)，1.84(m，2H)，1.67(d，3H，J＝6.8)

Embodiment 98

2-{4-(4 methylpiperazines-1-methyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol

Repeat the described experimental procedure of the embodiment of the invention 91 the first steps, the compound that different is with embodiment 90 gained { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-(4-methyl-piperazine-1-yl)-ketone 90 is made raw material, make this raw material and lithium aluminum hydride react according to the described same way as of the embodiment of the invention 91 the first steps, obtain title compound 2-{4-(4 methylpiperazines-1-methyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol 98 (90 mg, yellow solid), productive rate: 91%.

MS m/z(ESI)：471[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.68(s，1H)，8.62(s，1H)，8.37(s，1H)，8.01(dd，1H，J＝8.8)，7.73(d，1H，J＝8.8)，7.47(m，4H)，7.32(t，2H)，7.22(t，1H)，5.64(m，1H)，3.63(t，2H)，3.52(s，2H)，2.85(m，4H)，2.67(m，6H)，1.65(d，3H，J＝6.8)

Embodiment 99

[1,4 '] dipiperidino-1 '-Ji-[1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2- Hydroxyethyl)-1H-pyrroles-3-yl]-ketone

Repeat the described experimental procedure of the embodiment of the invention 53 the first steps, compound 2-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino that different is with embodiment 47 gained]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 makes raw material, make this raw material and [1 according to the described same way as of the embodiment of the invention 53 the first steps, 4 '] reaction of two piperidines, obtain title compound [1,4 '] dipiperidino-1 '-Ji-[1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-ketone 99 (120 mg, yellow solid), productive rate: 43%.

MS m/z(ESI)：667[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.20(s，1H)，8.90(s，1H)，8.61(d，1H，J＝4.4)，8.58(s，1H)，8.15(m，2H)，7.88(m，4H)，7.60(d，1H，J＝8.0)，7.55(s，1H)，7.38(t，1H)，7.29(d，1H，J＝8.8)，5.31(s，2H)，4.71(t，1H)，3.60(q，2H)，3.39(m，4H)，2.93(m，5H)，2.69(t，2H)，1.82(m，6H)，1.69(m，4H)

Embodiment 100

2-{4-morpholine-4-methyl isophthalic acid-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol

Repeat the described experimental procedure of the embodiment of the invention 91 the first steps, the compound that different is with embodiment 89 gained { 4-(2-hydroxyethyl)-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-morpholine-4-ketone 89 is made raw material, make this raw material and lithium aluminum hydride react according to the described same way as of the embodiment of the invention 91 the first steps, obtain title compound 2-{4-morpholine-4-methyl isophthalic acid-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol 100 (95mg, yellow solid), productive rate: 85%.

MS m/z(ESI)：458[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.79(s，1H)，8.70(s，1H)，8.41(s，1H)，8.01(d，1H，J＝8.8)，7.77(d，1H，J＝8.8)，7.69(s，1H)，7.49(d，3H)，7.32(t，2H)，7.22(t，1H)，5.65(m，1H)，3.97(s，2H)，3.78(m，4H)，3.66(t，2H)，3.02(m，4H)，2.74(t，2H)，1.65(d，3H，J＝6.0)

Embodiment 101

1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-methoxyl group Ethyl)-acid amides

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and 2-methoxyethyl amine according to described same way as of the embodiment of the invention 81 second step, obtain title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-methoxy ethyl)-acid amides 101 (130 mg, yellow solid), productive rate: 60%.

MS m/z(ESI)：484[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.14(s，1H)，8.79(s，1H)，8.25(dd，1H，J＝6.8)，8.19(d，1H，J＝2.0)，8.10(d，1H，J＝9.2)，8.01(t，1H)，7.89-7.94(m，2H)，7.45(m，2H)，4.80(s，1H)，3.67(t，2H)，3.46(t，2H)，3.40(m，2H)，3.29(s，3H)，2.90(t，2H)

Embodiment 102

1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-diethylamino The base ethyl)-acid amides

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make this raw material and N according to described same way as of the embodiment of the invention 81 second step, N-diethyl-1, the reaction of 2-quadrol, obtain title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-diethyllaminoethyl)-acid amides 102 (100 mg, yellow solid), productive rate: 43.29%.

MS m/z(ESI)：526[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.16(s，1H)，8.89(s，1H)，8.64(s，1H)，8.46(s，1H)，8.32(m，2H)，8.13(d，1H，J＝8.0)，8.02(m，1H)，7.92(d，1H，J＝8.8)，7.52(s，1H)，7.41(t，1H)，4.74(s，1H)，3.65(m，4H)，3.17(m，4H)，2.91(t，4H)，1.53-1.80(m，6H)

Embodiment 103

1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-piperidines-1- Ethyl)-acid amides

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and 2-piperidines-1-ethamine according to described same way as of the embodiment of the invention 81 second step, obtain title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-piperidines-1-ethyl)-acid amides 103 (154 mg, yellow solid), productive rate: 65.14%.

MS m/z(ESI)：537[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.16(s，1H)，8.91(s，1H)，8.61(s，1H)，8.50(s，1H)，8.39(t，1H)，8.31(dd，1H，J＝6.8)，8.10(dd，1H，J＝8.8)，8.01(m，1H)，7.87(d，1H，J＝9.2)，7.54(s，1H)，7.42(t，1H)，4.80(s，1H)，3.67(t，2H)，3.60(q，2H)，3.19(m，6H)，2.91(t，2H)，1.25(t，6H)

Embodiment 104

1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-morpholine-4- Ethyl)-acid amides

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and 2-morpholine-4-base-ethamine according to described same way as of the embodiment of the invention 81 second step, obtain title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-morpholine-4-ethyl)-acid amides 104 (128 mg, yellow solid), productive rate: 53.92%.

MS m/z(ESI)：540[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.14(s，1H)，8.82(s，1H)，8.63(s，1H)，8.28(dd，1H，J＝6.8)，8.22(s，1H)，8.12(dd，1H，J＝5.2)，8.02(s，1H)，7.94(m，2H)，7.46(t，2H)，4.81(s，1H)，3.66(m，6H)，3.42(m，4H)，2.90(t，2H)，2.50(m，4H)

Embodiment 105

1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-[2-(4 methyl Piperazine-1-yl)-ethyl]-acid amides

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and 2-(4-methyl-piperazine-1-yl)-ethamine according to described same way as of the embodiment of the invention 81 second step, obtain title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-[2-(4 methylpiperazines-1-yl)-ethyl]-acid amides 105 (90 mg, yellow solid), productive rate: 69.4%.

MS m/z(ESI)：553[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.05(s，1H)，8.72(s，1H)，8.64(s，1H)，8.22(dd，1H，J＝6.8)，8.13(dd，1H，J＝5.2)，8.07(s，1H)，7.90(m，3H)，7.49(t，1H)，7.43(s，1H)，4.81(s，1H)，3.65(t，2H)，3.35(m，12H)，2.89(t，2H)，2.30(t，3H)

Embodiment 106

[1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-morpholine-4-first Ketone

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and morpholine according to described same way as of the embodiment of the invention 81 second step, obtain title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 106 (158 mg, yellow solid), productive rate: 72.3%.

MS m/z(ESI)：496[M+1]

¹HNMR(400MHz，DMSOd ₆)：δ10.07(s，1H)，8.67(d，2H)，8.21(s，2H)，7.90(t，2H)，7.73(s，1H)，7.49(s，2H)，4.68(s，1H)，3.22(m，10H)，2.70(t，2H)

Embodiment 107

[1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-(4-methyl piperazine Piperazine-1-yl)-ketone

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and 4-methyl-piperazine according to described same way as of the embodiment of the invention 81 second step, obtain title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-(4-methylpiperazine-1-yl)-ketone 107 (184 mg, yellow solid), productive rate: 82.08%.

MS m/z(ESI)：509[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.97(s，1H)，8.64(d，2H)，8.18(d，2H，J＝9.2)，7.89(d，2H，J＝8.8)，7.70(s，1H)，7.48(m，2H)，4.69(s，1H)，3.63(m，6H)，2.70(t，2H)，2.44(m，4H)，2.28(s，3H)

Embodiment 108

[1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(3-morpholine -4-propyl group)-acid amides

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and 3-morpholine-4-base-propylamine according to described same way as of the embodiment of the invention 81 second step, obtain title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(3-morpholine-4-propyl group)-acid amides 108 (146 mg, yellow solid), productive rate: 59.9%.

MS m/z(ESI)：554[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.13(s，1H)，8.82(s，1H)，8.62(s，1H)，8.26(d，1H，J＝4.8)，8.20(s，1H)，8.11(d，1H，J＝8.8)，8.02(m，1H)，7.92(m，2H)，7.45(t，2H)，4.80(s，1H)，3.74(m，6H)，3.27(m，4H)，2.87(t，2H)，2.61(m，4H)，1.76(m，2H)

Embodiment 109

[1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-tetramethyleneimine-1- Ketone

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and tetramethyleneimine according to described same way as of the embodiment of the invention 81 second step, obtain title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-tetramethyleneimine-1-ketone 109 (190 mg, yellow solid), productive rate: 67.4%.

MS m/z(ESI)：480[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.12(s，1H)，8.75(s，1H)，8.63(s，1H)，8.23(m，2H)，7.89(m，3H)，7.48(t，2H)，4.80(s，1H)，3.65(m，4H)，3.48(m，2H)，2.79(t，2H)，1.87(m，4H)

Embodiment 110

[1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-piperidines-1-first Ketone

Repeat described experimental procedure of the embodiment of the invention 81 the first steps to the second step, compound 2-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that different is with embodiment 81 the first step gained]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a makes raw material, make the reaction of this raw material and piperidines according to described same way as of the embodiment of the invention 81 second step, obtain title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-piperidines-1-ketone 110 (200 mg, yellow solid), productive rate: 68.9%.

MS m/z(ESI)：494[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.91(s，1H)，8.63(s，2H)，8.19(m，2H)，7.89(m，2H)，7.65(s，1H)，7.48(m，2H)，4.69(t，1H)，3.57(m，6H)，2.68(t，2H)，1.64(m，2H)，1.53(m，4H)

Embodiment 111

4-dimethylamino-but-2-ene acid-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-three Methyl fluoride-1H-pyrroles-3-yl)-acid amides

Repeat the embodiment of the invention 67 the first steps to the described experimental procedure of eight steps, different is with compound [6-(3-amino-4-trifluoromethyl-pyrroles-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine 67i (150 mg of the 8th step gained, 0.284 mmol), 0.2 mL diisopropylethylamine, two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (86.74 mg, 0.341 mmol), 4-dimethylamino-but-2-ene acid (52 mg, 0.312 mmol) be dissolved in the 25 mL methylene dichloride, stir under the room temperature and spend the night, reaction finishes.With TLC chromatographic separation product, obtain title product 4-dimethylamino-but-2-ene acid-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-4-Trifluoromethyl-1 H-pyrroles-3-yl)-acid amides 111 (32 mg, yellow solid), productive rate: 17.6%.

MS m/z(ESI)：640[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.05(s，1H)，9.71(s，1H)，8.79(s，1H)，8.60(s，1H)，8.21(dd，1H，J＝8.8)，8.12(d，2H，J＝9.6)，8.04(s，1H)，7.90(d，1H，J＝8.8)，7.77(dd，1H，J＝9.2)，7.48(q，1H)，7.32(m，3H)，7.19(m，1H)，6.78(m，1H)，6.63(d，1H)，5.27(s，2H)，3.55(m，2H)，2.47(s，6H)

Embodiment 112

6-[3,4-two-(diethylin methyl)-pyrroles-1-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-benzene Base]-amine

The first step

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3; 4-dicarboxyl diethyl ester is in 250 mL eggplant-shape bottles; add embodiment 1 the 5th step gained compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (7.10 g successively; 0.014 mol); 1H-pyrroles-3; 4-dicarboxylate (2.97 g; 0.014 mol), potassiumphosphate (8.92 g, 0.042 mol); cuprous iodide (2.76 g; 0.014 mol), N, N '-dimethyl-1; 2-quadrol (1.23 g; 0.014 mol) with 100mL N, dinethylformamide, the mixed solution of gained are heated to 70 ℃ under nitrogen protection; stirring is spent the night, and reaction finishes.Reaction solution is poured in the 1000 mL water, stir, filter, solid further passes through column chromatographic isolation and purification, obtain this title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarboxyl diethyl ester 112a (3.3g, yellow solid), productive rate: 40%.

MS m/z(ESI)：588[M-1]

Second step

(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-hydroxymethyl-1H-pyrroles-3-yl)-methyl alcohol

In 250 mL eggplant-shape bottles, with lithium aluminum hydride (581 mg, 15.3mmol) be dissolved in the 75 mL tetrahydrofuran (THF)s, the solution of gained is under condition of ice bath, be cooled to 0 ℃, stir adding above-mentioned steps gained compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino down]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarboxyl diethyl ester 112a (1.5 g, 2.55 mmol), keep 2 hours afterreactions of ice bath reaction to finish.In reaction solution, drip 7.5 mL water, 7.5 mL 1N sodium hydroxide solution, stir and add 100 mL ethyl acetate down, diatomite filtration, with the washing of 200mL ethyl acetate, filtrate is washed with saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, concentrate under the filtrate decompression, obtain this compound (1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-hydroxymethyl-1H-pyrroles-3-yl)-methyl alcohol 112b (yellow solid) directly carries out next step reaction without separating.

MS m/z(ESI)：503[M-1]

The 3rd step

1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3, the 4-dicarbaldehyde

In 250 mL eggplant-shape bottles, with adjacent iodoxybenzene formic acid (2.86 g, 10.2mmol)) be dissolved in the 50 mL dimethyl sulfoxide (DMSO), the compound of adding above-mentioned steps gained under stirring (1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-hydroxymethyl-1H-pyrroles-3-yl)-methyl alcohol 112b (1.287g, 2.55mmol) the 25mL dimethyl sulphoxide solution, the mixed solution of gained at room temperature stirred 2 hours, and reaction finishes.Reaction solution is poured in the 500 mL frozen water, with ethyl acetate (250 mL * 4) extraction, organic phase is washed with saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of column chromatography, obtain this title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarbaldehyde 112c (760 mg, yellow solid), productive rate: 59.4%.MS m/z(ESI)：499[M-1]

The 4th step

6-[3,4-two-(diethylin methyl)-pyrroles-1-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine

Compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino with the above-mentioned steps gained]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarbaldehyde 112c (100 mg, 0.2 mmol) be dissolved in the 5 mL methylene dichloride, stir adding diethylamine (44 mg, 0.6 mmol) down, continue to stir after 6 hours, add triacetoxy boron hydride (170mg, 0.8 mmol), stirring is spent the night, and reaction finishes.In reaction solution, add 5 mL saturated nacl aqueous solutions, the 1mL saturated sodium bicarbonate solution, methylene dichloride (20 mL * 3) extraction, organic phase is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, concentrate, the residue that obtains is further by the separation and purification of TLC plate, obtain this title product { 6-[3,4-two-(diethylin methyl)-pyrroles-1-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 112 (73 mg, yellow solid), productive rate: 59.4%.

MS m/z(ESI)：615[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.04(s，1H)，8.78(s，1H)，8.59(s，1H)，8.14(dd，1H，J＝8.8)，8.07(d，1H，J＝2.4)，7.90(d，1H，J＝9.2)，7.83(m，3H)，7.47(q，1H)，7.32(m，3H)，7.19(t，1H)，5.27(s，2H)，3.93(s，4H)，2.91(q，8H)，1.14(t，12H)

Embodiment 113

[6-(3,4-, two-morpholine-4-methylpyrrole-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine

Repeat the embodiment of the invention 112 the first steps to the described experimental procedure of four steps, different is with compound 1-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino of the 3rd step gained]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarbaldehyde 112c makes raw material, make the reaction of this raw material and morpholine according to described same way as of the embodiment of the invention 112 the 4th step, [6-(3 to obtain title compound, 4-two-morpholine-4-methylpyrrole-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 113 (73 mg, yellow solid), productive rate: 59.4%.

MS m/z(ESI)：616[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.78(s，1H)，8.54(m，2H)，8.14(dd，1H，J＝9.2)，8.00(d，1H，J＝2.4)，7.83(d，1H，J＝8.8)，7.73(dd，1H，J＝8.8)，7.47(m，3H)，7.33(m，3H)，7.19(t，1H)，5.28(s，2H)，3.58(s，8H)，3.44(s，4H)，2.41(s，8H)

Embodiment 114

6-(3,4-, two-piperidines-1-methylpyrrole-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine

Repeat the embodiment of the invention 112 the first steps to the described experimental procedure of four steps, different is with compound 1-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino of the 3rd step gained]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarbaldehyde 112c makes raw material, make the reaction of this raw material and piperidines according to described same way as of the embodiment of the invention 112 the 4th step, obtain title compound 6-(3,4-two-piperidines-1-methylpyrrole-1-yl)-quinazoline-4-yl]-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine 114 (100 mg, yellow solid), productive rate: 78.1%.

MS m/z(ESI)：640[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.00(s，1H)，8.72(s，1H)，8.58(s，1H)，8.13(dd，1H，J＝8.8)，8.05(s，1H)，7.88(d，1H，J＝8.4)，7.72(m，3H)，7.48(q，1H)，7.33(m，3H)，7.19(t，1H)，5.27(s，2H)，3.86(s，4H)，2.83(s，8H)，1.63(s，8H)，1.53(s，4H)

Embodiment 115

6-[3,4-two-(dimethylaminomethyl) pyrroles-1-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluorine benzyloxy)-benzene Base]-amine

Repeat the embodiment of the invention 112 the first steps to the described experimental procedure of four steps, different is with compound 1-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino of the 3rd step gained]-quinazoline-6-yl }-1H-pyrroles-3,4-dicarbaldehyde 112c makes raw material, make the reaction of this raw material and dimethylamine according to described same way as of the embodiment of the invention 112 the 4th step, obtain title compound { 6-[3,4-two-(dimethylaminomethyl) pyrroles-1-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-amine 115 (40 mg, yellow solid), productive rate: 35.7%.

MS m/z(ESI)：560[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.59(s，1H)，9.24(s，1H)，8.60(s，1H)，8.22(d，1H，J＝2.4)，8.14(dd，1H，J＝8.8)，8.05(s，2H)，7.97(dd，1H，J＝8.8)，7.91(d，1H，J＝8.8)，7.48(q，1H)，7.31(m，3H)，7.16(t，1H)，5.27(s，2H)，4.28(s，4H)，2.66(s，12H)

Embodiment 116

2-{1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-[(2-morpholine-4-ethylamino)-first Base]-1H-pyrroles-3-yl }-ethanol

The first step

2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-methylol-1H-pyrroles-3-yl)-ethanol

In 500 mL single port flasks, with lithium aluminum hydride (1.48 g, 38.8mmol) be dissolved in the 150 mL tetrahydrofuran (THF)s, reaction solution under condition of ice bath, is cooled to 0～5 ℃, stirs compound 2-{4-[3-chloro-4-(3-fluoro-the benzyloxy)-phenylamino that in batches adds embodiment 10 gained down]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] (10 g, 19.4mmol), the mixed solution of gained at room temperature stirs following 3 hours afterreactions and finishes pyrroles-4-ketone 10.Mixed solvent quencher reaction with 100 mL tetrahydrofuran (THF)s and 50 mL water.Carry out separatory with pouring in the reaction solution in 150 mL water and the 150 mL ethyl acetate, with the further aqueous layer extracted of ethyl acetate (100mL * 3), the organic phase that merges is washed with saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, concentrate under the filtrate decompression, the solid that obtains washs with 5 mL ethyl acetate, obtain this title product 2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-methylol-1H-pyrroles-3-yl)-ethanol 116a (5.23g, gray solid), productive rate: 52.1%.

MS m/z(ESI)：519[M+1]

Second step

1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde

In 50 mL single port flasks; with adjacent iodoxy phenylformic acid (540 mg; 1.93mmol) be dissolved in the 5 mL dimethyl sulfoxide (DMSO); stir dropwise add down with the compound 2-of above-mentioned steps gained (1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-methylol-1H-pyrroles-3-yl)-ethanol 116a (1g; 1.93 3 mL dimethyl sulphoxide solutions mmol); after the reaction solution of gained at room temperature stirred 1 hour, reaction finished.Reaction solution is joined in 150 mL, 5% sodium hydrogen carbonate solution, there is solid to separate out, filter, dry under the vacuum, obtain this title product 1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b (1.1g, the khaki color solid) thick product directly carries out next step reaction without separating.

MS m/z(ESI)：518[M+1]

The 3rd step

2-{1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-3-yl }-ethanol

Crude product 1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino with the above-mentioned steps gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b (500 mg, 0.71 mmol) be dissolved in the 20 mL methylene dichloride, stir and add 2-morpholine-4-base-ethamine (185 mg down, 1.42 mmol), stir after 3 hours under the room temperature and add sodium triacetoxy borohydride (300 mg, 1.42mmol), the mixed solution of gained at room temperature stirs and spends the night, and reaction finishes.In reaction solution, add 5 mL saturated sodium bicarbonate solutions and 5 mL saturated nacl aqueous solutions, with methylene dichloride (100mL * 3) extractive reaction liquid, the organic phase that merges is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, the solid that obtains further carries out separation and purification by the TLC plate, obtain this title product 2-{1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-3-yl }-ethanol 116 (90 mg, yellow solid), productive rate: 20%.

MS m/z(ESI)：632[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ 9.75(s，1H)，8.52(s，1H)，8.48(s，1H)，8.06(d，1H)，7.99(s，1H)，7.81(d，1H，J＝8.8)，7.71(d，1H)，7.45(m，2H)，7.31(m，4H)，7.15(t，1H)，5.25(s，2H)，3.60(s，4H)，3.54(t，4H)，2.65(m，4H)，2.39(t，2H)，2.33(t，4H)

Embodiment 117

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-(6-{5-[(2-methoxyl group-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinoline Azoles quinoline-4-yl)-amine

Repeat described experimental procedure of the embodiment of the invention 52 the first steps to the second step, compound 3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with embodiment 52 the first step gained]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrrole-2-aldehyde 52a makes raw material, make the reaction of this raw material and 2-methoxyethyl amine according to described same way as of the embodiment of the invention 52 second step, obtain title compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-(6-{5-[(2-methoxyl group-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 117 (55 mg, yellow solid), productive rate 51.8%.

MS m/z(ESI)：532[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.94(s，1H)，9.67(s，1H)，8.54(s，1H)，8.44(s，1H)，8.03(m，2H)，7.75(m，2H)，7.47(m，1H)，7.3 1(m，3H)，7.20(m，1H)，6.80(t，1H)，6.44(t，1H)，5.27(s，2H)，3.87(s，2H)，3.39(t，2H)，3.19(s，3H)，2.68(t，2H)

Embodiment 118

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-(6-{5-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinoline Azoles quinoline-4-yl)-amine

Repeat described experimental procedure of the embodiment of the invention 52 the first steps to the second step, compound 3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with embodiment 52 the first step gained]-quinazoline-6-yl }-1-triisopropyl silicon-1H-pyrrole-2-aldehyde 52a makes raw material, make the reaction of this raw material and 2-morpholine-4-base-ethamine according to described same way as of the embodiment of the invention 52 second step, obtain title compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-(6-{5-[(2-morpholine-4-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 118 (26 mg, yellow solid), productive rate: 48.5%.

MS m/z(ESI)：587[M+1]

¹H NMR(400MHz，CDCl3)：δ10.60(s，1H)，8.61(s，1H)，7.71(m，4H)，7.44(d，1H，J＝8.8)，7.33(m，1H)，7.20(m，2H)，7.16(m，1H)，6.87(d，1H，J＝8.8)，6.76(s，1H)，6.28(s，1H)，5.07(s，2H)，3.87(s，2H)，3.71(t，4H)，2.50(m，8H)

Embodiment 119

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-methylsulfonyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Repeat the embodiment of the invention 51 described experimental procedures; different is so that compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 of the invention process 42 gained is made raw material; make the reaction of this raw material and methylsulfonyl chloride according to the embodiment of the invention 51 described same way as; obtain title compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-methylsulfonyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 119 (26 mg; yellow solid), productive rate: 48.5%.

MS m/z (ESI)：523[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.24(s，1H)，9.04(s，1H)，8.94(s，1H)，8.19(d，1H，J＝8.8)，8.14(s，1H)，7.86(s，1H)，7.75(d，1H，J＝8.4)，7.48(d，1H，J＝6.0)，7.39(m，1H)，7.30(m，5H)，7.81(m，1H)，5.27(s，2H)，3.55(s，3H)

Embodiment 120

2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-morpholine-4-methyl isophthalic acid H-pyrroles-3-yl }-ethanol

The first step

In 25 mL eggplant-shape bottles, add lithium aluminum hydride (50 mg, 1.31 mmol) with 3 mL tetrahydrofuran (THF)s, ice bath cooling drips compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl down gradually]-3 mL tetrahydrofuran solutions of morpholine-4-ketone 106 (150 mg, 0.319 mmol).Reaction solution is at room temperature stirred 4 hours afterreactions to finish, slowly drip methyl alcohol, reaction solution under reduced pressure concentrates, the residue that obtains carries out separation and purification with the TLC plate, obtain title product 2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-morpholine-4-methyl isophthalic acid H-pyrroles-3-yl }-ethanol 120 (54 mg, yellow solid), productive rate: 85.54%.

MS m/z(ESI)：482[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.88(s，1H)，8.60(s，1H)，8.53(s，1H)，8.18(m，2H)，7.86(d，2H，J＝8.4)，7.49(m，1H)，7.42(d，2H)，4.90(s，1H)，3.62(m，6H)，3.37(m，2H)，2.69(t，2H)，2.43(m，4H)

Embodiment 121

2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-piperidines-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol

Repeat the described experimental procedure of the embodiment of the invention 120 the first steps, compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl that different is with embodiment 110 final gained]-piperidines-1-ketone 110 makes raw material, make the reaction of this raw material and lithium aluminum hydride according to the described same way as of the embodiment of the invention 120 the first steps, obtain title compound 2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-piperidines-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol 121 (57 mg, yellow solid), productive rate: 78.13%.

MS m/z(ESI)：480[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ 9.90(s，1H)，8.55(d，2H)，8.15(m，2H)，7.83(d，2H，J＝8.8)，7.46(t，1H)，7.39(d，2H，J＝10.0)，5.20(s，1H)，3.62(m，2H)，3.29(s，2H)，2.67(t，2H)，2.38(m，4H)，1.49(m，4H)，1.41(m，2H)

Embodiment 122

2-[1-[4-((3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(4-methylpiperazine-1-methyl)-1H-pyrroles-3- Base]-ethanol

Repeat the described experimental procedure of the embodiment of the invention 120 the first steps, compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl that different is with embodiment 107 final gained]-(4-methylpiperazine-1-yl)-ketone 107 makes raw material, make the reaction of this raw material and lithium aluminum hydride according to the described same way as of the embodiment of the invention 120 the first steps, obtain title compound 2-[1-[4-((3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(4-methylpiperazine-1-methyl)-1H-pyrroles-3-yl]-ethanol 122 (40 mg, yellow solid), productive rate: 45.7%.

MS m/z(ESI)：480[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.90(s，1H)，8.59(d，2H)，8.18(d，2H)，8.13(d，1H，J＝8.8)，7.86(d，2H，J＝8.8)，7.48(t，1H)，7.38(d，2H)，5.00(s，1H)，3.62(s，2H)，3.33(s，2H)，2.67(t，2H)，2.42(m，8H)，2.15(s，3H)

Embodiment 123

2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-diethylin methyl isophthalic acid H-pyrroles -3-yl)-ethanol

Repeat the embodiment of the invention 116 the first steps to the described experimental procedure of three steps, different is with compound 1-{4-[3-chloro-4-(3--fluorine the benzyloxy)-phenylamino of embodiment 116 second step gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b makes raw material, make the reaction of this raw material and diethylamine according to described same way as of the embodiment of the invention 116 the 3rd step, obtain title compound 2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-diethylin methyl isophthalic acid H-pyrroles-3-yl)-ethanol 123 (14 mg, yellow solid), productive rate: 5%.

MS m/z(ESI)：674[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.54(s，1H)，8.50(s，1H)，8.11(dd，1H，J＝8.8)，8.01(s，1H)，7.83(d，1H，J＝8.8)，7.74(dd，1H，J＝8.8)，7.47(m，1H)，7.42(s，1H)，7.35(m，4H)，7.19(t，1H)，5.27(s，2H)，3.62(t，2H)，3.42(s，2H)，2.68(t，2H)，2.53(q，4H)，1.02(t，6H)

Embodiment 124

2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-dimethylamino methyl-1H-pyrroles -3-yl)-ethanol

Repeat the embodiment of the invention 116 the first steps to the described experimental procedure of three steps, different is with compound 1-{4-[3-chloro-4-(3--fluorine the benzyloxy)-phenylamino of embodiment 116 second step gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b makes raw material, make the reaction of this raw material and dimethylamine according to described same way as of the embodiment of the invention 116 the 3rd step, obtain title compound 2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-dimethylamino methyl-1H-pyrroles-3-yl)-ethanol 124 (122 mg, yellow solid), productive rate: 38.5%.

MS m/z(ESI)：546[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.54(s，1H)，8.51(d，1H，J＝2.4)，8.10(dd，1H)，8.01(d，1H，J＝2.4)，7.83(d，1H，J＝8.8)，7.74(dd，1H，J＝8.8)，7.48(m，1H)，7.43(d，1H)，7.35(m，4H)，7.29(t，1H)，5.27(s，2H)，5.10(s，1H)，3.61(t，2H)，3.28(s，2H)，2.66(t，2H)，2.19(s，6H)

Embodiment 125

4-({ [1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles -3-methyl]-amino }-methyl)-1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

Repeat the embodiment of the invention 116 the first steps to the described experimental procedure of three steps, different is with compound 1-{4-[3-chloro-4-(3--fluorine the benzyloxy)-phenylamino of embodiment 116 second step gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b makes raw material, make this raw material and 4-aminomethyl-1 according to described same way as of the embodiment of the invention 116 the 3rd step, 1-dioxo-six hydrogen-1 λ ^*6 ^*The reaction of-thiapyran-4-alcohol, obtain title compound 4-({ [1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-methyl]-amino-methyl)-1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 125 (103 mg, yellow solid), productive rate: 31.3%.

MS m/z(ESI)：680[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.55(s，1H)，8.50(s，1H)，8.10(d，1H，J＝9.6)，8.01(s，1H)，7.84(d，1H，J＝8.8)，7.75(dd，1H，J＝8.8)，7.49(m，1H)，7.43(s，1H)，7.36(m，4H)，7.20(m，1H)，5.27(s，2H)，3.64(t，2H)，3.58(s，2H)，3.10(m，4H)，2.67(t，2H)，2.50(m，2H)，2.10(m，2H)，1.60(m，2H)

Embodiment 126

2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-{[(1,1-dioxo-six hydrogen -1 λ ^* 6 ^* -thiapyran-4 methyl)-amino]-methyl }-1H-pyrroles-3-yl)-ethanol

Repeat the embodiment of the invention 116 the first steps to the described experimental procedure of three steps, different is with compound 1-{4-[3-chloro-4-(3--fluorine the benzyloxy)-phenylamino of embodiment 116 second step gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b makes raw material, make this raw material and C-(1,1-dioxo-six hydrogen-1 λ according to described same way as of the embodiment of the invention 116 the 3rd step ^*6 ^*-t thiapyran-4-yl)-reaction of methylamine, obtain title compound 2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-{[(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4 methyl)-amino]-methyl }-1H-pyrroles-3-yl)-ethanol 126 (115 mg, yellow solid), productive rate: 35.8%.

MS m/z(ESI)：664[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.82(s，1H)，8.55(m，2H)，8.10(d，1H，J＝8.8)，8.03(d，1H，J＝2.4)，7.86(d，1H，J＝8.8)，7.77(dd，1H，J＝7.2)，7.53(m，2H)，7.39(s，1H)，7.35(m，3H)，7.19(m，1H)，5.27(s，2H)，3.74(s，2H)，3.66(t，2H)，3.18(m，3H)，2.97(d，2H)，2.71(m，4H)，2.00(m，4H)

Embodiment 127

2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl } 4-[(2-first sulphur ether ethylamino)-first Base]-1H-pyrroles-3-yl }-ethanol

Repeat the embodiment of the invention 116 the first steps to the described experimental procedure of three steps; different is with compound 1-{4-[3-chloro-4-(3--fluorine the benzyloxy)-phenylamino of embodiment 116 second step gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 116b makes raw material; make the reaction of this raw material and 2-methylsulfonyl ethamine according to described same way as of the embodiment of the invention 116 the 3rd step; obtain title compound 2-(1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-4-[(2-methylsulfonyl ethylamino)-methyl]-1H-pyrroles-3-yl-ethanol 127 (97 mg; yellow solid), productive rate: 32.1%.

MS m/z(ESI)：624[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.77(s，1H)，8.55(m，1H)，8.51(s，1H)，8.10(dd，1H，J＝9.6)，8.01(d，1H，J＝2.8)，7.85(d，1H，J＝8.8)，7.76(dd，1H，J＝8.8)，7.49(m，2H)，7.37(m，4H)，7.19(m，1H)，5.27(s，2H)，3.65(t，4H)，3.28(m，2H)，3.02(m，2H)，2.68(t，2H)，2.51(t，3H)

Embodiment 128

[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-morpholine-4-ethyl)-1H-pyrroles -3-yl]-morpholine-4-ketone

The first step

Methylsulfonic acid 2-[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(morpholine-4-carbonyl)-1H-pyrroles-3-yl]-ethyl ester

In 50 mL eggplant-shape bottles, with [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-yl]-morpholine-4-base-ketone 27 (500 mg, 0.83 mmol) be dissolved in the 20 mL tetrahydrofuran (THF)s, stir and add 0.23 mL triethylamine down, the mixed solution of gained drips methylsulfonyl chloride (190 mg gradually under the ice bath cooling, 1.66mmol) 5 mL tetrahydrofuran solutions, reaction solution at room temperature stirs 1 hour afterreaction and finishes.Reaction solution is joined in the 50 mL water, there is yellow solid to separate out, filter, the solid that obtains is dry under vacuum, obtain this title product methylsulfonic acid 2-[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(morpholine-4-carbonyl)-1H-pyrroles-3-yl]-ethyl ester 128a (500 mg, yellow solid), productive rate: 90%.

MS m/z(ESI)：681[M+1]

Second step

[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-morpholine-4-ethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone

In 25 mL eggplant-shape bottles, compound methylsulfonic acid 2-[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino with the above-mentioned steps gained]-quinazoline-6-yl }-4-(morpholine-4-carbonyl)-1H-pyrroles-3-yl]-ethyl ester 128a (80 mg, 0.118 mmol) be dissolved in 2 mL[1,4] in the dioxane, mixed solution under agitation adds 1 mL morpholine, reacting by heating liquid to 70 ℃ reacts 4 hours afterreactions and finishes.Reaction solution is cooled to room temperature, be added drop-wise in the 50 mL water, separate out white solid, filter, the crude product of gained further carries out separation and purification by the TLC plate, obtain this title product [1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-morpholine-4-ethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 128 (50 mg, yellow solid), productive rate: 64%.

MS m/z(ESI)：672[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，9.00(s，1H)，8.60(s，1H)，8.20(d，2H)，7.90(m，3H)，7.80(s，1H)，7.47(m，1H)，7.32(m，3H)，7.19(m，1H)，5.28(s，2H)，3.97(s，2H)，3.81(s，2H)，3.67(s，8H)，3.48(s，2H)，3.40(s，2H)，3.14(s，2H)，3.04(s，2H)

Embodiment 129

[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-methoxy ethyl)-1H-pyrroles -3-yl]-morpholine-4-ketone

Repeat described experimental procedure of the embodiment of the invention 128 the first steps to the second step, compound methylsulfonic acid 2-[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with embodiment 128 the first step gained]-quinazoline-6-yl }-4-(morpholine-4-carbonyl)-1H-pyrroles-3-yl]-ethyl ester 128a makes raw material, make the reaction of this raw material and sodium methylate according to described same way as of the embodiment of the invention 128 second step, obtain title compound [1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-methoxy ethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 129 (25mg, yellow solid), productive rate: 32%.

MS m/z(ESI)：617[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ 10.10(s，1H)，8.80(s，1H)，8.57(s，1H)，8.18(d，1H)，8.09(s，1H)，7.84(m，3H)，7.50(m，2H)，7.30(m，3H)，7.18(t，1H)，5.27(s，2H)，3.62(s，8H)，3.53(t，2H)，3.27(s，3H)，2.78(t，2H)

Embodiment 130

[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-diethyllaminoethyl)-1H-pyrrole Cough up-the 3-yl]-morpholine-4-ketone

Repeat described experimental procedure of the embodiment of the invention 128 the first steps to the second step, compound methylsulfonic acid 2-[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with embodiment 128 the first step gained]-quinazoline-6-yl }-4-(morpholine-4-carbonyl)-1H-pyrroles-3-yl]-ethyl ester 128a makes raw material, make the reaction of this raw material and diethylamine according to described same way as of the embodiment of the invention 128 second step, obtain title compound [1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-diethyllaminoethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 130 (40 mg, yellow solid), productive rate: 48%.

MS m/z(ESI)：657[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，9.00(s，1H)，8.62(s，1H)，8.20(d，1H，J＝10.0)，8.14(s，1H)，7.92(m，3H)，7.90(s，1H)，7.47(m，1H)，7.32(m，3H)，7.19(m，1H)，5.28(s，2H)，3.67(s，8H)，3.50(t，2H)，3.19(q，4H)，2.96(t，2H)，1.26(t，6H)

Embodiment 131

[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-dimethylaminoethyl)-1H-pyrrole Cough up-the 3-yl]-morpholine-4-ketone

Repeat described experimental procedure of the embodiment of the invention 128 the first steps to the second step, compound methylsulfonic acid 2-[1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino that different is with embodiment 128 the first step gained]-quinazoline-6-yl }-4-(morpholine-4-carbonyl)-1H-pyrroles-3-yl]-ethyl ester 128a makes raw material, make the reaction of this raw material and dimethylamine according to described same way as of the embodiment of the invention 128 second step, obtain title compound [1-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-4-(2-dimethylaminoethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 131 (180 mg, yellow solid), productive rate: 65%.

MS m/z(ESI)：630[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，8.60(d，2H，J＝9.2)，8.13(dd，1H，J＝9.2)，8.00(d，1H，J＝2.0)，7.84(d，1H，J＝8.8)，7.73(dd，1H，J＝8.8)，7.66(d，1H，J＝1.6)，7.46(m，2H)，7.30(m，3H)，7.18(t，1H)，5.26(s，2H)，3.60(s，8H)，2.66(t，2H)，2.44(t，2H)，2.17(s，6H)

Embodiment 132

[1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3- Base]-morpholine-4-ketone

The first step

[1-(4-luorobenzyl)-1H-indazole-5-yl]-(6-iodo-quinazoline-4-yl)-amine

Repeat described experimental procedure of the 5th step of the embodiment of the invention 1, different is to make raw material with the compound 6-iodo-3H-quinazoline-4-one 1f that embodiment 1 the 4th goes on foot gained, make the reaction of this raw material and 1-(4-luorobenzyl)-1H-indazole-5-amine according to described same way as of the 5th step of the embodiment of the invention 1, obtain title compound [1-(4-luorobenzyl)-1H-indazole-5-yl]-(6-iodo-quinazoline-4-yl)-amine 132a (13 g, pale solid), productive rate 71.8%.

MS m/z(ESI)：496[M+1]

Second step

2-(4-{3-[2-(4-luorobenzyl 1)-4-vinyl-2H-pyrazole-3-yl]-allyl amino }-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone

In 250 mL eggplant-shape bottles, compound [1-(4-luorobenzyl)-1H-indazole-5-yl]-(6-iodo-quinazoline-4-yl)-amine 132a (5 g with the above-mentioned steps gained, 10 mmol), 6,7-dihydro-2H-pyrans is [3,4-c] pyrroles-4-ketone 10b (1.78 g also, 13 mmol), potassiumphosphate (6.37 g, 30 mmol), cuprous iodide (2.86 g, 15mmol) be dissolved in 50 mL N, in the dinethylformamide, mixture under agitation adds N, N '-dimethyl-1,2-quadrol (1.32 g, 15 mmol), reacting by heating liquid to 65 ℃, stirring is spent the night.Reaction solution is poured in the 250 mL frozen water, there is blackish green solid to separate out, suction filtration, the solid that obtains is with 300 mL methanol wash, and solid is dry under vacuum, obtain this title product 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b (5.1 g, blackish green solid), directly carry out next step reaction without separating.

MS m/z(ESI)：478[M+1]

The 3rd step

[1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone

With 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b (150 mg, 0.3 mmol) add in the 10 mL eggplant-shape bottles with 1 mL morpholine, mixture heating up to 120 ℃, stirring is spent the night, and reaction finishes.Reaction solution under reduced pressure concentrates, the residue dichloromethane extraction that obtains, organic phase under reduced pressure concentrates, the solid that obtains further separates by the TLC plate purifies, obtain yellow solid, vacuum-drying obtains title product [1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-morpholine-4-ketone 132 (27mg, light yellow solid), productive rate: 15%.

MS m/z(ESI)：592[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.49(s，1H)，9.06(m，1H)，8.51(s，1H)，8.31(s，1H)，8.18(dd，2H，J＝8.8)，7.92(s，1H)，7.88(m，2H)，7.76(d，1H，J＝8.8)，7.63(s，1H)，7.38(m，1H)，7.10(m，3H)，5.72(s，2H)，4.77(s，1H)，3.62(m，10H)，2.71(t，2H)

Embodiment 133

1-{4-[1-(4-luorobenzyl)-1H indazole-5-oxygen base]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3- Base]-(4-methyl-piperazine-1-yl)-ketone

Repeat the embodiment of the invention experimental procedure in three steps of 132 the first steps to the, different is with the compound of the second step gained with 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b makes raw material, make the reaction of this raw material and 1-methylpiperazine according to described same way as of the embodiment of the invention 132 the 3rd step, obtain title compound 1-{4-[1-(4-luorobenzyl)-1H indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-yl]-(4-methyl-piperazine-1-yl)-ketone 133 (10 mg, yellow solid), productive rate: 5.5%.

MS m/z(ESI)：605[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.30(s，1H)，8.75(s，1H)，8.52(s，1H)，8.31(s，1H)，8.12(m，2H)，7.86(m，1H)，7.76(m，3H)，7.52(s，1H)，7.49(m，1H)，7.07(m，3H)，5.72(s，2H)，4.76(s，1H)，3.59(m，6H)，2.70(s，2H)，2.51(m，4H)，2.21(m，3H)

Embodiment 134

1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic Acid-(2-diethyllaminoethyl)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 132 the first steps to the, different is with the compound of the second step gained with 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b makes raw material, make this raw material and N according to described same way as of the embodiment of the invention 132 the 3rd step, N-diethyl-1, the reaction of 2-quadrol, obtain title compound 1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-diethyllaminoethyl)-acid amides 134 (40 mg, yellow solid), productive rate: 21.5%.

MS m/z(ESI)：621[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.28(s，1H)，9.00(s，1H)，8.54(s，1H)，8.33(m，1H)，8.32(s，1H)，8.17(m，1H)，8.13(dd，1H，J＝9.2)，7.89(m，2H)，7.77(d，1H，J＝9.2)，7.59(s，1H)，7.38(m，1H)，7.11(m，3H)，5.72(s，2H)，4.80(s，1H)，3.66(t，2H)，3.45(t，2H)，2.91(m，8H)，1.10(s，6H)

Embodiment 135

1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic Acid-(3-morpholine-4-propyl group)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 132 the first steps to the, different is with the compound of the second step gained with 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b makes raw material, make the reaction of this raw material and 3-morpholine-4-propylamine according to described same way as of the embodiment of the invention 132 the 3rd step, obtain title compound 1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid (3-morpholine-4-propyl group)-acid amides 135 (20 mg, yellow solid), productive rate: 10.3%.

MS m/z(ESI)：649[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.19(s，1H)，8.90(s，1H)，8.35(s，1H)，8.26(s，1H)，8.17(s，1H)，7.98(s，1H)，7.96(dd，1H，J＝8.8)，7.74(m，2H)，7.58(d，1H，J＝8.8)，7.41(s，1H)，7.19(m，1H)，6.92(m，3H)，5.54(s，2H)，4.69(s，1H)，3.48(m，8H)，3.07(m，2H)，2.71(m，2H)，2.20(m，6H)

Embodiment 136

1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic Acid-(2-piperidines-1-ethyl)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 132 the first steps to the, different is with the compound of the second step gained with 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b makes raw material, make the reaction of this raw material and 2-piperidines-1-ethamine according to described same way as of the embodiment of the invention 132 the 3rd step, obtain title compound 1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid (2-piperidines-1-ethyl)-acid amides 136 (17 mg, yellow solid), productive rate: 8%.

MS m/z(ESI)：633[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.07(s，1H)，8.80(s，1H)，8.54(s，1H)，8.26(s，2H)，8.17(m，1H)，8.11(dd，1H，J＝8.8)，7.91(d，1H，J＝8.8)，7.76(s，2H)，7.47(s，1H)，7.38(m，1H)，7.11(m，3H)，5.72(s，2H)，4.80(s，1H)，3.67(t，2H)，3.55(m，2H)，3.10(m，4H)，2.92(m，4H)，1.72(s，4H)，1.44(m，2H)

Embodiment 137

1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic Acid-(2-tetramethyleneimine-1-base-ethyl)-acid amides

Repeat the embodiment of the invention experimental procedure in three steps of 132 the first steps to the, different is with the compound of the second step gained with 2-(4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b makes raw material, make the reaction of this raw material and 2-tetramethyleneimine-1-base-ethamine according to described same way as of the embodiment of the invention 132 the 3rd step, obtain title compound 1-{4-[1-(4-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-carboxylic acid-(2-tetramethyleneimine-1-base-ethyl)-acid amides 137 (16 mg, yellow solid), productive rate: 8.6%.

MS m/z(ESI)：619[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.08(s，1H)，8.84(s，1H)，8.54(s，1H)，8.28(s，1H)，8.18(s，1H)，8.10(m，1H)，7.91(d，1H)，7.78(m，2H)，7.48(s，1H)，7.39(s，1H)，7.39(m，1H)，7.11(m，3H)，5.72(s，2H)，4.80(s，1H)，3.67(m，2H)，3.54(m，2H)，3.10(m，4H)，2.93(m，4H)，1.91(m，4H)

Embodiment 138

1-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-third-2- Alcohol

The first step

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (447 mg with the invention process 42 gained, 1.007 mmol) be dissolved in 5 mLN, in the dinethylformamide, solution is under the ice bath cooling, add sodium hydride (16 mg, 0.4 mmol), mixed solution rises to room temperature, stir after 30 minutes, add 2-chloromethyloxirane (125 mg, 1.351 mmol), reacting by heating liquid to 60 ℃, stir 2 hours afterreactions and finish, add water quencher reaction.Reaction solution extracts with ethyl acetate (100 mL * 3), the organic phase anhydrous sodium sulfate drying that merges, filter, concentrate under the filtrate decompression, the residue of gained further passes through column chromatographic isolation and purification, obtain this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 138a (200 mg, yellow solid), productive rate: 39.8%.

MS m/z(ESI)：501[M+1]

Second step

1-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-propan-2-ol

With morpholine (35 mg, 0.402 mmol) be dissolved in 0.5 mL N, dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (7 mg, 0.175 mmol), stir compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 138a (68 mg that add the above-mentioned steps gained after 20 minutes under the room temperature, 0.136 0.5 mLN mmol), the solution of dinethylformamide, stir under the room temperature and spend the night, the mixed solution of gained obtains this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 138 (36 mg by the further separation and purification of TLC plate, yellow solid), productive rate: 45%.

MS m/z(ESI)：588[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ9.70(s，1H)，8.50(s，1H)，8.02(s，1H)，7.71(m，2H)，7.42(m，1H)，7.40(t，1H)，7.33(m，3H)，7.19(t，2H)，6.87(m，2H)，6.64(m，1H)，5.27(s，2H)，4.10(m，1H)，4.00(m，1H)，3.85(m，1H)，3.61(m，4H)，2.40(m，2H)，2.19(m，4H)

Embodiment 139

2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-tetramethyleneimine-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol

Repeat the described experimental procedure of the embodiment of the invention 120 the first steps, compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-yl that different is with embodiment 109 final gained]-tetramethyleneimine-1-ketone 109 makes raw material, make the reaction of this raw material and lithium aluminum hydride according to the described same way as of the embodiment of the invention 120 the first steps, obtain title compound 2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-tetramethyleneimine-1-methyl isophthalic acid H-pyrroles-3-yl }-ethanol 139 (62 mg, yellow solid), productive rate: 71.16%.

MS m/z(ESI)：466[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.90(s，1H)，8.52(d，2H)，8.14(d，2H)，7.80(m，2H)，7.46(m，1H)，7.42(s，1H)，7.33(s，1H)，5.10(s，1H)，3.61(t，2H)，3.46(s，2H)，2.66(t，2H)，2.50(m，4H)，1.70(s，4H)

Embodiment 140

2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-dimethylamino methyl-1H-pyrroles-3-yl }-ethanol

The first step

2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-methylol-1H-pyrroles-3-yl }-ethanol

In 50 mL eggplant-shape bottles, to be cooled to 0～5 ℃ under the 20 mL tetrahydrofuran (THF) condition of ice bath, stir and add lithium aluminum hydride (18.6 mg down, 0.49 mmol), product 2-[4-(the 3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl that in batches adds embodiment 81 the first step gained subsequently]-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 81a (100mg, 0.245 mmol), continuing to stir 30 minutes afterreactions under condition of ice bath finishes.In solution, add 0.1mL water and 0.1 mL, 20% sodium hydroxide solution, suction filtration, use 50 mL tetrahydrofuran (THF) washing leaching cakes successively, adding 20 mL methylene dichloride in the filtrate has solid to separate out, suction filtration, solid vacuum-drying obtains this title product 2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-methylol-1H-pyrroles-3-yl }-ethanol 140a (65 mg, yellow solid), productive rate: 64.1%.

MS m/z(ESI)：413[M+1]

Second step

1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde

With adjacent iodoxy phenylformic acid (44.1 mg; 0.157 mmol) be dissolved in the 3 mL methyl-sulphoxides; stir compound 2-{1-[4-(the 3-chloro-4-fluoroanilino)-quinazoline-6-yl that adds the above-mentioned steps gained down]-4-methylol-1H-pyrroles-3-yl }-ethanol 140a (65 mg; 0.157 mmol), stirring 2 hours afterreactions under the room temperature finishes.Reaction solution is poured in 100 mL, 5% sodium hydrogen carbonate solution, stir after 5 minutes, with ethyl acetate (100 mL * 3) extractive reaction liquid, the organic phase that merges under reduced pressure concentrates, the residue that obtains further passes through column chromatographic isolation and purification, obtain this title product 1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde 140b (32 mg, yellow solid), productive rate: 51.9%.

MS m/z(ESI)：411[M+1]

The 3rd step

In 50 mL eggplant-shape bottles with compound 1-[4-(the 3-chloro-4-fluoroanilino)-quinazoline-6-yl of above-mentioned steps gained]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde 140b (80 mg, 0.195 mmol) be dissolved in the 5 mL methylene dichloride, stir and add dimethylamine (0.2 mL down, 0.389 mmol) and sodium triacetoxy borohydride (165mg, 0.389 mmol), the mixed solution of gained at room temperature stirs and spends the night, and reaction finishes.5 mL sodium bicarbonates and 5 mL saturated sodium-chloride water solutions will be added in the reaction solution, after the layering, water layer extracts with methylene dichloride (50 mL * 3), the organic phase anhydrous sodium sulfate drying that merges filters, and concentrates under the filtrate decompression, the residue that obtains further carries out separation and purification by the TLC plate, obtain this title product 2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-dimethylamino methyl-1H-pyrroles-3-yl }-ethanol 140 (70 mg, yellow solid), productive rate: 40.9%.

MS m/z(ESI)：438[M-1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.00(s，1H)，8.62(s，1H)，8.35(m，1H)，8.12(m，1H)，8.05(m，1H)，7.92(m，2H)，7.65(d，2H)，7.44(t，1H)，5.10(s，1H)，4.17(s，2H)，3.67(t，2H)，2.78(s，6H)，2.72(t，2H)

Embodiment 141

2-{1-[4-((3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-[(2-methylsulfonyl-ethylamino)-methyl]-the 1H-pyrrole Cough up-the 3-yl-ethanol

Repeat the embodiment of the invention experimental procedure in three steps of 140 the first steps to the; different is with compound 1-[4-(the 3-chloro-4-fluoroanilino)-quinazoline-6-yl of the second step gained]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde 140b is as raw material; carry out the reaction of this raw material and 2-methylsulfonyl ethamine; obtain this title product 2-{1-[4-((3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-ethanol 141 (67 mg; yellow solid), productive rate: 33.3%.

MS m/z(ESI)：518[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ10.24(s，1H)，8.90(s，1H)，8.61(s，1H)，8.29(m，1H)，8.11(m，1H)，7.98(m，1H)，7.90(m，1H)，7.70(s，1H)，7.53(m，1H)，7.49(m，1H)，3.90(s，2H)，3.66(t，2H)，3.50(m，2H)，3.25(m，2H)，3.10(s，3H)，2.70(m，2H)

Embodiment 142

4-([1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-methyl]-ammonia Base }-methyl)-1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

Repeat the embodiment of the invention experimental procedure in three steps of 140 the first steps to the, different is with compound 1-[4-(the 3-chloro-4-fluoroanilino)-quinazoline-6-yl of the second step gained]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde 140b is as raw material, carry out this raw material and 4-aminomethyl-1,1-dioxy-six hydrogen-1 λ ^*6 ^*The reaction of-thiapyran-4-alcohol obtains this title product 4-({ [1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-methyl]-amino }-methyl)-1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 142 (76 mg, yellow solid), productive rate: 34.8%.

MS m/z(ESI)：574[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.29(s，1H)，8.85(s，1H)，8.64(s，1H)，8.31(dd，1H，J＝6.4)，8.12(dd，1H，J＝9.2)，8.00(m，1H)，7.91(d，1H，J＝9.2)，7.80(m，1H)，7.56(m，1H)，7.49(t，1H)，5.78(s，1H)，4.08(s，2H)，3.67(t，2H)，3.19(m，4H)，3.06(m，2H)，2.71(t，2H)，2.16(m，4H)

Embodiment 143

2-(1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-{[(1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-first Base)-amino]-methyl }-1H-pyrroles-3-yl)-ethanol

Repeat the embodiment of the invention experimental procedure in three steps of 140 the first steps to the, different is with compound 1-[4-(the 3-chloro-4-fluoroanilino)-quinazoline-6-yl of the second step gained]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde 140b is as raw material, carry out this raw material and C-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-reaction of methylamine, obtain this title product 2-(1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]-4-{[(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-methyl)-amino]-methyl }-1H-pyrroles-3-yl)-ethanol 143 (24 mg, yellow solid), productive rate: 11.1%.

MS m/z(ESI)：558[M+1]

Embodiment 144

2-{1-[4-(3-chlorine 4-fluoro-phenylamino)-quinazoline-6-yl]-4-diethylin methyl isophthalic acid H-pyrroles-3-yl }-ethanol

Repeat the embodiment of the invention experimental procedure in three steps of 140 the first steps to the, different is with compound 1-[4-(the 3-chloro-4-fluoroanilino)-quinazoline-6-yl of the second step gained]-4-(2-hydroxyl-ethyl)-1H-pyrroles-3-formaldehyde 140b is as raw material, carry out the reaction of this raw material and diethylamine, obtain this title product 2-{1-[4-(3-chlorine 4-fluoro-phenylamino)-quinazoline-6-yl]-4-diethylin methyl isophthalic acid H-pyrroles-3-yl }-ethanol 144 (98 mg, yellow solid), productive rate: 54.9%.

MS m/z(ESI)：468[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.63(s，1H)，9.13(s，1H)，8.62(s，1H)，8.40(m，1H)，8.14(m，2H)，8.10(s，1H)，7.90(d，1H，J＝8.8)，7.68(s，1H)，7.46(t，1H)，4.14(s，2H)，3.70(t，2H)，3.19(m，4H)，2.73(t，2H)，1.32(m，6H)

Embodiment 145

2-{1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-[(2-methylsulfonyl-second ammonia Base)-methyl]-1H-pyrroles-3-yl }-ethanol

The first step

2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-methylol-1H-pyrroles-3-yl)-ethanol

In 50 mL eggplant-shape bottles, with lithium aluminum hydride (220 mg, 5.86 mmol) be dissolved in the 15 mL tetrahydrofuran (THF)s, the solution of gained is cooled to-5 ℃ under condition of ice bath, stir final compound 2-{4-[3-chloro-4-(pyridine-2-the methoxyl group)-phenylamino that in batches adds embodiment 47 gained down]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 47 (1.45 g, 2.93 mmol), stir 30 minutes afterreactions and finish.In reaction solution, add 1 mL water, the saturated sodium hydroxide solution of 1 mL, filtering reacting liquid, mother liquor under reduced pressure concentrates, obtain this title product 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-methylol-1H-pyrroles-3-yl)-ethanol 145a (381 mg, yellow solid), productive rate: 33%.

MS m/z(ESI)：502[M+1]

Second step

2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde

In 25 mL eggplant-shape bottles; with adjacent iodoxy phenylformic acid (93 mg; 0.32 mmol) be dissolved in the 5 mL dimethyl sulfoxide (DMSO); stir the compound 2-that dropwise adds the above-mentioned steps gained down (1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-methylol-1H-pyrroles-3-yl)-ethanol 145a (147 mg; 0.29mmol) 2 mL dimethyl sulphoxide solutions; stirring is spent the night, and reaction finishes.Reaction solution is poured in the 100 mL water, have solid to generate, suction filtration, obtain this title product 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 145b (80 mg, yellow solid), productive rate: 55%.

MS m/z(ESI)：500[M+1]

The 3rd step

2-{1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-ethanol

With the compound 2-of above-mentioned steps gained (1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 145b (30 mg; 0.06 mmol) be dissolved in the 10 mL methyl alcohol; stir and add 2-methylsulfonyl ethylamine hydrochloride (19 mg down; 0.12 mmol); stir after 3 hours under the room temperature and add sodium triacetoxy borohydride (25.4 mg; 0.12 mmol), the mixed solution of gained at room temperature stirs and spends the night, and reaction finishes.Reaction solution under reduced pressure concentrates; the solid that obtains further carries out separation and purification by the TLC plate; obtain this title product 2-{1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-ethanol 145 (50 mg; yellow solid), productive rate: 31%.

MS m/z(ESI)：608[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.17(s，1H)，8.80(s，1H)，8.61(d，1H，J＝4.4)，8.55(s，1H)，8.13(s，1H)，8.07(d，1H，J＝9.2)，7.88(m，3H)，7.67(s，1H)，7.60(d，1H，J＝7.6)，7.53(s，1H)，7.37(t，1H)，7.30(d，1H，J＝8.8)，5.30(s，2H)，3.81(s，2H)，3.65(t，2H)，3.44(t，2H)，3.15(t，2H)，3.09(s，3H)，2.69(t，2H)

Embodiment 146

2-{4-[(2-methylsulfonyl-ethylamino)-methyl]-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3- Base }-ethanol

The first step

2-{4-methylol-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol

In 50 mL eggplant-shape bottles, with lithium aluminum hydride (197 mg, 5.2 mmol) be dissolved in the 15 mL tetrahydrofuran (THF)s, the solution of gained is cooled to-5 ℃ under condition of ice bath, stir compound 2-{4-[3-chloro-4-(pyridine-2-the methoxyl group)-phenylamino that in batches adds embodiment 77 second step gained down]-quinazoline-6-yl }-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 77b (1 g, 26 mmol), stir 30 minutes afterreactions and finish.In reaction solution, add 1 mL water, the saturated sodium hydroxide solution of 1 mL, filtering reacting liquid, mother liquor under reduced pressure concentrates, obtain this title product 2-{4-methylol-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol 146a (480mg, the off-white color solid), productive rate: 47%.

MS m/z(ESI)：389[M+1]

Second step

4-(2-hydroxyethyl l)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-formaldehyde

In 25 mL eggplant-shape bottles; with adjacent iodoxy phenylformic acid (415 mg; 1.48 mmol) be dissolved in the 5 mL dimethyl sulfoxide (DMSO); stir compound 2-{4-methylol-1-[4-(the 1-benzene ethylamino)-quinazoline-6-yl that dropwise adds the above-mentioned steps gained down]-1H-pyrroles-3-yl }-ethanol 146a (480 mg; 1.23 4 mL dimethyl sulphoxide solutions mmol); stirring is spent the night, and reaction finishes.Reaction solution is poured in the 100 mL water, had solid to generate, suction filtration obtains this title product 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-formaldehyde 146b (400 mg, yellow solid), productive rate: 84%.

MS m/z(ESI)：387[M+1]

The 3rd step

2-{4-[(2-methylsulfonyl-ethylamino)-methyl]-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol

Compound 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl with the above-mentioned steps gained]-1H-pyrroles-3-formaldehyde 146b (90 mg; 0.233 mmol) be dissolved in the 20 mL methylene dichloride; stir and add 2-methylsulfonyl ethylamine hydrochloride (74 mg down; 0.466 mmol); triethylamine (0.066 mL; 0.466 mmol); stir after 4 hours under the room temperature and add sodium triacetoxy borohydride (99 mg; 0.466 mmol); the mixed solution of gained at room temperature stirs and spends the night, and reaction finishes.Reaction solution under reduced pressure concentrates; the solid that obtains further carries out separation and purification by the TLC plate; obtain this title product 2-{4-[(2-methylsulfonyl-ethylamino)-methyl]-1-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol 146 (30 mg; yellow solid), productive rate: 26%.

MS m/z(ESI)：494[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.80(s，1H)，8.70(s，1H)，8.4(s，1H)，7.98(d，1H，J＝9.2)，7.80(d，2H，J＝8.8)，7.50(d，3H，J＝6.8)，7.32(t，2H)，7.23(t，1H)，5.65(m，1H)，4.09(s，2H)，3.67(t，4H)，3.41(t，2H)，3.15(s，3H)，2.74(t，2H)，1.65(d，3H，J＝7.2)

Embodiment 147

2-{4-diethylin methyl isophthalic acid-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol

Repeat the embodiment of the invention 146 the first steps to the described experimental procedure of three steps, different is with embodiment 146 second step compound 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-formaldehyde 146b makes raw material, make the reaction of this raw material and diethylamine according to described same way as of the embodiment of the invention 146 the 3rd step, obtain title compound 2-{4-diethylin methyl isophthalic acid-[4-(1-benzene ethylamino)-quinazoline-6-yl]-1H-pyrroles-3-yl }-ethanol 147 (35 mg, yellow solid), productive rate: 74%.

MS m/z(ESI)：444[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.00(s，1H)，8.93(s，1H)，8.43(s，1H)，8.04(d，1H，J＝9.2)，7.93(s，1H)，7.80(d，1H，J＝8.8)，7.60(s，1H)，7.53(d，2H，J＝7.2)，7.31(t，2H)，7.22(m，1H)，5.65(m，1H)，5.50(s，1H)，4.16(s，2H)，3.67(t，2H)，3.16(s，4H)，2.72(t，2H)，1.67(d，3H，J＝7.2)，1.30(q，6H)

Embodiment 148

1-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[(1, the 1-dioxo- Six hydrogen-1 λ ^* 6 ^* -thiapyran-4-methyl)-amino]-propan-2-ol

Repeat the embodiment of the invention 138 the first steps to the second experimental procedure in step, compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 138a that different is with embodiment 138 the first step gained is as raw material, according to embodiment described experiment method of 138 second step, carry out this raw material and C-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-reaction of methylamine, obtain this title product 1-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-[(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-methyl)-amino]-propan-2-ol 148 (34 mg, yellow solid), productive rate: 52.3%.

MS m/z(ESI)：664[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.80(s，1H)，8.61(s，1H)，8.49(s，1H)，8.05(m，2H)，7.80(dd，1H)，7.71(d，1H，J＝8.8)，7.45(m，2H)，7.33(m，3H)，7.28(t，1H)，6.89(t，1H)，6.70(t，1H)，5.60(s，1H)，5.27(s，2H)，4.10(d，2H)，3.98(m，1H)，3.03(m，4H)，2.70(m，4H)，1.70(m，1H)，1.30(m，4H)

Embodiment 149

2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl }-4-diethylin methyl isophthalic acid H-pyrrole Cough up-the 3-yl)-ethanol

Repeat the embodiment of the invention 145 the first steps to the described experimental procedure of three steps, different is with embodiment 145 second step compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 145b makes raw material, make the reaction of this raw material and diethylamine according to described same way as of the embodiment of the invention 145 the 3rd step, obtain title compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxyl group)-phenylamino]-quinazoline-6-yl-4-diethylin methyl isophthalic acid H-pyrroles-3-yl)-ethanol 149 (50 mg, yellow solid), productive rate: 30%.

MS m/z(ESI)：559[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ11.12(s，1H)，10.08(s，1H)，8.72(s，1H)，8.48(s，1H)，8.23(s，1H)，8.17(s，1H)，8.11(d，1H，J＝8.4)，7.72(m，3H)，7.49(s，1H)，7.37(q，1H)，7.10(m，3H)，6.89(s，1H)，6.74(s，1H)，5.72(s，2H)

Embodiment 150

[1-(3-luorobenzyl)-1H-indazole-5-yl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Under the nitrogen atmosphere in 50 mL eggplant-shape bottles, with [1-(3-luorobenzyl)-1H-indazole-5-yl]-(6-iodine quinazoline-4-yl)-amine 43b (250 mg, 0.505 mmol), 1-(triisopropyl silicon)-1H-pyrroles-3-boric acid (269 mg, 1.01mmol), four triphenylphosphine palladiums (2.3 mg, 0.02 mmol), salt of wormwood (138 mg, 1 mmol) is dissolved in 6 mLN, in the mixed solvent of dinethylformamide and 1.5 mL water, the mixture heating up to 70 that obtains ℃, afterreaction finished in 2 hours.Reaction solution is cooled to room temperature, pour in the 100mL frozen water, separate out white solid, stir after ten minutes, suction filtration, product are dry under vacuum, the solid that obtains further passes through column chromatography, obtain title product [1-(3-luorobenzyl)-1H-indazole-5-yl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 150 (130mg, yellow solid), productive rate: 59.3%.

MS m/z(ESI)：435[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.27(s，1H)，8.86(s，1H)，8.51(s，1H)，8.27(s，1H)，8.17(s，1H)，8.07(d，1H，J＝8.8)，7.87(m，1H)，7.76(s，3H)，7.56(s，1H)，7.39(q，1H)，7.07(m，3H)，5.71(s，2H)，3.99(s，2H)，3.67(m，2H)，2.73(m，2H)，2.62(m，6H)

Embodiment 151

2-(4-{[(1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-methyl)-amino]-methyl }-1-{4-[1-(3-fluorine benzyl Base)-1H-indazole-5-amino]-quinazoline-6-yl }-1H-pyrroles-3-yl)-ethanol

The first step

2-(1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-methylol-1H-pyrroles-3-yl)-ethanol

In 250 mL eggplant-shape bottles, with lithium aluminum hydride (340 mg, 5.2 mmol) be dissolved in the 50 mL tetrahydrofuran (THF)s, the solution of gained is cooled to-5 ℃ under condition of ice bath, stir the compound 2-that in batches adds embodiment 132 second step gained down (4-{3-[2-(4-luorobenzyl l)-4-vinyl-2H-pyrazole-3-yl]-allyl amino-quinazoline-6-yl)-6,7-dihydro-2H-pyrans [3,4-c] pyrroles-4-ketone 132b (2.26 g, 4.48 mmol), stir 3 hours afterreactions and finish.The mixed solvent quencher reaction that in reaction solution, adds 50 mL tetrahydrofuran (THF)s and water (volume ratio is 1: 1), add 100 mL ethyl acetate, stir, there is solid to generate, diatomite filtration, filtrate extracts with ethyl acetate (100 mL * 3), the organic phase that merges is evaporate to dryness under reduced pressure, obtain this title product 2-(1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl-4-methylol-1H-pyrroles-3-yl)-ethanol 151a (1.713g, yellow solid), productive rate: 75.19%.

Second step

1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde

In 50 mL eggplant-shape bottles; with adjacent iodoxy phenylformic acid (990 mg; 3.54 mmol) be dissolved in the 20 mL dimethyl sulfoxide (DMSO); stir the compound 2-that dropwise adds the above-mentioned steps gained down (1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl-4-methylol-1H-pyrroles-3-yl)-ethanol 151a (1.713 g; 3.37 5 mL dimethyl sulphoxide solutions mmol); stirring is spent the night, and reaction finishes.Pour reaction solution into 100 mL, 5% sodium hydrogen carbonate solution and 50 mL ethyl acetate, there is solid to generate, suction filtration, obtain this title product 1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 151b (4.5 g, yellow solid), product directly carries out next step reaction without separating.

MS m/z(ESI)：507[M+1]

The 3rd step

2-(4-{[(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-methyl)-amino]-methyl }-1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-1H-pyrroles-3-yl)-ethanol

Compound 1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino with the above-mentioned steps gained]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 151b (500 mg, 0.493 mmol) be dissolved in the 20 mL methylene dichloride, stir and add C-(1,1-dioxy-six hydrogen-1 λ down ^*6 ^*-thiapyran-4-yl)-and methylamine (161 mg, 0.987mmol), stirring added sodium triacetoxy borohydride (209 mg, 0.987 mmol) after 4 hours under the room temperature, and the mixed solution of gained at room temperature stirs and spends the night, and reaction finishes.Reaction solution under reduced pressure concentrates, and the solid that obtains further carries out separation and purification by the TLC plate, obtains this title product 2-(4-{[(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-methyl)-amino]-methyl }-1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-1H-pyrroles-3-yl)-ethanol 151 (80 mg, yellow solid), productive rate: 24.9%.

MS m/z(ESI)：654[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 11.10(s，1H)，9.80(s，1H)，8.56(d，2H)，8.21(dd，1H，J＝6.8)，8.11(d，1H，J＝8.8)，7.87(m，1H)，7.73(d，1H，J＝8.4)，7.47(m，2H)，6.91(s，1H)，6.71(s，1H)

Embodiment 152

2-(4-dimethylamino methyl-1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-1H-pyrroles -3-yl)-ethanol

Repeat the embodiment of the invention 151 the first steps to the described experimental procedure of three steps, different is with embodiment 151 second step compound 1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 151b makes raw material, make the reaction of this raw material and dimethylamine according to described same way as of the embodiment of the invention 151 the 3rd step, obtain title compound 2-(4-dimethylamino methyl-1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl-1H-pyrroles-3-yl)-ethanol 152 (60 mg, yellow solid), productive rate: 35%.

MS m/z(ESI)：536[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.27(s，1H)，8.86(s，1H)，8.51(s，1H)，8.27(s，1H)，8.17(s，1H)，8.07(d，1H，J＝8.8)，7.87(m，1H)，7.76(s，3H)，7.56(s，1H)，7.39(q，1H)，7.07(m，3H)，5.71(s，2H)，3.99(s，2H)，3.67(m，2H)，2.73(m，2H)，2.62(m，6H)

Embodiment 153

2-{1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-[(2-methylsulfonyl-ethylamino)- Methyl]-1H-pyrroles-3-yl }-ethanol

Repeat the embodiment of the invention 151 the first steps to the described experimental procedure of three steps; different is with embodiment 151 second step compound 1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 151b makes raw material; make the reaction of this raw material and 2-methylsulfonyl ethamine according to described same way as of the embodiment of the invention 151 the 3rd step; obtain title compound 2-{1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-ethanol 153 (35 mg; yellow solid), productive rate: 37%.

MS m/z(ESI)：614[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 10.24(s，1H)，8.83(s，1H)，8.50(s，1H)，8.27(s，1H)，8.16(s，1H)，8.06(d，1H)，7.80(m，3H)，7.67(s，1H)，7.53(s，1H)，7.37(q，1H)，7.07(m，3H)，5.71(s，2H)，3.80(s，2H)，3.65(t，2H)，3.44(t，2H)，3.16(t，2H)，3.08(s，3H)，2.69(t，2H)

Embodiment 154

(3-chloro-4-fluorophenyl)-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Repeat the experimental procedure of the embodiment of the invention 150, different is as raw material with (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-yl)-amine 48a, according to embodiment 150 described methods, carry out the reaction of this raw material and 1-(triisopropyl silicon)-1H-pyrroles-3-boric acid, obtain this title product (3-chloro-4-fluorophenyl)-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 154 (25 mg, brown solid), productive rate: 10%.

MS m/z(ESI)：339[M+1]

Embodiment 155

1-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles 1-yl)-3-(the 2-methylsulfonyl- Ethylamino)-propan-2-ol

Repeat the embodiment of the invention 138 the first steps to the second experimental procedure in step; compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 138a that different is with embodiment 138 the first step gained is as raw material; according to embodiment described experiment method of 138 second step; carry out the reaction of this raw material and 2-methylsulfonyl ethamine; obtain this title product 1-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles 1-yl)-3-(2-methylsulfonyl-ethylamino)-propan-2-ol 155 (17 mg; yellow solid), productive rate: 27.9%.

MS m/z(ESI)：624[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.69(s，1H)，8.52(d，2H)，8.02(d，2H)，7.78(dd，1H)，7.70(d，1H，J＝8.8)，7.49(q，1H)，7.41(s，1H)，7.32(m，3H)，7.19(t，1H)，6.88(s，1H)，6.66(s，1H)，5.27(s，2H)，5.10(d，1H)，4.03(d，2H)，3.80(m，1H)，3.23(m，2H)，3.15(t，2H)，3.02(s，3H)，2.95(t，2H)

Embodiment 156

2-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene is [c] pyrrole also Cough up-4-ketone-O-(2-diethyllaminoethyl)-oxime

The first step

5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-diethyllaminoethyl)-oxime also

In 50 mL eggplant-shape bottles, with 5,6-dihydro-2H-pentamethylene [c] pyrroles-4-ketone 16b (200 mg, 1.65mmol), (474 mg 2.31mmol) are dissolved in the 20 mL ethanol O-(2-diethyllaminoethyl)-hydroxylamine hydrochloride, stir and add sodium-acetate (406 mg down, 4.95 mmol), the mixed solution reflux of gained 4 hours, reaction finishes.Solution is cooled to room temperature, filters, and concentrates under the filtrate decompression, the residue that obtains obtains this title product 5 by the further separation and purification of column chromatography, and 6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-diethyllaminoethyl)-oxime 156a (155 mg also, yellow solid), productive rate: 40%

MS m/z(ESI)：254[M+1]

Second step

2-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-diethyllaminoethyl)-oxime also

In 50 mL eggplant-shape bottles; the compound 5 that adds the above-mentioned steps gained successively; 6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone O-(2-diethyllaminoethyl)-oxime 156a (70 mg also; 0.3mmol), (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-yl)-amine 1g (152 mg, 0.3mmol); potassiumphosphate (191 mg; 0.9 mmol), cuprous iodide (57mg, 0.3 mmol); N; (26 mg 0.3mmol) are dissolved in 3mLN to N '-dimethyl-1; in the dinethylformamide; mixture is heated to 70 ℃ under nitrogen protection, stirring is spent the night.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (30 mL * 3), the organic phase that merges is washed with saturated sodium-chloride successively, anhydrous sodium sulfate drying, filter, concentrate under the filtrate decompression, the residue that obtains TLC plate, solid is dry under vacuum, obtain this title product 2-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-diethyllaminoethyl)-oxime (46 mg, yellow solid) also, productive rate: 25.3%.

MS m/z(ESI)：614[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ10.13(s，1H)，8.92(s，1H)，8.60(s，1H)，8.17(m，3H)，7.88(d，2H，J＝9.2)，7.47(m，1H)，7.43(s，1H)，7.32(m，2H)，7.28(d，1H，J＝9.2)，7.19(t，1H)，5.27(s，2H)，4.40(t，2H)，3.14(m，2H)，3.05(q，2H)，2.90(t，2H)，1.26(m，10H)

Embodiment 157

(Z)-the 2-{4-[3-chloro-4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H- Pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime also

The first step

5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime also

In 50 mL eggplant-shape bottles, with 5,6-dihydro-2H-pentamethylene [c] pyrroles-4-ketone 16b (200 mg, 1.65mmol), (507mg 2.31mmol) is dissolved in the 20 mL ethanol O-(2-morpholine-4-ethyl)-hydroxylamine hydrochloride, stir and add sodium-acetate (406 mg down, 4.95 mmol), the mixed solution reflux of gained 6 hours, reaction finishes.Solution is cooled to room temperature, filters, and decompression concentrates down, the residue that obtains obtains this title product 5 by the further separation and purification of column chromatography, and 6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime 157a (328 mg also, white solid), productive rate: 80%

MS m/z(ESI)：250[M+1]

Second step

(Z) 2-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime also

In 50 mL eggplant-shape bottles; the compound 5 that adds the above-mentioned steps gained successively; 6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime 157a (100 mg also; 0.4 mmol), (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline-4-yl)-amine 1g (203 mg, 0.4 mmol); potassiumphosphate (255 mg; 1.2 mmol), and cuprous iodide (76 mg, 0.4mmol); N; (35 mg 0.4mmol) are dissolved in 3 mLN to N '-dimethyl-1; in the dinethylformamide; mixture is heated to 70 ℃ under nitrogen protection, stir 20 hours afterreactions and finish.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (30 mL * 3), the organic phase that merges is washed with saturated sodium-chloride successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is with the further separation and purification of HPLC, obtain this title product (Z) 2-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime 157 (80 mg also, yellow solid), productive rate: 32%.

MS m/z(ESI)：628[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.82(s，1H)，8.62(d，2H)，8.13(d，1H，J＝8.4)，8.02(s，1H)，7.87(d，1H，J＝9.2)，7.74(d，2H，J＝8.0)，7.46(q，1H)，7.30(m，4H)，7.18(t，1H)，5.26(s，2H)，4.19(t，2H)，3.55(t，4H)，3.03(t，2H)，2.89(t，2H)，2.67(t，2H)，2.48(m，4H)

Embodiment 158

(E)-the 2-{4-[3-chloro-4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dioxy-2H- Pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime also

Repeat the embodiment of the invention 157 the first steps to the second experimental procedure in step, the thick product in second step is carried out HPLC preparation to be separated and obtains this title product (E)-2-{4-[3-chloro-{ 4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-5,6-dihydro-2H-pentamethylene is [c] pyrroles-4-ketone-O-(2-morpholine-4-ethyl)-oxime 158 (60 mg also, yellow solid), productive rate 24%.

MS m/z(ESI)：628[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.69(s，1H)，8.59(d，2H)，8.14(d，1H，J＝8.8)，8.01(s，1H)，7.82(d，1H，J＝8.8)，7.74(s，2H)，7.47(q，1H)，7.33(m，4H)，7.18(t，1H)，5.25(s，2H)，4.16(t，2H)，3.58(t，4H)，3.04(t，2H)，2.82(t，2H)，2.61(t，2H)，2.50(m，4H)

Embodiment 159

[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Repeat the experimental procedure of the embodiment of the invention 150, different is as raw material with (6-iodo-quinazoline-4-yl)-[3-methyl-4-(6-methyl-pyridine-3-oxo)-phenyl]-amine 66a, according to embodiment 150 described modes, carry out the reaction of this raw material and 1-(triisopropyl silicon)-1H-pyrroles-3-boric acid, obtain this title product (3-chloro-4-fluorophenyl)-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 159 (30 mg, brown solid), productive rate: 21%.

MS m/z(ESI)：408[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ8.51(s，1H)，8.41(s，1H)，8.10(m，2H)，7.70(d，1H，J＝8.8)，7.67(s，1H)，7.59(dd，1H，J＝8.8)，7.35(s，1H)，7.27(m，2H)，7.98(d，1H，J＝8.8)，6.84(t，1H)，6.70(t，1H)，2.49(s，3H)，2.25(s，3H)

Embodiment 160

N-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl]-first Sulphonamide

Repeat the invention process 51 described experimental procedures, compound [3-chloro-4-(pyridine-2-methoxyl group)-phenyl]-(6-pyrroles-1-base-quinazoline-4-yl)-amine 42 that different is with embodiment 42 gained is as raw material, according to embodiment 51 described modes, carry out the reaction of this raw material and N-(2-bromo-ethyl)-Toluidrin, obtain this title product N-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethyl]-Toluidrin 160 (114 mg, yellow solid), productive rate: 44%.

MS m/z(ESI)：566[M+1]

¹HNMR(400MHz，DMSO-d6)：δ 9.76(s，1H)，8.55(s，1H)，8.51(s，1H)，8.04(m，2H)，7.74(m，2H)，7.48(m，2H)，7.31(m，4H)，7.20(t，1H)，6.95(t，1H)，6.69(t，1H)，5.28(s，2H)，4.04(t，2H)，3.38(t，2H)，2.83(s，3H)

Embodiment 161

4-{[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-third Amido]-methyl }-1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

Repeat the embodiment of the invention 138 the first steps to the second experimental procedure in step, compound [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-[6-(1-oxiranylmethyl radical-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 138a that different is with embodiment 138 the first step gained is as raw material, according to embodiment described experiment method of 138 second step, carry out this raw material and C-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-reaction of methylamine, obtain this title product 4-{[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxy-propylamine base]-methyl-1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 161 (30 mg, yellow solid), productive rate: 44.2%.

MS m/z(ESI)：680[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.77(s，1H)，8.59(s，1H)，8.50(s，1H)，8.04(m，2H)，7.76(m，2H)，7.48(m，2H)，7.33(m，3H)，7.19(t，1H)，6.90(m，2H)，6.63(s，1H)，5.27(s，2H)，4.06(m，4H)，3.79(m，1H)，3.23(m，2H)，3.18(m，4H)，2.01(m，4H)

Embodiment 162

4-({ [[1-[4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3- Methyl]-amino }-methyl)-1,1-dioxo-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

Repeat the embodiment of the invention 151 the first steps to the described experimental procedure of three steps, different is with embodiment 151 second step compound 1-{4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-quinazoline-6-yl }-4-(2-hydroxyethyl)-1H-pyrroles-3-formaldehyde 151b makes raw material, make this raw material and 4-aminomethyl-1 according to described same way as of the embodiment of the invention 151 the 3rd step, 1-dioxy-six hydrogen-1 λ ^*6 ^*The reaction of-thiapyran-4-alcohol, obtain title compound 4-([1-[4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl]-4-(2-hydroxyethyl)-1H-pyrroles-3-methyl]-amino-methyl)-1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 162 (125 mg, yellow solid), productive rate: 37.8%.

MS m/z(ESI)：670[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 9.89(s，1H)，8.56(s，1H)，8.49(s，1H)，8.21(s，1H)，8.17(s，1H)，8.10(dd，1H)，7.83(m，1H)，7.76(m，1H)，7.72(dd，1H)，7.45(s，1H)，7.38(m，2H)，7.07(m，3H)，5.72(s，2H)，4.75(s，2H)，3.63(t，4H)，3.15(m，2H)，2.94(m，2H)，2.67(t，2H)，2.59(s，2H)，1.98(m，4H)

Embodiment 163

(3-ethynyl phenyl)-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

The first step

(3-ethynyl-phenyl)-(6-iodo-quinazoline-4-yl)-amine

Repeat described experimental procedure of the 5th step of the embodiment of the invention 1, different is to make raw material with the compound 6-iodo-3H-quinazoline-4-one 1f that embodiment 1 the 4th goes on foot gained, make the reaction of this raw material and 3-ethynyl-aniline according to described same way as of the embodiment of the invention 1 the 5th step, obtain title compound (3-ethynyl-phenyl)-(6-iodo-quinazoline-4-yl)-amine 163a (2 g, pale solid), productive rate 65%.

MS m/z(ESI)：372[M+1]

Second step

(3-ethynyl-phenyl)-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

Repeat the experimental procedure of the embodiment of the invention 150, different is as raw material with (6-iodo-quinazoline-4-yl)-(3-ethynyl phenyl)-amine 163a, according to embodiment 150 described modes, carry out the reaction of this raw material and 1-(triisopropyl silicon)-1H-pyrroles-3-boric acid, obtain this title product (3-ethynyl-phenyl)-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 163 (10 mg, white solid), productive rate: 5.7%.

MS m/z(ESI)：311[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ 8.51(s，1H)，8.44(s，1H)，8.09(d，1H，J＝8.8)，7.95(s，1H)，7.80(d，1H，J＝8.4)，7.71(d，1H，J＝8.4)，7.38(t，2H)，7.27(d，1H，J＝7.6)，6.83(s，1H)，6.70(s，1H)，3.30(s，1H)

Embodiment 164

4-{[(4-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-ammonia Base]-methyl }-1.1-dioxy-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-alcohol

The first step

4-bromo-1H-pyrrole-2-aldehyde

Under the argon atmospher, 1H-pyrrole-2-aldehyde 164a (3.04g, 32 mmol) is dissolved in the 150 mL tetrahydrofuran (THF)s, dry ice-propanone is bathed and is cooled to-70 ℃, adds N-bromine succinimide (5.62 g, 32 mmol) in batches, keeps-78 ℃ of stirrings reaction in 1 hour to finish.Add 100mL water and 100 mL normal hexanes, temperature rises to room temperature, suction filtration, filtrate water is by normal hexane (100 mL * 3) extraction, the organic phase that merges is washed with saturated nacl aqueous solution successively, anhydrous sodium sulfate drying filters, and decompression concentrates down, mixed solvent (the normal hexane: tetrahydrofuran (THF)=20: 1) that adds 30 mL normal hexanes and tetrahydrofuran (THF) in the residue, at room temperature stirred 1 hour, and had solid to separate out, filter, filter cake washs 3 times with normal hexane, obtain 4-bromo-1H-pyrrole-2-aldehyde 164b (2.2 g, brown solid), productive rate: 40%.

MS m/z(ESI)：174[M+1]

Second step

4-bromo-2-formyl radical pyrroles-1-t-butyl formate

With 4-bromo-1H-pyrrole-2-aldehyde 164b (1 g, 5.78 mmol) be dissolved in the 50 mL acetonitriles, add tert-Butyl dicarbonate (1.89g, 8.67 mmol) and 4-Dimethylamino pyridine (353 mg successively under stirring, 2.89 mmol), solution at room temperature stirs to react in 30 minutes and finishes.Reaction solution under reduced pressure concentrates; tetrahydrofuran (THF)=20: 1) and 50 mL water add 50 mL normal hexanes and tetrahydrofuran (THF) mixed solvent (normal hexane: in the residue; separatory, organic phase is water successively, the saturated nacl aqueous solution solution washing; anhydrous sodium sulfate drying; filter, decompression concentrates down, obtains 4-bromo-2-formyl radical pyrroles-1-t-butyl formate 164c (1.2 g; pale brown look solid), productive rate: 76%.

MS m/z(ESI)：274[M+1]

The 3rd step

2-formyl radical-4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-pyrroles-1-t-butyl formate

Under the argon atmospher; with 4-bromo-2-formyl radical pyrroles-1-t-butyl formate 164c (200 mg; 0.73 mmol), connection boric acid pinacol ester (280 mg, 1.1 mmol); four (triphenyl) phosphine palladium (60 mg; 0.073 mmol), Potassium ethanoate (216 mg, 2.2 mmol) is dissolved in the 10 mL tetrahydrofuran (THF)s; mixed solution is heated to 80 ℃, and backflow is spent the night.Reaction solution under reduced pressure concentrates, and the residue of gained carries out separation and purification by silica gel column chromatography, obtains 2-formyl radical-4-(4,4; 5,5-tetramethyl--[1,3; 2] dioxy boron penta ring-2-yl)-and pyrroles-1-t-butyl formate 164d (45 mg, yellow solid), productive rate: 19%.

MS m/z(ESI)：322[M+1]

The 4th step

4-{4-[1-(3-luorobenzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-the 1H-pyrrole-2-aldehyde is in the 100mL eggplant-shape bottle; add compound 2-formyl radical-4-(4; 4; 5; 5-tetramethyl--[1; 3; 2] dioxy boron penta ring-2-yl)-and pyrroles-1-t-butyl formate 164d (584 mg, 1.82mmol), [1-(4-luorobenzyl)-1H-indazole-5-yl]-(6-iodo-quinazoline-4-yl)-amine 132a (500mg; 1.82 mmol); salt of wormwood (1g, 4.56mmol), 30 mLN; the mixed solvent of dinethylformamide and 7mL water; add under the nitrogen protection four (triphenyl) phosphine palladium (310mg, 0.182mmol), mixed solution is heated to 70～75 ℃; follow the tracks of reaction process with thin-layer chromatography, afterreaction finished in 4 hours.Reaction solution is poured in the 250 mL frozen water, had solid to separate out, suction filtration, filter cake is by the further separation and purification of silica gel column chromatography, it is amino to obtain 4-{4-[1-(3-luorobenzyl)-1H-indazole-5-base]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 164e (168 mg, yellow solid), productive rate 20%.

MS m/z(ESI)：322[M+1]

¹HNMR(400MHz，CD30D-d ₄)：δ12.48(s，1H)，9.89(s，1H)，9.60(s，1H)，8.82(s，1H)，8.48(s，1H)，8.20(m，3H)，7.96(s，1H)，7.75(m，3H)，7.64(s，1H)，7.35(m，1H)，7.06(m，3H)，5.72(s，2H)

The 5th step

4-{[(4-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-amino]-methyl }-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol

Under the nitrogen atmosphere, in 100 mL eggplant-shape bottles, add 4-{4-[1-(3-luorobenzyl)-1H-indazole-5-base amino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 164e (120 mg, 0.259 mmol) and 4-aminomethyl-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol (84 mg, 0.466 mmol) is dissolved in the 6 mL methylene dichloride, and stirring at room adds three (acetoxyl group) sodium borohydride (165 mg, 0.78 mmol), stirred overnight at room temperature after 6 hours.In reaction solution, add 5 mL saturated sodium bicarbonate solutions, extraction, layering, the organic phase decompression concentrates down, the residue that obtains is further by silica gel column chromatography (methylene dichloride: separation and purification methyl alcohol=10: 1), it is amino to obtain this title product 4-{[(4-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-amino]-methyl }-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 164 (25 mg, yellow solid), productive rate: 15.4%.

MS m/z(ESI)：626[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ11.15(s，1H)，9.93(s，1H)，8.69(s，1H)，8.44(s，1H)，8.25(s，1H)，8.17(s，1H)，8.06(d，1H，J＝8.8Hz)，7.76(s，1H)，7.69(d，1H，J＝8.8Hz)，7.48(s，1H)，7.38(m，1H)，7.08(m，3H)，6.75(s，1H)，5.72(s，2H)，3.91(s，2H)，3.52(m，1H)，3.19(m，4H)，3.00(m，2H)，2.02(m，4H)

Embodiment 165

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine

Under the nitrogen atmosphere; it is amino to add 4-{4-[1-(3-luorobenzyl)-1H-indazole-5-base in 100 mL eggplant-shape bottles]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 164e (100 mg; 0.216 mmol), 2-methylsulfonyl ethylamine hydrochloride (100 mg; 0.43 mmol) and triethylamine (0.2 mL; 5 mmol), be dissolved in the 6 mL methylene dichloride, stirring at room adds three (acetoxyl group) sodium borohydride (137 mg after 6 hours; 0.648 mmol), stirred overnight at room temperature.In reaction solution, add 5 mL saturated sodium bicarbonate solutions; extraction; layering; the organic phase decompression concentrates down; the residue that obtains is further by silica gel column chromatography (methylene dichloride: separation and purification methyl alcohol=10: 1); obtain this title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 165 (30 mg, yellow solid), productive rate: 24.4%.

MS m/z(ESI)：570[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ11.32(s，1H)，10.05(s，1H)，8.71(s，1H)，8.45(s，1H)，8.26(s，1H)，8.17(s，1H)，8.05(d，1H，J＝8.8Hz)，7.77(s，1H)，7.70(d，1H，J＝8.8Hz)，7.56(s，1H)，7.37(s，1H)，7.07(m，3H)，6.80(s，1H)，5.72(s，2H)，4.04(s，2H)，3.20(s，2H)，3.10(s，3H)，3.05(m，2H)

Embodiment 166

[6-(5-[{ (1,1-dioxy-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-ylmethyl)-amino]-methyl }-1H-pyrroles-3-yl)-quinazoline-4- Base]-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-amine

Under the nitrogen atmosphere, in 100 mL eggplant-shape bottles, add 4-{4-[1-(3-luorobenzyl)-1H-indazole-5-base amino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 164e (200 mg, 0.46 mmol) and C-(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-and methylamine hydrochloride (180 mg, 0.90 mmol), be dissolved in the 10 mL methylene dichloride, stirring at room adds three (acetoxyl group) sodium borohydride (275 mg, 1.3 mmol), stirred overnight at room temperature after 6 hours.In reaction solution, add 5 mL saturated sodium bicarbonate solutions; extraction; layering; the organic phase decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=15: 1); obtain this title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 166 (58 mg, yellow solid), productive rate: 22%.

MS m/z(ESI)：610[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ11.25(s，1H)，9.92(s，1H)，8.69(s，1H)，8.45(s，1H)，8.24(s，1H)，8.17(s，1H)，8.06(d，1H，J＝8.8Hz)，7.75(s，1H)，7.71(d，1H，J＝8.8Hz)，7.53(s，1H)，7.38(m，1H)，7.08(m，3H)，6.80(s，1H)，5.72(s，2H)，4.02(s，2H)，3.10(m，4H)，2.75(m，2H)，2.15(m，2H)，2.02(m，1H)，1.682(m，2H)

Embodiment 167

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1-(tolyl-4-alkylsulfonyl)-1H-pyrroles-2- Carboxylate methyl ester

The first step

2,2,2-, three chloro-1-(1H-pyrroles-2-yl)-ethyl ketone

With the pyrroles (1.4 mL, 20mmol) and trichoroacetic chloride (2.4 mL 21.4mmol) are dissolved in respectively in the 12 mL ether, and the diethyl ether solution that stirs down the pyrroles drops in the diethyl ether solution of trichoroacetic chloride, stirs after 1 hour under the room temperature, and reaction finishes.In reaction solution, add 30 mL10% solution of potassium carbonate, separatory, organic phase under reduced pressure concentrates, the crude product that obtains obtains 2,2 by the further separation and purification of silica gel column chromatography, 2-three chloro-1-(1H-pyrroles-2-yl)-ethyl ketone 167a (3.79g, gray solid), productive rate: 89.6%.

MS m/z(ESI)：213[M+1]

Second step

2,2,2-, three chloro-1-(4-iodo-1H-pyrroles-2-yl)-ethyl ketone

With iodine chloride (0.91 mL, 18.2mmol) be dissolved in the 15 mL methylene dichloride, slowly be added drop-wise to 2,2,2-, three chloro-1-(1H-pyrroles-2-yl)-ethyl ketone 167a (3.79g, 17.8mmol) 30 mL dichloromethane solutions in, stirred 2 hours under the room temperature, add 10% sodium carbonate solution cancellation reaction, separatory, organic phase is passed through water successively, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters, decompression concentrates down, the residue that obtains obtains 2,2 with ethyl acetate and normal hexane recrystallization, 2-three chloro-1-(4-iodo-1H-pyrroles-2-yl)-ethyl ketone 167b (5.152g, ash

The look solid), productive rate: 85.5%.

MS m/z(ESI)：339[M+1]

The 3rd step

4-iodo-1H-pyrroles-2-carboxylate methyl ester

(436 mg 8.07mmol) are dissolved in the 10 mL methyl alcohol, and the solution of gained is added drop-wise to 2 gradually with sodium methylate, 2, (2.276g 6.72mmol) in the 15 mL methyl alcohol, stirs 1 hour afterreaction and finishes 2-three chloro-1-(4-iodo-1H-pyrroles-2-yl)-ethyl ketone 167b under the room temperature.The reaction solution decompression is concentrated down, add 100 mL water and 100 mL methyl tertiary butyl ethers, separatory, organic phase are successively by water, and saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, decompression concentrates down, obtains 4-iodo-1H-pyrroles-2-carboxylate methyl ester 167c (1.353 g, gray solid), productive rate: 80.2%.

MS m/z(ESI)：252[M+1]

The 4th step

4-iodo-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester

With 4-iodo-1H-pyrroles-2-carboxylate methyl ester 167c (1.353 g, 5.4mmol) be dissolved in the 5 mL methylene dichloride, stir and add triethylamine (1.65 mL down successively, 11.88mmol), the 4-Dimethylamino pyridine (62 mg, 0.5mmol) and Tosyl chloride (1.13 g, 5.94mmol), mixed solution at room temperature stirred 16 hours, and reaction finishes.Add 1N HCl cancellation reaction; separatory; organic phase is used saturated sodium bicarbonate (100 mL * 3) washing successively, saturated nacl aqueous solution (100 mL * 3) washing, anhydrous sodium sulfate drying; filter; decompression concentrates down, and the crude product that obtains further by the methyl tertiary butyl ether recrystallization, obtains 4-iodo-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester 167d (1.834 g; faint yellow solid), productive rate: 83.9%.

MS m/z(ESI)：406[M+1]

The 5th step

4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester

With 4-iodo-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester 167d (288 mg; 0.7mmol); duplex tetramethyl ethylene ketone boric acid ester (235 mg; 0.91mmol) and Potassium ethanoate (210 mg 2.1mmol) are dissolved in N, in the dinethylformamide; stir and add dichloro [1 down; 1 '-ferrocene phosphoric acid] in the 1mL dichloromethane solution of palladium, mixed solution is heated to 80 ℃, and afterreaction finished in 18 hours.With adding 100 mL water and 100 mL ether in the reaction solution, filter separatory; organic phase is used 100 mL water successively, the washing of 100 mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying; filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography; obtain title product 4-(4,4,5; 5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester 167e (105 mg; colorless solid), productive rate: 37%.

MS m/z(ESI)：406[M+1]

The 6th step

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1-(tolyl-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester

With 4-(4; 4; 5; 5-tetramethyl--[1; 3; 2] dioxy boron penta ring-2-yl)-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester 167e (105 mg; 0.26mmol); [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (130 mg, 0.26mmol), salt of wormwood (93.9 mg; 0.65mmol) and tetra-triphenylphosphine palladium (45 mg; 0.026mmol) being dissolved in 6 mL N, in the mixed solvent of dinethylformamide and 2 mL water, reaction solution is heated to 55 ℃ of stirrings and spends the night.Filtering reacting liquid; filtrate is used ethyl acetate extraction; the organic phase that merges is successively by water, and saturated nacl aqueous solution washs, anhydrous sodium sulfate drying; filter; decompression concentrates down, and the residue that obtains obtains 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino by the further separation and purification of silica gel column chromatography]-quinazoline-6-yl }-1-(tolyl-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester 167 (58 mg; light yellow solid), productive rate: 32.8%.

MS m/z(ESI)：657[M+1]

¹H NMR(400 MHz，CDCl-3)：δ8.72(s，1H)，8.09(d，J＝2.4Hz，1H)，8.06(s，1H)，7.93(d，J＝2.0Hz，2H)，7.91(s，2H)，7.89(d，J＝2.4Hz，1H)，7.81(s，1H)，7.60(dd，J＝1.6Hz，1H)，7.41(d，J＝2.0Hz，1H)，7.34(br，3H)，7.23(br，2H)，7.00(m，2H)，5.15(s，2H)，3.74(s，3H)，2.43(s，3H)

Embodiment 168

4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-1,1-dioxy-six hydrogen -1 λ ^* 6 ^* -thiapyran-4-alcohol

The first step

1-oxo-6-sulfo--spiral shell [2.5] octane

Under the nitrogen atmosphere, under the ice bath cooling, trimethylammonium oxygen sulfuration iodine (13.5 g, 61 mmol) and sodium hydride (2.46g, 6.15 mmol) are dissolved in the 60 mL dimethyl sulfoxide (DMSO), after mixed solution at room temperature stirs 1 hour, drip the 80 mL dimethyl sulphoxide solutions of tetrahydric thiapyran-4-ketone 168a (6.79 g, 60 mmol), temperature control is not higher than 15 ℃, stir and rise to room temperature naturally after 10 minutes, afterreaction finished in 3 hours.Reaction solution is poured in the 350 mL frozen water, with extracted with diethyl ether (400mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, obtains 1-oxo-6-sulfo--spiral shell [2.5] octane 168b (7.09 g, white solid), productive rate: 92%.

MS m/z(ESI)：131[M+1]

Second step

1-oxo-6-sulfo--spiral shell [2.5] octane 6, the sliding thing of 6-dioxy

1-oxo-6-sulfo--spiral shell [2.5] octane 168b (7 g, 53.8 mmol) is dissolved in the 100 mL acetonitriles, stirs adding 50 mL water down, stir and add ozone (99 g after 5 minutes successively, 161 mmol) and yellow soda ash (51 g 0.48mol), stir 1 hour afterreaction and finish under the room temperature.In reaction solution, add 300 mL methylene dichloride, stirred 30 minutes, filter, filter cake washed with dichloromethane (150mL * 2), filtrate under reduced pressure concentrates, and obtains crude product 1-oxo-6-sulfo--spiral shell [2.5] octane 6,6-dioxide 168c (7.48 g, yellow solid), product directly carries out next step reaction without separating.

MS m/z(ESI)：163[M+1]

The 3rd step

4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (89 mg, 0.2 mmol) and sodium hydride (24 mg, 0.6 mmol) be dissolved in 2 mLN, in the dinethylformamide, stir under the room temperature and add 1-oxo-6-sulfo--spiral shell [2.5] octane 6 after 30 minutes, (40 mg 0.24mmol), stir 1.5 hours afterreactions and finish 6-dioxide 168c under the room temperature.In reaction solution, add 100 mL water, water extracts with ethyl acetate (100 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product 4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol 168 (40 mg, yellow solid), productive rate: 33%.

MS m/z(ESI)：608[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.726(s，1H)，8.535(s，1H)，8.503(s，1H)，8.031(d，J＝8.4 Hz，2H)，7.726(t，J＝8.4Hz，2H)，7.484(d，J＝6.4Hz，1H)，7.407(s，1H)，7.322(m，3H)，7.190(s，1H)，6.907(s，1H)，6.679(s，1H)，5.274(s，2H)，5.256(s，1H)，3.994(s，2H)，3.181(m，2H)，3.008(d，J＝12.8Hz，2H)，2.005(d，J＝7.6Hz，2H)，1.83 1(d，J＝13.6Hz，2H)

Embodiment 169

6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]- Amine

Will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (434 mg, 1mmol) be dissolved in the N of 6 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (200) mg, 5 mmol), stirred 30 minutes.

Other gets 2-bromo-N, N-diethyl ethylamine hydrobromide (287 mg, 1.1 2 mLN mmol), dinethylformamide solution, add sodium hydride (44 mg, 1.83 mmol), after stirring 30 minutes under 0 ℃, solution is added the above-mentioned reaction solution of putting into, and the solution of gained stirs 30 minutes afterreactions down at 0 ℃ and finishes.Reaction solution is poured in the 40 mL frozen water, separatory, water layer extracts with ethyl acetate (25 mL * 4), the organic phase that merges is successively by saturated nacl aqueous solution (10 mL * 2) washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains prepares the plate separation and purification by thin-layer chromatography, obtain title product { 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 169 (300 mg, yellow solid), productive rate 56.3%.

MS m/z(ESI)：534[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.84(s，1H)，8.82(s，1H)，8.46(s，1H)，8.25(s，1H)，8.18(s，1H)，8.05(d，1H，J＝8.4)，7.75(s，2H)，7.72(d，1H，J＝8.4)，7.47(s，1H)，7.40(dd，1H，J＝7.2，J＝14)，7.13(dd，3H，J＝8.4，J＝19.2)，6.93(s，1H)，6.69(s，1H)，5.72(s，2H)，4.01(br s，2H)，2.81(br s，2H)，2.55(br s，4H)，0.97(s，6H)

Embodiment 170

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[(3R, 8aR)-1-(six oxygen pyrrolo-[2,1-c] [1,4] oxazinyl-3-Ji Jia Base)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine

The first step

(3R, 8aR)-3-(chloromethyl)-six hydrogen-1H-pyrroles [2,1-c] [1,4] oxazine

Epoxy chloropropane 170a (157 ml, 2 mol) is added in the dry round-bottomed flask, and the ice bath cooling dripped D-dried meat ammonia alcohol 170b (20 g, 0.2 mol) after 20 minutes, 40 ℃ of reactions 0.5 hour.Steam excessive epoxy chloropropane.Drip the vitriol oil (60 ml) under the ice bath, reacted 1.5 hours down at 150-180 ℃.Reaction solution poured in the frozen water (200 ml) react with cancellation, be 8 with ammoniacal liquor regulator solution pH value, n-hexane/ethyl acetate (1/1,300 ml) extraction, water merges organic phase with ethyl acetate (200ml * 3) extraction, with saturated nacl aqueous solution (100 ml) washing organic phase, use anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain title product (3R, 8aR)-3-(chloromethyl)-six hydrogen-1H-pyrroles [2,1-c] [1,4] oxazine 170c (6.882 g, brown oily liquids), productive rate 19.8%.

MS m/z(ESI)：585[M+1]

Second step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[(3R, 8aR)-1-(hexahydropyrrolo also [2,1-c] [1,4] oxazinyl-3-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine

In the single port flask of 25 mL, (444 mg, 1 mmol) is dissolved in 6 mLN with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (120 mg, 3 mmol), stir after 30 minutes and to add (3R, 8aR)-3-(chloromethyl)-six hydrogen-1H-pyrroles [2,1-c] [1,4] oxazine 170c (211 mg, 1.2 mmol) stir reaction in 4 hours and finish under the room temperature.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[(3R, 8aR)-1-(hexahydropyrrolo also [2,1-c] [1,4] oxazinyl-3-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 170 (5 mg, yellow solid), productive rate: 6.5%.

MS m/z(ESI)：585[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.0(m，1H)，3.62(t，J＝12Hz，2H)，3.51(s，2H)，3.0(br，H)，2.31(m，1H)，2.1(br，3H)，1.4-1.6(m，2H)，1.1237(m，2H)

Embodiment 171

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(1-methyl-tetramethyleneimine-2-yl)-ethyl]-1H-pyrroles-3-yl }-quinoline Azoles quinoline-4-yl)-amine

In the single port flask of 25 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (100 mg, 0.22 mmol) be dissolved in 6 mLN, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (27 mg, 1.13 mmol), stir and add 2-(2-chloroethyl)-1-crassitude hydrochloride (50 mg after 30 minutes, 0.27 mmol), stirring reaction in 4 hours under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(1-methyl-tetramethyleneimine-2-yl)-ethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-amine 171 (27 mg, faint yellow solid), productive rate: 78%.

MS m/z(ESI)：558[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，3.97(m，2H)，2.08(m，3H)，1.66(m，2H)，1.24-1.30(m，7H)

Embodiment 172

4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-piperidines-4-alcohol

The first step

1-oxo-6-azepine-spiral shell [2.5] octane-6-carboxylic acid tert-butyl ester

Bathe under the cooling at cryosel, 100 mL dimethyl sulfoxide (DMSO) are added drop-wise to trimethylammonium oxygen sulfuration iodine (40g gradually, 0.18mol) and the mixture of sodium hydride (7.48 g, 0.18 mol) in, in the dropping process, maintain the temperature at 0～5 ℃, stir the 100mL dimethyl sulphoxide solution that drips 4-oxo-piperidines-1-carboxylic acid tert-butyl ester 172a (34.1g, 0.17 mol) down, rise to room temperature after dropwising gradually, at room temperature stirred 3 hours, reaction finishes.Reaction solution is poured in the 100 mL frozen water, used extracted with diethyl ether, the organic phase of merging is used anhydrous sodium sulfate drying successively, filter, decompression concentrates down, obtains compound 1-oxo-6-azepine-spiral shell [2.5] octane-6-carboxylic acid tert-butyl ester 172b (32g, yellow solid), productive rate: 83.4%.

MS m/z(ESI)：214[M+1]

Second step

4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (223 mg, 0.5 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 1.5 mmol), stir adding 1-oxo-6-azepine-spiral shell [2.5] octane-6-carboxylic acid tert-butyl ester 172b (50 mg after 30 minutes, 0.27 mmol), stirring reaction in 1 hour under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester 172c (193 mg, faint yellow solid), productive rate: 58.7%.

MS m/z(ESI)：659[M+1]

The 3rd step

With 4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester 172c (90 mg, 0.137 mmol) be dissolved in the 25 mL methylene dichloride, under condition of ice bath, be cooled to 0 ℃, drip trifluoroacetic acid (25 mL gradually, 1.38mol), rise to room temperature, stir 40 minutes afterreactions and finish.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product 4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-piperidines-4-alcohol trifluoroacetate 172 (92 mg, the yellow-green colour solid), productive rate: 100%.

MS m/z(ESI)：559[M+1]

¹H NMR(400 MHz，DMSO-d ₆)：δ10.742(s，1H)，8.733(s，1H)，8.687(s，1H)，8.598(d，J＝12Hz，1H)，8.340(d，J＝9.2Hz，1H)，8.194(d，J＝8.8Hz，1H)，7.942(s，1H)，7.784(d，J＝8.4Hz，1H)，7.690(t，J＝4.4z，1H)，7.491(m，3H)，7.201(t，J＝8.8Hz，1H)，6.926(s，1H)，5.308(s，1H)，5.173(d，J＝12Hz，1H)，3.059(d，J＝4.gHz，2H)，1.708(t，J＝11.4Hz，2H)，1.584(d，J＝13.6Hz，4H)，1.342(s，2H)

Embodiment 173

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(3-piperidines-1-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (111 mg, 0.25 mmol) and sodium hydride (65.3 mg, 1.25 mmol) be dissolved in 5 mLN, in the dinethylformamide, stir after 30 minutes under the room temperature and add 1-(3-chloropropyl)-piperidine hydrochlorate (70.5 mg, 0.3 mmol), be heated to 50 ℃, afterreaction finished in 2 hours.In reaction solution, add 100 mL water and 100 mL, separatory, water extracts with ethyl acetate (100 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(3-piperidines-1-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 173 (30 mg, red solid), productive rate: 21.1%.

MS m/z(ESI)：570[M+1]

¹H NMR(400 MHz，DMSO-d ₆)：δ 9.68(s，1H)，8.53(s，1H)，8.50(s，1H)，8.05(s，1H)，8.03(d，J＝8.8Hz，1H)，7.76(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.50(t，J＝8.8Hz，1H)，7.43(s，1H)，7.33(m，3H)，7.19(t，J＝8.8Hz，1H)，6.89(s，1H)，6.66(s，1H)，5.27(s，2H)，3.96(t，J＝6.8Hz，2H)，2.33(br，4H)，2.23(br，2H)，1.92(m，2H)，1.52(br，4H)，1.31(br，2H)

Embodiment 174

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-[1-(2-morpholine-4-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

Will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (434 mg, 1 mmol) is dissolved in the N of 6 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (200mg, 5 mmol), stirred 30 minutes.

Other gets 4-(2-bromotrifluoromethane l)-morpholine hydrobromate (302 mg, 1.1 2 mL N mmol), dinethylformamide solution, add sodium hydride (44 mg, 1.83 mmol), after stirring 30 minutes under 0 ℃, solution is added the above-mentioned reaction solution of putting into, the solution of gained stirs 2 hours afterreactions down at 0 ℃ and finishes.Reaction solution is poured in the 100 mL frozen water, separatory, water layer extracts with ethyl acetate (25 mL * 4), and the organic phase of merging is successively by saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains prepares the plate separation and purification by thin-layer chromatography, obtains title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-{ 6-[1-(2-morpholine-4-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 174 (300mg, yellow solid), productive rate 54.8%.

MS m/z(ESI)：548[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ9.84(s，1H)，8.61(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.05(d，1H，J＝8.8Hz)，7.75(s，2H)，7.71(d，1H，J＝8.8Hz)，7.46(s，1H)，7.38(m，1H)，7.08(m，3H)，6.93(s，1H)，6.68(s，1H)，5.72(s，2H)，4.07(m，2H)，3.58(m，4H)，2.71(m，2H)，2.45(m，4H)

Embodiment 175

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-[1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

Will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (434 mg, 1 mmol) be dissolved in the N of 6 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (200 mg, 5 mmol), stir after 30 minutes, add 1-(2-chloroethyl)-pyrrolidine hydrochloride (187 mg, 1.1mmol), stir after 30 minutes under the room temperature, be heated to 50 ℃, afterreaction finished in 1.5 hours.Reaction solution is poured in the 100 mL frozen water, there is solid to separate out, filter, filter cake is dissolved in the 100mL ethyl acetate, by anhydrous sodium sulfate drying, filtering and concentrating, the residue that obtains further separates by the HPLC preparative chromatography, obtain title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-{ 6-[1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 175 (700mg, faint yellow solid), productive rate 40%.

MS m/z(ESI)：532[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ9.87(s，1H)，8.65(s，1H)，8.45(s，1H)，8.24(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.75(s，2H)，7.71(d，1H，J＝8.8Hz)，7.51(s，1H)，7.38(m，1H)，7.08(m，3H)，6.96(s，1H)，6.72(s，1H)，5.72(s，2H)，4.18(m，2H)，3.10(m，2H)，2.75(m，4H)，1.77(m，4H)

Embodiment 176

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-methylsulfonyl-ethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

The first step

Methylsulfonic acid 2-methylsulfonyl ethyl ester

(248 mg, 2 mmol) are dissolved in the methylene dichloride of 10 mL dryings with 2-methylsulfonyl ethanol, stir to add pyridine (316 mg down; 4 mmol), solution is cooled to 0 ℃, adds methylsulfonyl chloride (344 mg; 3 mmol), mixed solution rises to room temperature, stirs reaction in 2 hours and finishes.The reaction solution decompression is concentrated down; in residue, add 15 mL water; use ethyl acetate extraction; the organic phase that merges is successively by saturated nacl aqueous solution washing (10 mL * 2), and anhydrous sodium sulfate drying filters; decompression concentrates down; obtain methylsulfonic acid 2-methylsulfonyl ethyl ester 176a (240mg, faint yellow solid), productive rate: 60%.

MS m/z(ESI)：203[M+1]

Second step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-methylsulfonyl-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine

In the single port flask of 25 mL; with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (89 mg; 0.2 mmol) be dissolved in 3 mLN, in the dinethylformamide, under condition of ice bath; be cooled to 0 ℃; add sodium hydride (24 mg, 1 mmol), stir and drip methylsulfonic acid 2-methylsulfonyl ethyl ester (49 mg after 30 minutes gradually; 0.24 mmol), stirring reaction in 4 hours under the room temperature finishes.Add 10 mL water in the reaction solution; with ethyl acetate extraction (10 mL * 4); the organic phase that merges is washed by saturated nacl aqueous solution successively; anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=5: 2); obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(2-methylsulfonyl-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 176 (60 mg; faint yellow solid), productive rate: 54%.

MS m/z(ESI)：551[M+1]

¹H NMR(400 MHz，DMSO-d ₆)：δ9.70(s，1H)，8.55(s，1H)，8.50(s，1H)，8.05(m，1H)，8.02(m，1H)，7.73(m，2H)，7.52(m，2H)，7.34(m，3H)，7.19(m，1H)，7.01(s，1H)，6.72(s，1H)，5.27(s，2H)，4.40(t，2H)，3.72(t，2H)，2.82(s，3H)

Embodiment 177

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(tetra oxygen furyl-2-base oxygen base)-ethyl]-1H-pyrroles-3-yl }- Quinazoline-4-yl)-amine

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (120 mg, 0.27 mmol) and sodium hydride (32.4 mg, 0.81 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir after 30 minutes under the room temperature and add 2-(2-bromine oxethyl)-tetrahydropyrans (70 mg, 0.3 mmol), stirring 30 minutes afterreactions under the room temperature finishes.In reaction solution, add 100 mL saturated nacl aqueous solution cancellation reaction, with ethyl acetate extraction (100mL * 3), the organic phase anhydrous sodium sulfate drying that merges, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(tetrahydrofuran (THF)-2-base oxygen base)-ethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-amine 177 (190mg, yellow solid), productive rate: 55.2%.

MS m/z(ESI)：573[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.05(s，1H)，8.03(d，J＝8.8Hz，1H)，7.76(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.50(t，J＝8.8Hz，1H)，7.43(s，1H)，7.33(m，3H)，7.19(t，J＝8.8Hz，1H)，6.93(s，1H)，6.67(s，1H)，5.27(s，2H)，4.57(br，1H)，4.14(br，2H)，3.90(br，1H)，3.70(br，1H)，3.57(m，2H)，2.90(br，1H)，2.74(br，1H)，1.38(br，4H)

Embodiment 178

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-third -2-alcohol

The first step

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 100 mL eggplant-shape bottles, will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (1.3 g, 3 mmol) be dissolved in the N of 30 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (1 g, 6.6 mmol), stir after 30 minutes, add epoxy chloropropane (0.42 mL under the room temperature, 5.35 mmol), 2 hours afterreactions finish.Reaction solution is poured in the 100 mL frozen water, there is solid to separate out, obtain [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (1.8 g, yellow solid), product directly carries out next step reaction without separating.

MS m/z(ESI)：491[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ8.68(s，1H)，8.16(s，1H)，8.10(s，1H)，8.06(s，2H)，7.99(d，1H，J＝8.8Hz)，7.90(d，1H，J＝8.8Hz)，7.65(d，1H，J＝8.8Hz)，7.39(d，1H，J＝8.8Hz)，7.34(m，1H)，7.20(s，1H)，7.02(m，2H)，6.92(d，1H，J＝9.6Hz)，6.80(s，1H)，6.62(s，1H)，5.63(s，2H)，4.29(m，1H)，3.98(m，1H)，3.33(m，1H)，2.90(m，1H)，2.56(m，1H)

Second step

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (1.8 g, 3.67mmol) be dissolved in the 40 mL methyl alcohol, stir and add morpholine (510 mg down, 5.87mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 178 (600 mg, yellow solid), productive rate: 35.3%.

MS m/z(ESI)：578[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ9.82(s，1H)，8.60(s，1H)，8.44(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.43(s，1H)，7.38(m，1H)，7.10(m，3H)，6.88(s，1H)，6.67(s，1H)，5.72(s，2H)，4.96(s，1H)，3.97(m，3H)，3.61(m，4H)，2.43(m，4H)，2.26(m，2H)

Embodiment 179

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(the 2-methylsulfonyl- Ethylamino)-propan-2-ol

In 100 mL eggplant-shape bottles; with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (134 g; 0.27 mmol) be dissolved in the 10 mL methyl alcohol; stir and add 2-methylsulfonyl ethylamine hydrochloride (66 mg down; 0.47mmol) and 0.3 mL triethylamine, the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated; the residue that obtains is by the further separation and purification of silica gel column chromatography; obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-methylsulfonyl-ethylamino)-propan-2-ol 179 (29 mg; yellow solid), productive rate: 17.5%.MS m/z(ESI)：614[M+1]

¹HNMR(400MHz，CD3OD-d ₆)：δ9.96(s，1H)，8.69(s，1H)，8.44(s，1H)，8.24(s，1H)，8.17(s，1H)，8.04(d，1H，J＝8.8Hz)，7.76(s，2H)，7.69(d，1H，J＝8.8Hz)，7.48(s，1H)，7.38(m，1H)，7.08(m，3H)，6.90(s，1H)，6.72(s，1H)，5.72(s，2H)，4.10(m，3H)，3.39(m，4H)，3.12(m，3H)，2.91(m，2H)

Embodiment 180

3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-propane-1,2-glycol trifluoro Acetate

In the 100mL eggplant-shape bottle, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (130 g, 0.25 mmol) be dissolved in the 10 mL dioxane, stir and add 1 mL trifluoracetic acid and 1 mL water down, reaction solution is heated to 80 ℃, and afterreaction finished in 2 hours.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1), obtain this title product 3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-propane-1,2-glycol trifluoroacetate 180 (158 mg, yellow solid), productive rate: 100%.

MS m/z(ESI)：519[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ8.60(s，1H)，8.58(s，1H)，8.19(d，1H)，7.71(d，1H)，7.60(d，1H)，7.41(m，1H)，7.32(d，1H)，7.29(m，1H)，7.15(d，1H)，7.05(m，1H)6.86(s，1H)，6.80(s，1H)，5.24(s，2H)，4.15(d，1H)，3.95(d，1H)，3.90(m，1H)，3.66(s，1H)，3.51(d，2H)

Embodiment 181

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-piperidines-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (230mg, 0.5 mmol) and sodium hydride (113 mg, 2.5 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir after 30 minutes under the room temperature and add 1-(2-chloroethyl)-piperidine hydrochlorate (70.5 mg, 0.3 mmol), be heated to 50 ℃, afterreaction finished in 2 hours.In reaction solution, add 200 mL water and 200 mL, separatory, water extracts with ethyl acetate (200 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(3-piperidines-1-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 181 (65 mg, the orange solid), productive rate: 21%.

MS m/z(ESI)：557[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.68(s，1H)，8.53(s，1H)，8.50(s，1H)，8.05(s，1H)，8.02(d，J＝8.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.92(s，1H)，6.65(s，1H)，5.27(s，2H)，3.96(br，2H)，2.70(br，2H)，2.42(br，4H)，1.51(m，4H)，1.20(m，2H)

Embodiment 182

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(3-morpholine-4-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (654 mg, 1.48 mmol) be dissolved in 5 mLN, in the dinethylformamide, under the cooling of dry ice ethanol bath, add sodium hydride (176 mg, 4.43 mmol), stir and add 4-(3-bromopropyl)-morpholine after 30 minutes (367 mg 1.77mmol), rise to stirred overnight at room temperature.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(3-morpholine-4-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 182 (110 mg, faint yellow solid), productive rate: 13%.

MS m/z(ESI)：572[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ 9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.0(t，J＝14Hz，2H)，3.67(m，4H)，2.51(m，4H)，2.27(m，2H)，1.9(m，2H)

Embodiment 183

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1- Morpholine-4-base-ethyl ketone

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (100mg, 0.225 mmol) and sodium-chlor (27 mg, 0.675 mmol) be dissolved in 10 mL N, in the dinethylformamide, stir under the room temperature and add 2-chloro-1-morpholine-4-base-ethyl ketone (44 mg after 30 minutes, 0.27 mmol), stirring 30 minutes afterreactions finishes.In reaction solution, add 100 mL saturated nacl aqueous solution cancellation reaction, water ethyl acetate extraction (100mL * 3), the organic phase that merges is successively by water (100 mL * 3) washing, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-morpholine-4-base-ethyl ketone 183 (50 mg, yellow solid), productive rate: 38.9%.

MS m/z(ESI)：573[M+1]

¹H NMR(400MHz，CD3OD-d ₆)：δ9.69(s，1H)，8.53(s，1H)δ8.50(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(d，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.47(m，2H)，7.32(m，3H)，7.19(m，1H)，6.94(s，1H)，6.66(s，1H)，5.27(s，2H)，4.06(m，2H)，3.58(m，4H)，2.45(br，4H)

Embodiment 184

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid (2-methylsulfonyl-second Base)-acid amides

The first step

2,2,2-, three fluoro-1-(1H-pyrroles-2-yl)-ketone

With pyrroles (23.8 mL, 345 mmol) be dissolved in the 100 mL ether, slowly be added drop-wise to constant pressure funnel in the 100mL diethyl ether solution of chloroacetyl chloride (41.9 mL, 375 mmol), have heat to emit in the dropping process, cool off with ice bath, after dropwising, after reaction solution at room temperature stirs 1.5 hours, drip 80 mL salt of wormwood (30 g with constant pressure funnel, 217 mmol) solution has a large amount of bubbles to emerge.After dropwising, organic phase is by anhydrous sodium sulfate drying, and decompression steams solvent down, and the residue n-hexane dissolution filters, and obtains 2,2,2-three fluoro-1-(1H-pyrroles-2-yl)-ketone 184a (55.4g, pale solid), productive rate: 75.6%.

Second step

2,2,2-, three fluoro-1-(4-iodo-1H-pyrroles-2-yl)-ketone

With 2,2,2-three fluoro-1-(1H-pyrroles-2-yl)-ketone 184a (32.1 g, 151 mmol) be dissolved in the methylene dichloride that 150 mL heavily steam, stir and drip iodine chloride (25 g down, 153.8 in 80 mL dichloromethane solutions mmol), after dropwising, after reaction solution at room temperature stirs 2 hours, add 100 mL, 10% solution of potassium carbonate cancellation reaction, separatory, with 100mL 1 N sodium sulfite solution and 100 mL water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters organic phase successively, decompression concentrates down, obtain crude product 2,2,2-three fluoro-1-(4-iodo-1H-pyrroles-2-yl)-ketone 184b (50.78g, white solid), product directly carries out next step reaction without separating.

The 3rd step

4-iodo-1H-pyrroles-2-methyl-formiate

With crude product 2,2,2-three fluoro-1-(4-iodo-1H-pyrroles-2-yl)-ketone 184b (50.78g) is dissolved in the 250 mL methyl alcohol, stir and drip sodium methylate (9.857g down, 180 mmol) 40 mL methanol solutions after dropwising, at room temperature stir reaction in 1 hour and finish.Reaction solution is under reduced pressure concentrated, residue methyl tert-butyl ether and moisture liquid, organic phase is successively by 50 mL water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, obtains crude product 4-iodo-1H-pyrroles-2-methyl-formiate 184c (29.435g, pale solid), product directly carries out next step reaction without separating.

The 4th step

4-iodo-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-methyl-formiate

Crude product 4-iodo-1H-pyrroles-2-methyl-formiate 184c (29.4g) is dissolved in the 180 mL methylene dichloride, stir and add triethylamine (26 g down successively, 258 mmol), 4-Dimethylamino pyridine (1.43g, 11.7 mmol) and p-methyl benzene sulfonic chloride (24.6 g, 129 mmol), mixed solution at room temperature stirs and spends the night.In reaction solution, add 1N hydrochloric acid soln cancellation reaction; organic phase is passed through saturated sodium bicarbonate solution successively; the saturated nacl aqueous solution washing; anhydrous sodium sulfate drying; filter, decompression concentrates down, the residue that obtains silica gel column chromatography separating purification (normal hexane and ethyl acetate=4: 1); obtain 4-iodo-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-methyl-formiate 184d (22.87g, white solid).

MS m/z(ESI)：405[M+1]

The 5th step

4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-methyl-formiate

With 4-iodo-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-methyl-formiate 184d (4.05 g, 10 mmol), duplex pinacol boric acid ester (3.43 g; 13 mmol); dichloro [1,1 '-ferrocene phosphoric acid] palladium (746 mg, 1 mmol) and Potassium ethanoate (3 g; 30 mmol) be dissolved in 30 mLN; in the dinethylformamide, under argon atmospher, add in the methylene dichloride that 1 mL heavily steams; reaction solution is heated to 80 ℃, stirs 18 hours afterreactions and finish.Reaction solution is under reduced pressure concentrated; the residue ether dissolution that obtains; filter; remove insolubles, organic phase is successively by 1 N hydrochloric acid soln, and water and saturated nacl aqueous solution wash; anhydrous sodium sulfate drying; filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=10: 1); obtain 4-(4; 4,5,5-tetramethyl--[1; 3; 2] dioxy boron penta ring-2-yl)-and 1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-methyl-formiate 184e (3.03 g, white solid), productive rate: 74.7%.

MS m/z(ESI)：406[M+1]

The 6th step

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1-(tolyl-4-methylsulfonyl)-1H-pyrroles-2-methyl-formiate

With 4-(4; 4; 5; 5-tetramethyl--[1; 3; 2] dioxy boron penta ring-2-yl)-1-(toluene-4-alkylsulfonyl)-1H-pyrroles-2-methyl-formiate 184e (2.91 g, 7.1 mmol) and [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine 1g (3.53 g, 7.1 mmol) be dissolved in 30 mL N; in the dinethylformamide; stir and add triphenylphosphine palladium (0.82g, 0.71 mmol) and salt of wormwood (2.59 g, 17.75 mmol) down; add 10 mL water; the adularescent insolubles is separated out, reacting by heating liquid to 60 ℃, and afterreaction finished in 24 hours.Add 100 mL water and 100 mL ethyl acetate in the reaction solution; separatory; organic phase washes with water successively; the saturated nacl aqueous solution washing; anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=1: 1); obtain 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1-(tolyl-4-methylsulfonyl)-1H-pyrroles-2-methyl-formiate 184f (3.45 g; yellow solid), productive rate: 73.9%.

MS m/z(ESI)：657[M+1]

The 7th step

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-formic acid is 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1-(tolyl-4-methylsulfonyl)-1H-pyrroles-2-methyl-formiate 184f (350 mg; 0.53 mmol) with hydronium(ion) oxidation lithium (224 mg; 5.3mmol) join in the microwave reaction bottle; add 4 mL methyl alcohol and 2 mL water; under 100 ℃, microwave reaction 2 hours.Reaction solution is poured in the 10 mL water, with 1 N salt acid for adjusting pH value=6, is filtered, obtain 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-formic acid 184g (248 mg, yellow solid), productive rate: 95%.

MS m/z(ESI)：489[M+1]

¹H NMR(400MHz，DMSO-d6)：δ12.09(s，1H)，11.90(s，1H)，9.63(s，1H)，8.62(s，1H)，8.51(s，1H)，8.37(s，1H)，8.04(m，2H)，7.79(m，1H)，7.60(m，1H)，7.49(m，1H)，7.32(m，4H)，7.19(m，1H)，5.27(s，2H)

The 8th step

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid (2-methylsulfonyl-ethyl)-acid amides

With 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-formic acid 184g (49mg; 0.1 mmol) with 2-methylsulfonyl ethylamine hydrochloride (103 mg; 0.8 mmol) be dissolved in the 8 mL anhydrous methylene chlorides; stir and add N down; N-diisopropylethylamine (103 mg; 0.8 mmol) with two (dioxo-3-oxazolidine) inferior phosphoryl chlorides (102 mg, 0.4 mmol), room temperature reaction in following 2 hours finishes.Reaction solution is under reduced pressure concentrated; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=8: 1); obtain title product 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carboxylic acid (2-methylsulfonyl-ethyl)-acid amides 184 (21 mg; yellow solid), productive rate: 35.4%.

MS m/z(ESI)：595[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ11.86(s，1H)，9.74(s，1H)，8.65(s，1H)，8.53(s，1H)，8.37(s，1H)，8.04(m，2H)，7.76(m，2H)，7.60(m，1H)，7.49(m，1H)，7.32(m，4H)，7.19(m，1H)，5.27(s，2H)，3.68(t，J＝6.8Hz，2H)，3.38(t，J＝6.8Hz，2H)，3.06(s，3H)

Embodiment 185

(S)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base- Propan-2-ol

The first step

(S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 100 mL eggplant-shape bottles, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (459 mg, 1.034 mmol) be dissolved in the N of 5 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (96 mg, 2.4 mmol), stir after 30 minutes, add (R)-2-chloromethyloxirane (148 mg under the room temperature, 1.6 mmol), 1 hour afterreaction finishes.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (100 mL * 3), the organic phase that merges is successively by water (100 mL * 3) washing, saturated nacl aqueous solution (100mL) washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=150: 1,100: 1), obtain (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 185a (240 mg, yellow solid) productive rate: 70%.

MS m/z(ESI)：501[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ11.100(s，1H)，8.319(s，1H)，7.902(s，1H)，7.846(s，1H)，7.539(s，1H)，7.480(s，1H)，7.323(m，2H)，7.251(s，1H)，7.115(s，2H)，7.020(s，1H)，6.838(s，1H)，6.497(s，1H)，5.209(s，2H)，4.492(d，J＝12.8Hz，1H)，4.118(m，1H)，3.189(s，1H)，2.837(s，1H)，2.651(s，1H)

Second step

(S)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol

In 100 mL eggplant-shape bottles, with (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 185a (240 mg, 0.48 mmol) and morpholine (69 mg, 0.793 mmol) be dissolved in the 10 mL anhydrous methanols, reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=60: 1,50: 1,40: 1), obtain this title product (S)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 185 (170 mg, yellow solid), productive rate: 60.3%.

MS m/z(ESI)：588[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ 9.70(s，1H)，8.54(s，1H)，8.50(s，1H)，8.05(s，1H)，8.02(s，1H)，7.76(dd，J＝8.8Hz 2.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.49(m，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.4Hz，1H)，6.88(s，1H)，6.66(s，1H)，5.27(s，2H)，4.06(dd，J＝13.6Hz 3.6Hz，1H)，3.96(m，1H)，3.87(m，1H)，3.61(m，4H)，2.42(m，4H)，2.28(m，2H)

Embodiment 186

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-third -2-alcohol

The first step

(R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 100 mL eggplant-shape bottles, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (561 mg, 1.264 mmol) be dissolved in the N of 5 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (112 mg, 2.8 mmol), stir after 30 minutes, add (S)-2-chloromethyloxirane (190 mg under the room temperature, 2.054 mmol), 1 hour afterreaction finishes.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (100 mL * 3), the organic phase that merges is successively by water washing, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=150: 1,100: 1), obtain (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (317 mg, yellow solid) productive rate: 50.2%.

MS m/z(ESI)：501[M+1]

¹HNMR(400 MHz，DMSO-d6)：δ11.100(s，1H)，8.319(s，1H)，7.902(s，1H)，7.846(s，1H)，7.539(s，1H)，7.480(s，1H)，7.323(m，2H)，7.251(s，1H)，7.115(s，2H)，7.020(s，1H)，6.838(s，1H)，6.497(s，1H)，5.209(s，2H)，4.492(d，J＝12.8Hz，1H)，4.118(m，1H)，3.189(s，1H)，2.837(s，1H)，2.651(s，1H)

Second step

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol

In 100 mL eggplant-shape bottles, with (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (315 mg, 0.702 mmol) and morpholine (87 mg, 1 mmol) be dissolved in the 10 mL anhydrous methanols, reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=60: 1,40: 1), obtain this title product (R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 186 (271 mg, yellow solid), productive rate: 65.8%.

MS m/z(ESI)：588[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.50(s，1H)，8.05(s，1H)，8.02(s，1H)，7.76(dd，J＝8.8Hz 2.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.49(m，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.4Hz，1H)，6.88(s，1H)，6.66(s，1H)，5.27(s，2H)，4.06(dd，J＝13.6Hz 3.6Hz，1H)，3.96(m，1H)，3.87(m，1H)，3.61(m，4H)，2.42(m，4H)，2.28(m，2H)

Embodiment 187

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2,5-pyrrolin-1- Base)-propan-2-ol

The first step

[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 100 mL eggplant-shape bottles, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (890 mg, 2 mmol) be dissolved in 10 mL N, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (176 mg, 4.4 mmol), stir after 30 minutes, add 2-chloromethyloxirane (300mg under the room temperature, 3.2 mmol), 1 hour afterreaction finishes.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (100 mL * 3), the organic phase that merges is washed by water (100 mL * 3) successively by organic phase successively, saturated nacl aqueous solution (100mL * 3) washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (700mg, yellow solid), productive rate: 70%.

MS m/z(ESI)：501[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ11.100(s，1H)，8.3 19(s，1H)，7.902(s，1H)，7.846(s，1H)，7.539(s，1H)，7.480(s，1H)，7.323(m，2H)，7.251(s，1H)，7.115(s，2H)，7.020(s，1H)，6.838(s，1H)，6.497(s，1H)，5.209(s，2H)，4.492(d，J＝12.8Hz，1H)，4.118(m，1H)，3.189(s，1H)，2.837(s，1H)，2.651(s，1H)

Second step

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2,5-pyrrolin-1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (1.8 g, 3.67mmol) and 2,5-dihydro-1H-pyrroles (41.5 mg, 0.6mmol) be dissolved in the 10 mL anhydrous methanols, after the reflux 3 hours, reaction finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2,5-pyrrolin-1-yl)-propan-2-ol 187 (110 mg, yellow solid), productive rate: 64.4%.

MS m/z(ESI)：570[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.704(s，1H)，8.544(s，1H)，8.496(s，1H)，8.035(t，J＝6.4Hz，2H)，7.763(m，1H)，7.704(d，J＝13.6Hz，1H)，7.475(t，J＝7Hz，1H)，7.421(s，1H)，7.322(m，3H)，7.205(d，J＝9.6Hz，1H)，6.880(s，1H)，6.656(s，1H)，5.813(s，2H)，5.274(s，2H)，4.997(d，J＝4.4Hz，1H)，4.08(d，J＝13.6Hz，1H)，3.884(m，2H)，3.492(m，4H)，2.557(d，J＝5.6Hz，2H)

Embodiment 188

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-piperidines-1-base-third-2- Alcohol

In the 100mL eggplant-shape bottle, with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187b (150 mg, 0.3 mmol) and piperidines (51.1 mg, 0.6 mmol) be dissolved in the 10 mL anhydrous methanols, reflux reaction in 3 hours finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-piperidines-1-base-propan-2-ol 188 (135 mg, yellow solid), productive rate: 77%.

MS m/z(ESI)：586[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.700(s，1H)，8.536(s，1H)，8.496(s，1H)，8.037(m，2H)，7.765(m，1H)，7.703(d，J＝8.8Hz，1H)，7.484(s，1H)，7.413(s，1H)，7.322(m，3H)，7.193(t，J＝8.6 Hz，1H)，6.870(s，1H)，6.653(s，1H)，5.273(s，2H)，4.863(s，1H)，4.042(m，1H)，3.930(s，1H)，3.852(m，1H)，2.377(s，4H)，2.208(m，2H)，1.522(m，4H)，1.393(m，2H)

Embodiment 189

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-diethylin-third-2- Alcohol

In the 100mL eggplant-shape bottle, with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187b (150 mg, 0.3 mmol) and quadrol (43.9 mg, 0.6 mmol) be dissolved in the 10 mL anhydrous methanols, reflux reaction in 3 hours finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-diethylin-propan-2-ol 189 (120 mg, yellow solid), productive rate: 70%.

MS m/z(ESI)：574[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.699(s，1H)，8.539(s，1H)，8.495(s，1H)，8.034(t，J＝6.4Hz，2H)，7.752(m，1H)，7.703(d，J＝8.8Hz，1H)，7.485(d，J＝7.2Hz，1H)，7.426(s，1H)，7.323(m，3H)，7.194(s，1H)，6.884(s，1H)，6.656(s，1H)，5.274(s，2H)，4.078(d，J＝12Hz，1H)，3.829(s，2H)，2.509(br，4H)，2.351(s，2H)，0.968(t，J＝7.2Hz，6H)

Embodiment 190

1-[1,4 '] dipiperidino-1 '-Ji-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1- Base)-ethyl ketone

The first step

1-[1,4 '] dipiperidino-1 '-Ji-2-chloro-ethyl ketone

(90 mg, 0.54 mmol) is dissolved in the 10 mL tetrahydrofuran (THF)s with the 4-piperidinyl piperidine, adds triethylamine (108mg, 1.07 mmol), and ice bath is cooled to 0 ℃, stirs down to add chloroacetyl chloride (67 mg, 0.59 mmol), stirs 30 minutes afterreactions and finishes.In reaction solution, add 10 mL water, boil off tetrahydrofuran (THF) under the decompression, the solution that obtains ethyl acetate extraction (50 mL * 3), the organic phase of merging is successively by water washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=1: 1), obtain compound 1-[1,4 '] dipiperidino-1 '-Ji-2-chloro-ethyl ketone (65 mg, yellow oily liquid), productive rate: 50%.

MS m/z(ESI)：245[M+1]

Second step

1-[1,4 '] dipiperidino-1 '-Ji-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl ketone

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (80 mg, 0.18 mmol) and sodium hydride (21.6 mg, 0.54 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir after 30 minutes under the room temperature and add 1-[1,4 '] dipiperidino-1 '-Ji-2-chloro-ethyl ketone 190a (53 mg, 0.216 mmol), stir 30 minutes afterreactions and finish.In reaction solution, add 100 mL saturated nacl aqueous solution cancellation reaction, water ethyl acetate extraction (100 mL * 3), the organic phase that merges is successively by water (100 mL * 3) washing, saturated nacl aqueous solution washing (100 mL * 3), anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product 1-[1,4 '] dipiperidino-1 '-Ji-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl ketone 190 (40 mg, yellow solid), productive rate: 34%.

MS m/z(ESI)：653[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.54(s，1H)δ＝8.50(s，1H)，δ＝8.02(m，2H)，7.77(dd，J＝2.4Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.48(m，1H)，7.31(m，4H)，7.19(m，1H)，6.82(s，1H)，6.66(s，1H)，5.27(s，2H)，4.95(d，J＝4Hz，2H)，4.14(d，J＝12.8Hz，1H)，3.83(d，J＝13.6Hz，1H)，3.15(m，3H)，2.84(t，J＝10.8Hz，1H)，2.24(br，1H)，1.86(t，J＝12.4Hz，2H)，1.68(br，4H)，1.39(m，3H)

Embodiment 191

(S)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-morpholine-3-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]- Amine

The first step

2-benzyl amino-3-hydroxy-propionic acid

In the there-necked flask of 100 mL, add L-Serine (4.1 g, 40 mmol) and the 2M sodium hydroxide solution (20 mL 1.6g), stir and to drip phenyl aldehyde (8.3 g down, 80 mmol), stir after 15 minutes, ice bath is cooled to 5 ℃, adds sodium borohydride (0.86 g, 22 mmol), stirring reaction in 2 hours under the room temperature finishes.With ether washing reaction liquid, under the ice bath cooling, regulate pH=6.5 with concentrated hydrochloric acid, suction filtration obtains 2-benzyl amino-3-hydroxy-propionic acid 191a (4.05 g, white solid), productive rate: 51.9%.

MS m/z(ESI)：196[M+1]

Second step

4-benzyl-5-oxo-morpholine-3-formic acid

2-benzyl amino-3-hydroxy-propionic acid 191a (7.2 g, 36 mmol) is dissolved in the 50 mL tetrahydrofuran (THF)s, and ice bath is cooled to 0 ℃, the saturated sodium carbonate solution (15.4 g, 11 mmol) that adds 5 ℃ dropwises the back and adds chloroacetyl chloride (7.2 mL, 60 mmol), stirring reaction in 3 hours finishes.Add 10 mL, 50% sodium hydroxide solution in the reaction solution, stir after 10 minutes with n-hexane extraction (20 mL * 2), water is cooled to 0 ℃, concentrated hydrochloric acid is regulated pH＜2, places 6 hours down at-20 ℃, filters, the solid vacuum-drying that obtains, obtain 4-benzyl-5-oxo-morpholine-3-formic acid 191b (6.6 g, white solid), productive rate: 76%.

MS m/z(ESI)：234[M-1]

The 3rd step

(R)-(4-benzyl morpholine-3-yl)-methyl alcohol

4-benzyl-5-oxo-morpholine-3-formic acid 191b (10 g, 42.5 mmol) is dissolved in the 10 mL toluene, and under the argon atmospher, the ice bath cooling adds red aluminum solutions (65 mL, 0.21 mol) down, and reaction solution at room temperature stirs reaction in 24 hours and finishes.In reaction solution, drip ethanol, generate until no bubble, regulate pH=12 with the 2M sodium hydroxide solution, add 100mL water, separatory, water washs three times with the 2N hydrochloric acid soln, regulate pH=8 with the 2M sodium hydroxide solution, with ethyl acetate extraction (50 mL * 3), the organic phase anhydrous sodium sulfate drying of merging, filter, decompression concentrates down, obtain (R)-(4-benzyl morpholine-3-yl)-methyl alcohol 191c (8 g, yellow oily liquid) productive rate: 86.9%.

MS m/z(ESI)：208[M+1]

The 4th step

(S)-(4-benzyl morpholine-3-yl)-methyl mesylate

(R)-(4-benzyl morpholine-3-yl)-methyl alcohol 191c (1.035 g, 5 mmol) and pyridine (790 mg, 10 mmol) are dissolved in the 20 mL methylene dichloride, under condition of ice bath, be cooled to 0 ℃, drip methylsulfonyl chloride (859 mg gradually, 7.5 mmol), stirring is spent the night under the room temperature.50 mL water will be added in the reaction solution, be spin-dried for solvent under the decompression, ethyl acetate extraction (50 mL * 3), the organic phase of merging are successively by saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=1: 1), obtain (S)-(4-benzyl morpholine-3-yl)-methyl mesylate 191d (1.4 g, colourless oil liquid), productive rate: 98%.

MS m/z(ESI)：286[M+1]

The 5th step

(S)-(morpholine-3-yl)-methyl mesylate

(S)-(4-benzyl morpholine-3-yl)-methyl mesylate 191d (285 mg, 1 mmol) is dissolved in the 15 mL ethanol, adds 50 mg Pd/C, vacuumize, charge into hydrogen, stir reaction in 2 hours under the room temperature and finish.Filtering reacting liquid, filtrate under reduced pressure concentrate, and obtain (S)-(morpholine-3-yl)-methyl mesylate 191e (185 mg, pale yellow oily liquid body) productive rate: 95%.

MS m/z(ESI)：195[M+1]

The 6th step

(R)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-morpholine-3-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) and sodium hydride (60 mg, 2.5mmol) be dissolved in 6 mL N, in the dinethylformamide, stir and add (S)-(morpholine-3-yl)-methyl mesylate 191e (116 mg after 30 minutes, 0.6 mmol), reaction solution at room temperature stirs to react in 2 hours and finishes.In reaction solution, add 15 mL water and 20 mL ethyl acetate, water ethyl acetate extraction (20 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=40: 1,20: 1), obtain (R)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-morpholine-3-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 191 (105 mg, faint yellow solid), productive rate: 89%.

MS m/z(ESI)：544[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ 9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，3.88(m，2H)，3.62(m，2H)，3.36(m，1H)，3.13(m，1H)，3.03(m，1H)，2.80(m，1H)，2.72(m，1H)

Embodiment 192

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-methyl-piperazine-1- Base)-ethyl ketone

The first step

2-chloro-1-(4-methyl-piperazine-1-yl)-ethyl ketone

(2 g, 20 mmol) are dissolved in the 60 mL tetrahydrofuran (THF)s with the 1-methylpiperazine, are cooled to-70 ℃ in the dry ice ethanol bath, stir down and drip chloroacetyl chloride (2.26 g, 30 mmol) gradually, dropwise to stir 30 minutes afterreactions finish under the ice bath cooling.In reaction solution, add 20 mL water, boil off tetrahydrofuran (THF) under the decompression, the solution that obtains is with dichloromethane extraction (100 mL * 3), and the organic phase of merging is successively by water washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=1: 1), obtain 2-chloro-1-(4-methyl-piperazine-1-yl)-ethyl ketone 192a (500 mg, yellow solid), productive rate: 14.2%.

MS m/z(ESI)：177[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-methyl-piperazine-1-yl)-ethyl ketone

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (200 mg, 0.45 mmol) and sodium hydride (54 mg, 1.35 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir under the room temperature and add 2-chloro-1-(4-methyl-piperazine-1-yl)-ethyl ketone 192a (95 mg after 30 minutes, 0.54mmol), reaction solution is heated to 50 ℃, and afterreaction finished in 2 hours.In reaction solution, add 100 mL saturated nacl aqueous solution cancellation reaction, water ethyl acetate extraction (100 mL * 3), the organic phase that merges is successively by water (100 mL * 3) washing, saturated nacl aqueous solution washing (100 mL * 3), anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(4-methyl-piperazine-1-yl)-ethyl ketone 192 (85 mg, yellow solid), productive rate: 32.3%.

MS m/z(ESI)：586[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ 9.70(s，1H)，8.54(s，1H)，8.49(s，1H)，8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.97(s，2H)，3.49(m，4H)，2.36(m，2H)，2.29(m，2H)，2.21(s，3H)

Embodiment 193

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-methyl-piperazine-1- Base)-propan-2-ol

With [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (153 mg, 0.306 mmol) be dissolved in the 15 mL methyl alcohol, stir and add 1-methylpiperazine (48 mg down, 0.48 mmol), 7 hours afterreactions of reflux finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=50: 1,20: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-methyl-piperazine-1-yl)-propan-2-ol 193 (120 mg, yellow solid), productive rate: 65.2%.

MS m/z(ESI)：601[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.68(s，1H)，8.52(s，1H)，8.48(s，1H)，8.02(m，2H)，7.75(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.47(q，J＝7.2Hz，1H)，7.39(s，1H)，7.31(m，3H)，7.1 8(t，J＝8.4Hz，1H)，6.85(s，1H)，6.64(s，1H)，5.26(s，2H)，4.89(s，1H)，4.02(m，1H)，3.92(m，1H)，3.84(m，1H)，2.41(dr，4H)，2.33(dr，4H)，2.22(m，5H)

Embodiment 194

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[4-(2-methylsulfonyl Base-ethylamino)-piperidines-1-yl]-propan-2-ol

The first step

4-(2-methylsulfonyl 1-ethylamino)-piperidines-1-t-butyl formate

With 2-methylsulfonyl ethylamine hydrochloride (527 mg; 3.25 mmol) be dissolved in the tetrahydrofuran solution that heavily steams; add 4 mL triethylamines; stir under the room temperature and add 4-oxo-piperidines-1-t-butyl formate 194a (525 mg after 1 hour; 2.5 mmol); continue stirring and add three (acetoxyl group) sodium borohydride (1.96 g, 15 mmol) after 1 hour, stir 1 hour afterreaction under the room temperature and finish.The 30 mL shrends reaction of going out will be added in the reaction solution; decompression steams tetrahydrofuran (THF) down; water ethyl acetate extraction (50 mL * 3); the organic phase that merges is filtered by anhydrous sodium sulfate drying, and decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=1: 1); obtain 4-(2-methylsulfonyl 1-ethylamino)-piperidines-1-t-butyl formate 194b (567 mg, off-white color solid), productive rate: 73.9%.

MS m/z(ESI)：307[M+]

Second step

(2-methylsulfonyl-ethyl)-piperidin-4-yl amine trifluoroacetate

4-(2-methylsulfonyl 1-ethylamino)-piperidines-1-t-butyl formate 194b (567 mg, 1.85 mmol) is dissolved in the 15 mL methylene dichloride, stirs down and drip 6 mL trifluoroacetic acids, stirred 1 hour under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, and residue is by silica gel column chromatography separating purification (ethyl acetate: methyl alcohol=3: 1), obtain (2-methylsulfonyl-ethyl)-piperidin-4-yl amine trifluoroacetate 194c (835 mg, yellow solid), productive rate: 91%.

MS m/z(ESI)：208[M+1]

The 3rd step

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[4-(2-methylsulfonyl-ethylamino)-piperidines-1-yl]-propan-2-ol

In 100 mL eggplant-shape bottles; with (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (244 mg; 0.5 mmol) be dissolved in the 30 mL methyl alcohol; stir and add triethylamine (0.5 mL down successively; 2.5 mmol) with (2-methylsulfonyl-ethyl)-piperidin-4-yl amine trifluoroacetate 194c (432 mg; 1 mmol), the mixed solution heating reflux reaction spends the night.Reaction solution is under reduced pressure concentrated; the residue that obtains by the further separation and purification of silica gel column chromatography (: methylene dichloride: methyl alcohol=8: 1); obtain this title product (R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-[4-(2-methylsulfonyl-ethylamino)-piperidines-1-yl]-propan-2-ol 194 (186 mg; yellow solid), productive rate: 29%.

MS m/z(ESI)：707[M+]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.72(s，1H)，8.55(s，1H)，8.50(s，1H)，8.05(s，1H)，8.03(d，J＝8.8Hz，1H)，7.77(d，J＝8.8Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.48(t，J＝8.8Hz，1H)，7.42(s，1H)，7.31(m，3H)，7.19(t，J＝8.8Hz，1H)，6.89(s，1H)，6.68(s，1H)，5.27(s，2H)，4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，3.08(br，9H)，2.57(br，1H)，2.40(br，5H)，1.18(t，J＝7.2Hz，4H)

Embodiment 195

1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-third -2-alcohol

In 100 mL eggplant-shape bottles, add 2 mL diethylamine and 2 mL methyl alcohol, stir and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (150mg down, 0.283 mmol), reaction solution being heated to 50 ℃ of reactions spends the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate by thin layer and carries out separation and purification, obtain this title product 1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-propan-2-ol 195 (92mg, yellow solid), productive rate: 56.8%.

MS m/z(ESI)：564[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ9.91(s，1H)，8.71(s，1H)，8.45(s，1H)，8.25(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.76(s，2H)，7.70(d，1H，J＝8.8Hz)，7.52(s，1H)，7.38(m，1H)，7.08(m，3H)，6.93(s，1H)，6.74(s，1H)，5.72(s，2H)，4.08(m，3H)，3.18(m，4H)，3.00(m，2H)，1.22(m，6H)

Embodiment 196

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles e-2-carboxylic acid (1,1-dioxy-six hydrogen -1 λ ^* 6 ^* -thiapyran-4-ylmethyl)-acid amides

With 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-formic acid 184g (122 mg, 0.25 mmol) and C-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-and methylamine hydrochloride (75 mg, 0.375 mmol) is dissolved in the 10 mL anhydrous methylene chlorides, stirs to add N down, N-diisopropylethylamine (129 mg, 1 mmol) and two (dioxo-3-oxazolidine) inferior phosphoryl chloride (127 mg, 0.5 mmol), reaction is 2 hours under the room temperature.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=50: 1,30: 1), obtain title product 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles e-2-carboxylic acid (1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-ylmethyl)-and acid amides 196 (12 mg, yellow solid), productive rate: 7.6%.

MS m/z(ESI)：634[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ11.93(s，1H)，9.68(s，1H)，8.63(s，1H)，8.48(s，1H)，8.13(d，J＝9.2Hz，1H)，8.0(s，1H)，7.70(m，2H)，7.60(s，1H)，7.45(m，1H)，7.28(m，4H)，7.16(m，1H)，5.25(s，2H)，3.21(m，2H)，3.10(m，4H)，2.05(m，2H)，1.80(m，1H)1.68(m，2H)

Embodiment 197

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(4-methyl-piperazine-1-yl)-ethyl]-1H-pyrroles-3-yl }-the quinoline azoles Quinoline-4-yl)-amine

With 1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-propan-2-ol 195 (197 mg, 0.337 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, ice bath is cooled to 0 ℃, add lithium aluminum hydride (38 mg, 1 mmol), stirring 10 minutes afterreactions finishes.In reaction solution, add Disodium sulfate decahydrate cancellation reaction, filtering reacting liquid, the filter cake methanol wash, filtrate under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=10: 1: 1d), obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(4-methyl-piperazine-1-yl)-ethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-amine 197 (55mg, yellow solid), productive rate: 26%.

MS m/z(ESI)：572[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.49(s，1H)，8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.04(m，2H)，2.68(m，2H)，3.46(m，4H)，2.32(m，4H)，3.15(s，3H)

Embodiment 198

6-[1-(2-[1,4 '] dipiperidino-1 '-Ji-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy Base)-phenyl]-amine

With 1-[1,4 '] dipiperidino-1 '-Ji-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl ketone 190 (220 mg, 0.337 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, ice bath is cooled to 0 ℃, add lithium aluminum hydride (38 mg, 1 mmol), stirring 10 minutes afterreactions finishes.In reaction solution, add sal soda cancellation reaction, filtering reacting liquid, the filter cake methanol wash, filtrate under reduced pressure concentrates, the residue that obtains by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=10: 1: 1d), obtain title product 6-[1-(2-[1,4 '] dipiperidino-1 '-Ji-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 198 (72 mg, yellow solid), productive rate: 33.5%.

MS m/z(ESI)：640[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ 9.69(s，1H)，8.53(s，1H)，8.50(s，1H)，8.03(m，2H)，7.77(dd，J＝2.4Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.43(m，2H)，7.30(m，3H)，7.19(m，1H)，6.91(s，1H)，6.65(s，1H)，5.27(s，2H)，4.03(t，J＝6.8Hz，2H)，2.96(d，J＝6.4Hz，2H)，2.66(t，J＝6.4Hz，2H)，2.44(br，4H)，2.21(br，1H)，1.98(m，2H)，1.69(d，J＝6.0Hz，2H)，1.44(m，8H)

Embodiment 199

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[2-(tetrahydrofuran (THF)-2-base oxygen base)-ethyl]-1H-pyrroles-3-yl }- Quinazoline-4-yl)-amine

Will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (119 g, 0.276 mmol) be dissolved in 1 mLN, in the dinethylformamide, ice bath is cooled to 0 ℃, and the adding sodium hydride (100 mg, 0.8mmol), stir after 30 minutes, (25mg, 0.359mmol), afterreaction finished in 30 minutes to add 2-(2-bromine oxethyl)-tetrahydrofuran (THF).Reaction solution is poured in the 50 mL frozen water, there is solid to separate out, filter, filter cake passes through silica gel column chromatography separating purification, obtain title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[2-(tetrahydrofuran (THF)-2-base oxygen base)-ethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-amine 199 (86.9mg, yellow solid), productive rate: 56%.

MS m/z(ESI)：563[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ9.86(s，1H)，8.62(s，1H)，8.46(s，1H)，8.23(s，1H)，8.18(s，1H)，8.04(d，1H，J＝8.8Hz)，7.73(m，3H)，7.46(s，1H)，7.38(m，1H)，7.09(m，3H)，6.93(s，1H)，6.69(s，1H)，5.72(s，2H)，4.57(m，1H)，4.14(m，2H)，3.91(m，1H)，3.71(m，1H)，3.59(m，1H)，339(m，1H)，1.63(m，6H)

Embodiment 200

1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-propyl group]-piperidines-4-alcohol

The first step

4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester

(10g 0.05mmol) is dissolved in the 30 mL methyl alcohol, stirs to add cobalt dichloride solution (6.53g down with compound 4-oxo-piperidines-1-carboxylic acid tert-butyl ester 200a, 0.05mmol), add sodium borohydride (3.8g 0.1mmol), stirs 1 hour afterreaction and finishes in batches.Filtering reacting liquid, filtrate under reduced pressure concentrate, and the residue that obtains obtains compound 4-hydroxy base-piperidines-1-carboxylic acid tert-butyl ester 200b (9g, faint yellow solid), productive rate: 90% by the further separation and purification of silica gel column chromatography.

MS m/z(ESI)：202[M+1]

Second step

Piperidines-4-alcohol trifluoroacetate

(1g 4.98mmol) is dissolved in the 15 mL trifluoroacetic acid solution, and ice bath is cooled to 0 ℃, stirs 2 hours afterreactions and finishes with compound 4-hydroxy base-piperidines-1-carboxylic acid tert-butyl ester 200b.Decompression is concentration of reaction solution down, and the product piperidines of gained-4-alcohol trifluoroacetate 200c (500 mg, yellow solid) directly carries out next step reaction without separating.

The 3rd step

1-(3-bromopropyl)-piperidines-4-alcohol

With compound piperidines-4-alcohol trifluoroacetate 200c (500 mg, 2.33mmol) be dissolved in the 10 mL methylene dichloride, stir down and add 1, the 3-dibromopropane (2.82g, 13.95mmol), ice bath is cooled to 0 ℃, dropwise add triethylamine (705mg, 6.98mmol), stir 1 hour afterreaction and finish, there is solid to generate.Filtering reacting liquid, filtrate under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain compound-(3-bromopropyl)-piperidines-4-alcohol 200d (672 mg, the pale yellow oily liquid body), product directly carries out next step reaction without separating.

MS m/z(ESI)：222[M+1]

The 4th step

In the single port flask of 25 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (445 mg, 1 mmol) is dissolved in 6 mLN, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (72 mg, 3 mmol), stir and drip 1-(3-bromopropyl)-piperidines-4-alcohol (672 mg after 30 minutes gradually, 2 mmol) 1mL triethylamine solution stirs reaction in 4 hours and finishes under the room temperature.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=4: 1), obtain this title product 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-propyl group]-piperidines-4-alcohol 200 (10 mg, faint yellow solid), productive rate: 1.7%.

MS m/z(ESI)：587[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.gHz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.08(m，1H)，3.89(m，4H)，3.50(m，4H)，1.2(m，6H)

Embodiment 201

(R) 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-third Base]-piperidines-4-alcohol

In 100 mL eggplant-shape bottles, with (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (250 mg, 0.5 mmol) with 4-hydroxy piperidine (50 mg, 0.5mmol) be dissolved in the 10 mL anhydrous methanols, reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=10: 1), obtain this title product (R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 201 (105 mg, yellow solid), productive rate: 35%.

MS m/z(ESI)：602[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，5.0(br，1H)，3.9-4.4(m，3H)，3.5(m，1H)，3.4(m，1H)，3.1(m，2H)，1.9(br，2H)，1.7(br，2H)，1.26(m，4H)

Embodiment 202

(R)-1-(3-(4-(3-chloro-4-(3-fluorine benzyloxy) phenylamino) quinazoline-6-yl)-1H-pyrroles-1-yl)-3-((S)-2-(hydroxyl first Base) propan-2-ol tetramethyleneimine-1-yl)

The first step

(S)-2-methylol-tetramethyleneimine-1-t-butyl formate

(759 mg, 20 mmol) are dissolved in the 20 mL tetrahydrofuran solutions with lithium aluminum hydride, and reflux was cooled to room temperature after 15 minutes, add 10 mL tetrahydrofuran solutions of L-proline(Pro) (1.15 g, 10 mmol), and 3 hours afterreactions of reflux finish.Reaction solution is down to room temperature, add 30 mL saturated ammonium chloride solutions, water ethyl acetate extraction (20 mL * 3), the organic phase of merging is washed by saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, decompression concentrates down, adds sodium bicarbonate (840 mg, 10 mmol) stirring in the residue and adds tert-Butyl dicarbonate (3.485 g after 5 minutes, 16 mmol), mixed solution at room temperature stirs to react in 24 hours and finishes.Reaction solution is regulated pH=7 with 2N hydrochloric acid, water ethyl acetate extraction (20 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, decompression concentrates down, obtains (S)-2-methylol-tetramethyleneimine-1-t-butyl formate 202a (2.57 g, colourless oil liquid).

MS m/z(ESI)：202[M+1]

Second step

(S)-tetramethyleneimine-2-base methyl alcohol

In 50 mL there-necked flasks, add (S)-2-methylol-tetramethyleneimine-1-t-butyl formate 202a (100.6 mg, 0.5 mmol) and be dissolved in the 20 mL methylene dichloride, ice bath is cooled to 0 ℃, and the adding trifluoroacetic acid (2.2 mL, 28mmol), stirred 1.5 hours under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, obtain compound (S)-tetramethyleneimine-2-base methyl alcohol 202b and directly carry out next step reaction without separating.

MS m/z(ESI)：102[M+1]

The 3rd step

(R)-1-(3-(4-(3-chloro-4-(3-fluorine benzyloxy) phenylamino) quinazoline-6-yl)-1H-pyrroles-1-yl)-3-((S)-2-(methylol) tetramethyleneimine-1-yl) propan-2-ol

In 100 mL eggplant-shape bottles, with (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (150 mg, 0.3 mmol) and (S)-tetramethyleneimine-2-base methyl alcohol 202b (25.3mg, 0.25 mmol) be dissolved in the 12 mL anhydrous methanols, add the reaction in 6 hours of 1 mL triethylamine reflux and finish.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=50: 1), obtain this title product (R)-1-(3-(4-(3-chloro-4-(3-fluorine benzyloxy) phenylamino) quinazoline-6-yl)-1H-pyrroles-1-yl)-3-((S)-2-(methylol) tetramethyleneimine-1-yl) propan-2-ol 202 (28 mg, yellow solid), productive rate: 18.6%.

MS m/z(ESI)：602[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.935(s，1H)，8.686(s，1H)，8.483(s，1H)，8.094(s，1H)，8.035(d，J＝8.8Hz，1H)，7.830(d，J＝8.4Hz，1H)，7.685(d，J＝8.4Hz，1H)，7.480(m，2H)，7.317(m，3H)，7.190(t，J＝8.4Hz，1H)，6.870(s，1H)，6.707(s，1H)，5.271(s，2H)，5.048(s，1H)，4.606(s，1H)，4.118(d，J＝12.8Hz，1H)，3.795(m，2H)，3.417(t，J＝5.2Hz，2H)，2.717(m，1H)，2.456(d，J＝6Hz，2H)，2.316(m，1H)，2.221(t，J＝8.4Hz，1H)，1.792(m，1H)，1.629(t，J＝24Hz，2H)，1.536(d，J＝6Hz，1H)

Embodiment 203

(S)-1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]- Piperidines-4-alcohol hydrochloride

In 100 mL eggplant-shape bottles, with (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 185a (250 mg, 0.5 mmol) with 4-hydroxy piperidine (50 mg, 0.5mmol) be dissolved in the 10 mL anhydrous methanols, reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=10: 1), obtain this title product (S)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 203a (105 mg, yellow solid), productive rate: 35%.

MS m/z(ESI)：602[M+1]

¹H NMR(400 MHz，CD30D-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.1(m，2H)，3.9(br，1H)，3.55(s，1H)，3.4(m，1H)，3.05(s，4H)，2.5(m，2H)，1.85(br，2H)，1.55(br，2H)

Embodiment 204

(S)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-cyclopropyl amino- Propan-2-ol

In 100 mL eggplant-shape bottles, with (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 185a (216 mg, 0.4 mmol) and cyclopropylamine (0.1 mL, 0.8 mmol) be dissolved in the 20 mL anhydrous methanols, reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=10: 1), obtain this title product (S)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-cyclopropyl amino-propan-2-ol 204a (202 mg, yellow solid), productive rate: 83.8%.

MS m/z(ESI)：558[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.74(s，1H)，8.56(s，1H)，8.49(s，1H)，8.03(s，1H)，8.02(d，J＝8.8Hz，1H)，7.77(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(t，J＝8.8Hz，1H)，7.43(s，1H)，7.33(m，3H)，7.16(t，J＝8.8Hz，1H)，6.88(s，1H)，6.71(s，1H)，5.27(s，2H)，4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，2.69(m，2H)，2.23(br，1H)，0.43(m，4H)

Embodiment 205

(R)-1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-third Base]-4-methylol-piperidines-4-alcohol

The first step

1-oxygen-6-azaspiro [2.5] octane trifluoroacetate

1-oxygen-6-azepine-spiral shell [2.5] octane-6-t-butyl formate 205a (509 mg, 2.39 mmol) is dissolved in the 200mL methylene dichloride, under condition of ice bath, is cooled to 0 ℃, add 5 mL trifluoroacetic acids, stirred 30 minutes under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, obtain colourless oil liquid crude product 1-oxo-6-azaspiro [2.5] octane trifluoroacetate 205b, product directly carries out next step reaction without separating.

Second step

(R)-1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-4-methylol-piperidines-4-alcohol

In 100 mL eggplant-shape bottles, with (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (154 mg, 0.3 mmol) be dissolved in the 25 mL methyl alcohol, stir and add 1-oxygen-6-azaspiro [2.5] octane trifluoroacetate 205b (0.1 mL down successively, 0.8 mmol) and salt of wormwood (41.4mg, 0.3mmol), reflux 4 hours, reaction finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=20: 1), obtain this title product (R)-1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-4-methylol-piperidines-4-alcohol 205 (632 mg, yellow solid), productive rate: 41.2%.

MS m/z(ESI)：632[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ 9.76(s，1H)，8.56(s，1H)，8.49(s，1H)，8.04(s，1H)，8.02(d，J＝8.8Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.47(t，J＝8.8Hz，1H)，7.45(s，1H)，7.32(m，3H)，7.20(t，J＝8.8Hz，1H)，6.87(s，1H)，6.66(s，1H)，5.27(s，2H)，4.56(br，1H)4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，3.52(s，2H)，3.43(br，4H)，3.18(t，J＝6.0Hz，2H)，1.38(d，J＝12.8Hz，2H)，1.25(d，J＝9.6Hz，2H)

Embodiment 206

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-methoxyl group-third-2- Alcohol

In 100 mL eggplant-shape bottles, with (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 185a (150 mg, 0.3 mmol) with 4-methyl-piperazine-1-base amine (38mg, 0.33 mmol) be dissolved in the 20 mL anhydrous methanols heating reflux reaction 3 hours.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain this title product (R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-methoxyl group-propan-2-ol 206 (76 mg, yellow solid), productive rate: 47.6%.

MS m/z(ESI)：533[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.05(s，1H)，8.03(d，J＝8.8Hz，1H)，7.77(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.50(t，J＝8.8Hz，1H)，7.43(s，1H)，7.33(m，3H)，7.19(t，J＝8.8Hz，1H)，6.87(s，1H)，6.66(s，1H)，5.27(s，2H)，5.20(d，J＝4.8Hz，1H)，4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，3.3 1(s，3H)，3.36(m，2H)

Embodiment 207

(S)-1-[1,4 '] dipiperidino-1 '-Ji-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrrole Cough up-the 1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 185a (100mg, 0.2 mmol) with 4-piperidinyl piperidine (43 mg, 0.4mmol) be dissolved in the 20 mL anhydrous methanols, 5 hours afterreactions of reflux finish.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=50: 1,5: 1), obtain this title product (S)-1-[1,4 '] dipiperidino-1 '-Ji-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol 207 (73 mg, faint yellow solid), productive rate: 54%.

MS m/z(ESI)：669[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)δ＝8.49(s，1H)，δ＝8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.88(m，1H)，4.02(m，1H)，3.87(m，2H)，2.90(m，2H)，2.42(m，4H)，2.21(m，3H)，1.94(m，2H)，1.64(m，2H)，1.36(m，6H)

Embodiment 208

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[4-(2-hydroxyethyl)-piperazine Piperazine-1-yl]-propan-2-ol

With [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg, 0.4mmol) be dissolved in the 10 mL methyl alcohol, stir successively and add 2 mL triethylamines and 2-piperazine-1-base-ethanol (0.06 mL down, 0.44 mmol), the reaction solution reflux, afterreaction finished in 4 hours.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-[4-(2-hydroxyethyl)-piperazine-1-yl]-propan-2-ol 208 (156 mg, yellow solid), productive rate: 60%.

MS m/z(ESI)：631[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(s，1H)，8.02(d，J＝8.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.87(s，1H)，6.65(s，1H)，5.27(s，2H)，4.90(d，J＝4.0Hz，1H)，4.35(m，1H)4.06(t，J＝12.8Hz，1H)，3.94(br，1H)，3.85(m，1H)，3.49(m，2H)，2.35(br，10H)，2.20(m，2H)

Embodiment 209

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-methylsulfonyl-piperazine Piperazine-1-yl)-propan-2-ol

The first step

1-methylsulfonyl piperazine

(1.72g, 20 mmol) are dissolved in the 10 mL methylene dichloride with piperazine, and (2 mL, 40mmol), under the ice bath cooling, (5.55 mL, 24mmol), mixed solution at room temperature stirs to react in 1 hour and finishes to add methylsulfonyl chloride to add triethylamine under stirring.Reaction solution under reduced pressure concentrates, and the residue that obtains obtains compound 1-methylsulfonyl piperazine two 209a (2g, white solid), productive rate: 64% by the further separation and purification of silica gel column chromatography.

MS m/z(ESI)：165[M+1]

Second step

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-methylsulfonyl-piperazine-1-yl)-propan-2-ol

1-methylsulfonyl piperazine 209a (66 mg; 0.4mmol) be dissolved in the 10 mL methyl alcohol; stir successively and add 2 mL triethylamines and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg down; 0.4mmol), 2 hours afterreactions of mixed solution reflux finish.Reaction solution under reduced pressure concentrates; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1); obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-methylsulfonyl-piperazine-1-yl)-propan-2-ol 209 (19 mg; white solid), productive rate: 7.2%.MS m/z(ESI)：665[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，5.0(s，1H)，4.0(m，3H)，3.15(t，J＝17.6Hz，4H)，2.9(s，3H)，2.6(m，4H)，2.3(s，2H)

Embodiment 210

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-pyridine-2-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

The first step

Methylsulfonic acid (2-pyridin-4-yl) ethyl ester

(2.4 g, 20 mmol) are dissolved in the 20 mL methylene dichloride, under condition of ice bath with 2-pyridine-2-base-ethanol, be cooled to 0 ℃, add triethylamine (5.5 mL, 40 mmol) and methylsulfonyl chloride (2.3 mL successively, 30 mmol), stirred 2 hours under the room temperature, reaction finishes.30 mL water will be added in the reaction solution, decompression steams methylene dichloride down, with ethyl acetate extraction (60 mL * 3), the organic phase of merging is successively by saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=3: 1), obtain methylsulfonic acid (2-pyridine-2-yl) ethyl ester 210a (3.9 g, yellow oily liquid), productive rate: 97%.

MS m/z(ESI)：202[M+1]

Second step

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) be dissolved in the N of 6 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 1.5 mmol), stir and add methylsulfonic acid (2-pyridine-2-yl) ethyl ester 210a (151 mg after 20 minutes, 0.75 mmol), stirring reaction in 2 hours under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(2-pyridine-2-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 210 (235 mg, yellow solid), productive rate: 85.6%.

MS m/z(ESI)：550[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.69(s，1H)，8.53(m，3H)，8.02(m，2H)，7.75(m，1H)，7.70(m，2H)，7.48(m，1H)，7.42(s，1H)，7.25(m，6H)，6.85(s，1H)，6.62(s，1H)，5.27(s，2H)，4.35(t，J＝7.2Hz，2H)，3.26(t，J＝7.2Hz，2H)

Embodiment 211

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(1,1-dioxy-six hydrogen -1 λ ^* 6 ^* -thiapyran-4-base is amino)-propan-2-ol

With 1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-base amine hydrochlorate (103 mg, 0.56 mmol) with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (163 mg, 0.33 mmol) be dissolved in the 10 mL methyl alcohol, stir and add triethylamine (82 mg down, 0.81 mmol), reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-base is amino)-propan-2-ol 211 (92 mg, yellow solid), productive rate: 21.7%.

MS m/z(ESI)：650[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ8.55(s，1H)，8.50(s，1H)，8.04(m，2H)，7.77(d，J＝9.2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.48(m，1H)，7.43(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.89(s，1H)，6.66(s，1H)，5.27(s，2H)，5.07(s，1H)，4.05(m，1H)，3.88(m，2H)，3.13(dr，4H)，3.01(m，2H)，2.72(m，2H)，1.24(m，4H)

Embodiment 212

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

The first step

Methylsulfonic acid (2-pyridine-2-yl) methyl esters

(2.18 g, 20 mmol) are dissolved in the 30 mL methylene dichloride, under condition of ice bath with 2-pyridin-4-yl-methyl alcohol, be cooled to 0 ℃, add triethylamine (5.5 mL, 40 mmol) and methylsulfonyl chloride (2.4 mL successively, 30 mmol), stirred 2 hours under the room temperature, reaction finishes.30 mL water will be added in the reaction solution, decompression steams methylene dichloride down, with ethyl acetate extraction (30 mL * 3), the organic phase that merges is filtered successively by anhydrous sodium sulfate drying, and decompression concentrates down, residue is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain methylsulfonic acid (2-pyridine-2-yl) methyl esters 212a (2.3 g, sorrel solid), productive rate: 61.5%.

MS m/z(ESI)：188[M+1]

Second step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridin-4-yl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) be dissolved in the N of 6 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 1.5 mmol), stir and add methylsulfonic acid (2-pyridine-2-yl) methyl esters 212a (136 mg after 20 minutes, 0.73 mmol), stirring reaction in 2 hours under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 212 (22 mg, yellow solid), productive rate: 84%.

MS m/z(ESI)：536[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.69(s，1H)，8.57(m，2H)，8.50(s，1H)，8.01(m，2H)，7.76(m，3H)，7.49(m，2H)，7.33(m，4H)，7.16(m，2H)，7.02(s，1H)，6.73(s，1H)，5.27(m，4H)

Embodiment 213

(R)-1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4- Base-propan-2-ol

The first step

(R)-4-epoxy ethyl methylmorpholine

In 100 mL eggplant-shape bottles, (5 g 57mmol) are dissolved in the 2.5 mL trimethyl carbinols with morpholine, under argon atmospher, reaction solution is cooled to 0 ℃, slowly drip (R)-2-chloromethyloxirane 213a (5.4g, 59mmol), keep 0 ℃ to stir after 30 minutes, rise to room temperature reaction and spend the night.Under the ice bath cooling, keep below 15 ℃, (after dropwising, 2 hours afterreactions of reaction finish under this temperature for 6.3g, tetrahydrofuran solution 56mmol) to drip 30 mL potassium tert.-butoxides.Reaction solution is poured in the 100 mL frozen water, extract with methylene dichloride (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying filters, and decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain compound (R)-4-epoxy ethyl methylmorpholine 213b (5.65g, yellow oily liquid), productive rate: 69.2%.

MS m/z(ESI)：144[M+1]

Second step

(R)-1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol

Will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (200 mg, 0.46mmol) be dissolved in 4 mLN, in the dinethylformamide, 0 ℃ adds sodium hydride (150 mg down, 3.75mmol), stir after 30 minutes, add (R)-4-epoxy ethyl methylmorpholine 213b (98 mg, 0.69mmol), reaction solution at room temperature stirs and spends the night.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (40 mL * 4), merge organic phase, successively with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product (R)-1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 213 (56 mg, faint yellow solid), productive rate: 21.1%.

MS m/z(ESI)：578[M+1]

Embodiment 214

(S)-1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base -propan-2-ol

The first step

(S)-4-epoxy ethyl methylmorpholine

In the 100mL eggplant-shape bottle, (5 g 57mmol) are dissolved in the 2.5 mL trimethyl carbinols with morpholine, under argon atmospher, reaction solution is cooled to 0 ℃, slowly drip (S)-2-chloromethyloxirane 214a (5.4g, 59mmol), keep 0 ℃ to stir after 30 minutes, rise to room temperature reaction and spend the night.Under the ice bath cooling, keep below 15 ℃, (after dropwising, 2 hours afterreactions of reaction finish under this temperature for 6.3g, tetrahydrofuran solution 56mmol) to drip 30 mL potassium tert.-butoxides.Reaction solution is poured in the 100 mL frozen water, extract with methylene dichloride (50 mL * 4), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying filters, and decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain compound (S)-4-epoxy ethyl methylmorpholine 214b (6.3g, yellow oily liquid), productive rate: 69.2%.

MS m/z(ESI)：144[M+1]

Second step

(S)-1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol

Will 6-[1-(2-diethylin-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 150 (200 mg, 0.46mmol) be dissolved in 4 mLN, in the dinethylformamide, (150 mg 3.75mmol), stir after 30 minutes to add sodium hydride under 0 ℃, add (S)-4-epoxy ethyl methylmorpholine 214b (98 mg, 0.69mmol), reaction solution at room temperature stirs and spends the night, and reaction finishes.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (40 mL * 4), merge organic phase, successively with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product (S)-1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-morpholine-4-base-propan-2-ol 214 (70 mg, faint yellow solid), productive rate: 35.1%.

MS m/z(ESI)：578[M+1]

Embodiment 215

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-piperidines-1-base-ethyl ketone

The first step

2-chloro-1-piperidines-1-base-ethyl ketone

(850 mg, 10 mmol) are dissolved in the 40 mL methylene dichloride with piperidines, add triethylamine (2.02 g, 20 mmol), and ice bath is cooled to-78 ℃, stir down to add chloroacetyl chloride (1.13 g, 10 mmol), stir 30 minutes afterreactions and finish.In reaction solution, add 10 mL frozen water, decompression is steaming vibrating dichloromethane down, residue is with ethyl acetate extraction (20mL * 3), and the organic phase of merging is by water washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=1: 1), obtain compound 2-chloro-1-piperidines-1-base-ethyl ketone 215a (1.52 g, the sorrel oily liquids), productive rate: 94.4%.

MS m/z(ESI)：162[M+1]

Second step

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) be dissolved in 4 mLN, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 1.5 mmol), stir adding 2-chloro-1-piperidines-1-base-ethyl ketone 215a (121 mg after 20 minutes, 0.75 mmol), stirring reaction in 1.5 hours under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=30: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-piperidines-1-base-ethyl ketone 215 (101 mg, yellow solid), productive rate: 35.4%.

MS m/z(ESI)：570[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.54(s，1H)，8.50(s，1H)，8.03(m，2H)，7.75(m，2H)，7.47(m，1H)，7.31(m，4H)，7.19(m，1H)，6.82(s，1H)，6.65(s，1H)，5.27(s，2H)，4.94(s，2H)，3.46(t，J＝5.2Hz，4H)，3.31(m，1H)，1.46-1.61(br，6H)

Embodiment 216

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N, N-diethyl-acetyl Amine

The first step

2-chloro-N, the N-diethyl acetamide

(11.6 g, 159 mmol) are dissolved in the 60 mL tetrahydrofuran (THF)s with diethylamine, are cooled to-78 ℃ in the dry ice ethanol bath, stir down and drip chloroacetyl chloride (6 g, 53 mmol) gradually, dropwise under the ice bath cooling and stir 30 minutes, and reaction finishes.In reaction solution, add 20 mL water, boil off tetrahydrofuran (THF) under the decompression, the solution that obtains is with ethyl acetate extraction (100 mL * 3), and the organic phase of merging is successively by water washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, obtains crude product 2-chloro-N, N-diethyl acetamide 216a (6.2 g, yellow oily liquid), product directly carries out next step reaction without separating.

MS m/z(ESI)：150[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N, N-diethyl-ethanamide

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (500 mg, 1.12 mmol) and sodium hydride (134 mg, 3.36 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir under the room temperature and add 2-chloro-N after 30 minutes, (184 mg 1.23mmol), stir 30 minutes afterreactions and finish N-diethyl acetamide 216a under the room temperature.In reaction solution, add 100mL saturated nacl aqueous solution cancellation reaction, water ethyl acetate extraction (100 mL * 3), the organic phase that merges is successively by water (100 mL * 3) washing, saturated nacl aqueous solution washing (100 mL * 3), anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (ethyl acetate: normal hexane=1: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N, N-diethyl-ethanamide 216 (385 mg, yellow solid), productive rate: 57.4%.

MS m/z(ESI)：558[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.72(s，1H)，8.55(s，1H)，8.50(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.47(m，1H)，7.31(m，4H)，7.19(m，1H)，6.84(s，1H)，6.66(s，1H)，5.27(s，2H)，4.93(s，2H)，3.39(m，4H)，1.18(t，J＝6.8Hz，3H)，1.06(t，J＝1.2Hz，3H)

Embodiment 217

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-the N-ring Propyl group-ethanamide

The first step

2-chloro-N-cyclopropyl-ethanamide

(2.26 g, 20 mmol) are dissolved in the 30 mL ether with chloroacetyl chloride, under condition of ice bath, are cooled to 0 ℃, slowly drip cyclopropylamine (2.28 g, 40 mmol), dropwise after 1 hour, have solid to separate out.Add 30 mL chloroforms, stirred 15 minutes, and filtered, filtrate under reduced pressure concentrates, the white solid that obtains dissolves with 50 mL methylene dichloride, wash (50 mL * 3) with water, organic phase is filtered by anhydrous sodium sulfate drying, decompression concentrates down, the 2-chloro-N-cyclopropyl that obtains-ethanamide 217a (1.32 g, white solid), productive rate: 50%

MS m/z(ESI)：134[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-cyclopropyl-ethanamide

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (167 mg, 0.375 mmol) be dissolved in the N of 2.5 mL dryings, in the N-methylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (45 mg, 1.13 mmol), stir adding 2-chloro-N-cyclopropyl-ethanamide 217a (60 mg after 20 minutes, 0.45 mmol), stirring reaction in 3 hours under the room temperature finishes.In reaction solution, add 50 mL water, with ethyl acetate extraction reaction solution (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying successively, filter, decompression concentrates down, the residue that obtains by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-cyclopropyl-ethanamide 217 (110 mg, yellow solid), productive rate: 54%.

MS m/z(ESI)：541[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.710(s，1H)，8.546(s，1H)，8.495(s，1H)，8.230(d，J＝3.2Hz，1H)，8.028(t，J＝4.8Hz，2H)，7.754(m，1H)，7.705(d，J＝6.8Hz，1H)，7.469(t，J＝5.4Hz，1H)，7.322(m，4H)，7.197(t，J＝3.8Hz，1H)，6.833(t，J＝1.6Hz，1H)，6.665(d，J＝1.2Hz，1H)，5.266(s，2H)，4.540(s，1H)，2.670(m，1H)，0.649(m，2H)，0.448(m，2H)

Embodiment 218

4-[(4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-amino]-piperazine Pyridine-1-t-butyl formate

The first step

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole-2-aldehyde

With 30 mL N, dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add phosphorus oxychloride (825mg, 5.392 mmol), reaction rose to stirring at room after 1 hour, cooling reaction solution to 0 ℃ adds 3 hours afterreactions of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (1.565 g, 3.525 mmol) stirring at room and finishes.50 mL water will be added in the reaction solution, regulate pH＞11 with the 2N sodium hydroxide solution, add 50 mL tetrahydrofuran (THF)s, water ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=2: 1), obtain 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 218a (424 mg, yellow solid), productive rate: 25.5%.

Second step

4-[(4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-amino]-piperidines-1-t-butyl formate

With 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 218a (424mg, yellow solid) and 4-amino-piperadine-1-t-butyl formate (133 mg, 0.67 mmol) be dissolved in the 20 mL methylene dichloride, at room temperature stir and add three (acetoxyl group) sodium borohydride (313 mg after 2 hours, 1.476 mmol), mixed solution at room temperature stirs and spends the night.50 mL water will be added in the reaction solution, decompression steams methylene dichloride down, water ethyl acetate extraction (50 mL * 3), the organic phase that merges is filtered by anhydrous sodium sulfate drying, and decompression concentrates down, the residue that obtains separates by Combi Flash, obtain title product 4-[(4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-amino]-piperidines-1-t-butyl formate 218 (132 mg, yellow solid), productive rate: 62.6%.

MS m/z(ESI)：657[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ11.18(dr，1H)，9.85(s，1H)，8.58(m，2H)，8.08(s，1H)，7.95(d，J＝8.8Hz，1H)，7.81(m，2H)，7.48(m，1H)，7.31(m，3H)，7.19(m，1H)，7.01(s，1H)，6.44(s，1H)，5.27(s，2H)，4.22(dr，2H)，3.90(m，2H)，3.18(m，1H)，2.68(dr，2H)，1.92(m，4H)，1.37(s，9H)

Embodiment 219

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2-piperidines-1-base-second Amino)-propan-2-ol

With [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (150 mg, 0.3 mmol) be dissolved in the 10 mL methyl alcohol, stir successively and add 2-piperidines-1-base-ethamine (42.3 mg down, 0.33 mmol), 3 hours afterreactions of mixed solution reflux finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-piperidines-1-base-ethylamino)-propan-2-ol 219 (22 mg, yellow solid), productive rate: 11.7%.

MS m/z(ESI)：629[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)δ＝8.49(s，1H)，δ＝8.03(d，J＝gHz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.01(m，1H)，3.88(m，2H)，3.51(m，2H)，2.60(t，J＝6.6Hz，2H)，2.35(m，6H)，1.47(br，4H)1.36(m，2H)

Embodiment 220

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2-methoxyl group-second ammonia Base)-propan-2-ol

With [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (150 mg, 0.3 mmol) be dissolved in 20 mL Virahols and 1, in the mixed solvent of 2-ethylene dichloride (1: 1), stir and add 2-methoxyethyl amine (67.5 mg down, 0.9 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=15: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-methoxyl group-ethylamino)-propan-2-ol 220 (90 mg, yellow solid), productive rate: 52.3%.

MS m/z(ESI)：586[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.49(s，1H)，8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，5.05(br，1H)，4.01(m，1H)，3.88(m，2H)，3.51(m，2H)，3.26(br，2H)，3.25(s，3H)，2.67(t，J＝5.6Hz，2H)

Embodiment 221

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-piperazine-1-base-third-2- Alcohol

With [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (150 mg, 0.3 mmol) be dissolved in the 20 mL Virahols, stir adding Piperazine anhydrous (80 mg, 0.9 mmol) down, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-piperazine-1-base-propan-2-ol 221 (140mg, yellow solid), productive rate: 70%.

MS m/z(ESI)：587[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.49(s，1H)，δ＝8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.88(br，1H)，4.09(m，1H)，3.94(br，1H)，3.84(m，1H)，2.68(m，4H)，2.33(br，4H)，2.25(t，J＝2.8Hz，2H)

Embodiment 222

4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group amino]- Hexalin

4-Trans-4-Amino Cyclohexanol hydrochloride (75.8 mg, 0.5 mmol, Alfa) be dissolved in the 10 mL methyl alcohol, stir successively and add 2 mL triethylamines and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg down, 0.4 mmol), 2 hours afterreactions of mixed solution reflux finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product 4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group amino]-hexalin 222 (94 mg, yellow solid), productive rate: 38.3%.

MS m/z(ESI)：616[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.5(s，1H)，4.05(m，1H)，3.95(m，2H)，2.7(m，1H)，2.55(s，1H)，2.5(m，2H)，2.2(m，1H)，1.8(m，4H)，1.25(m，4H)

Embodiment 223

1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl]-tetramethyleneimine -2-yl }-methyl alcohol

The first step

2-chloro-1-(2-methylol-tetramethyleneimine-1-yl)-ethyl ketone

(505 mg, 5 mmol) are dissolved in the 10 mL tetrahydrofuran (THF)s with the 2-hydroxymethyl pyrrolidine, under acetone-the dry ice bath condition, be cooled to one 78 ℃, add 1 mL triethylamine, stir after 15 hours, drip chloroacetyl chloride (0.38mL, 5 mmol), stir 1 hour afterreaction and finish.Reactant under reduced pressure concentrates, residue carries out separation and purification (methylene dichloride: methyl alcohol=15: 1) by silica gel column chromatography, obtain colourless oil liquid crude product 2-chloro-1-(2-methylol-tetramethyleneimine-1-yl)-ethyl ketone 223a, product directly carries out next step reaction without separating.

MS m/z(ESI)：178[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(2-methylol-tetramethyleneimine-1-yl)-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (444 mg, 1 mmol) is dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (72 mg, 3 mmol), stir adding 2-chloro-1-(2-methylol-tetramethyleneimine-1-yl)-ethyl ketone 223a (213 mg after 30 minutes, 1.2 mmol), stirring reaction in 1 hour under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=8: 1), obtain 2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(2-methylol-tetramethyleneimine-1-yl)-ethyl ketone 223b (70 mg, faint yellow solid), productive rate: 10%.

MS m/z(ESI)：587[M+1]

The 3rd step

1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl]-tetramethyleneimine-2-yl }-methyl alcohol

With 2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(2-methylol-tetramethyleneimine-1-yl)-ethyl ketone 223b (190 mg, 0.29 mmol) be dissolved in the 20 mL tetrahydrofuran (THF)s, stir and add lithium aluminum hydride (32.6 mg down, 0.86 mmol), 3 hours afterreactions finish.In reaction solution, add methyl alcohol cancellation reaction, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography, obtain title product 1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethyl]-tetramethyleneimine-2-yl-methyl alcohol 223 (40 mg, yellow solid), productive rate: 24%.

MS m/z(ESI)：573[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.4(m，2H)，4.05(m，2H)，3.45(m，5H)，2.33(br，1H)，1.82(br，1H)，1.62(m，2H)，1.55(br，1H)

Embodiment 224

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-pyridin-4-yl-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

The first step

Methylsulfonic acid (2-pyridin-4-yl) ethyl ester

(174 mg, 1.42 mmol) are dissolved in the 20 mL methylene dichloride, under condition of ice bath with 2-pyridin-4-yl-ethanol, be cooled to 0 ℃, add triethylamine (352 mg, 3.5 mmol) and methylsulfonyl chloride (200 mg successively, 1.75mmol), to stir 1 hour under the room temperature, reaction finishes.50 mL water will be added in the reaction solution, decompression steams methylene dichloride down, with ethyl acetate extraction (100mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying successively, filter, decompression concentrates down, and the crude product methylsulfonic acid that obtains (2-pyridin-4-yl) ethyl ester 224a (266 mg, pink colour oily liquids) directly carries out next step reaction without separating.

MS m/z(ESI)：202[M+1]

Second step

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (225 mg, 0.51 mmol) be dissolved in the N of 3 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (45 mg, 1.13 mmol), stir and add methylsulfonic acid (2-pyridin-4-yl) ethyl ester 224a (266 mg after 20 minutes, 1.32 mmol), stirring reaction in 1.5 hours under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(2-pyridin-4-yl-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 224 (5 mg, yellow solid), productive rate: 1.8%.

MS m/z(ESI)：550[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.68(s，1H)，8.49(m，4H)，8.01(m，2H)，7.75(m，1H)，7.70(d，J＝8.4Hz，1H)，7.49(m，1H)，7.43(s，1H)，7.32(m，3H)，7.24(m，2H)，7.19(m，1H)，6.87(s，1H)，6.64(s，1H)，5.27(s，2H)，4.25(t，J＝7.2Hz，2H)，3.14(t，J＝7.2Hz，2H)

Embodiment 225

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(1.1-dioxy-six hydrogen -1 λ ^* 6 ^* -thiapyran-4-yl)-ethanamide

The first step

2-chloro-N-(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-ethanamide

With 1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-base amine hydrochlorate (32 mg, 0.173 mmol) is dissolved in the 5 mL tetrahydrofuran (THF)s, under condition of ice bath, be cooled to 0 ℃, add triethylamine (37 mg, 0.366 mmol), stir adding chloroacetyl chloride (32 mg, 0.283 mmol) down, 0 ℃ is stirred 2 hours afterreactions down and finishes.Reactant under reduced pressure concentrates, and the residue washed with dichloromethane obtains compound 2-chloro-N-(1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-and ethanamide 225a, product directly carries out next step reaction without separating.

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-ethanamide

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (52 mg, 0.117 mmol) be dissolved in 1 mLN, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (29 mg, 0.725 mmol), stir adding 2-chloro-N-(1,1-dioxo-six hydrogen-1 λ after 30 minutes ^*6 ^*-thiapyran-4-yl)-and 1 mLN of ethanamide 225a (39 mg, 0.173 mmol), dinethylformamide solution stirs reaction in 1.5 hours and finishes under the room temperature.Reaction solution adds 50 mL water, ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=1 00: 1,60: 1), obtain 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-and ethanamide 225 (15 mg, yellow solid), productive rate: 20.3%.

MS m/z(ESI)：634[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.72(s，1H)，8.55(s，1H)，8.51(s，1H)，8.31(d，J＝7.2Hz 1H)，8.03(m，2H)，7.76(d，J＝8.8Hz，1H)，7.71(d，J＝8.0Hz，1H)，7.49(m，1H)，7.34(m，3H)，7.18(m，1H)，6.86(s，1H)，6.68(s，1H)，5.28(s，2H)，4.62(s，2H)，4.02(m，1H)，3.13(m，4H)，1.31(m，4H)

Embodiment 226

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-cyclopropyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

The first step

Methylsulfonic acid cyclopropyl methyl esters

(720 g, 10 mmol) are dissolved in the 20 mL ether with cyclopropyl-carbinol, under condition of ice bath, are cooled to 0 ℃, add triethylamine (2.8 mL, 20 mmol) and methylsulfonyl chloride (1.2 mL, 15 mmol) successively, stir 2 hours under the room temperature, and reaction finishes.Filtering reacting liquid, filter cake washs with ether, and filtrate under reduced pressure is spin-dried for, and obtains methylsulfonic acid cyclopropyl methyl esters 226a (1.49 g, colourless oil liquid), productive rate: 99.3%.

MS m/z(ESI)：151[M+1]

Second step

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (146 mg, 0.33 mmol) be dissolved in the N of 4 mL dryings, in the dinethylformamide, stir and add sodium hydride (40 mg, 0.99 mmol) down, adding methylsulfonic acid cyclopropyl methyl esters 226a (74 mg after 30 minutes, 0.5mmol), stir reaction in 2 hours down at 55 ℃ and finish.Reaction solution adds 30 mL frozen water, with ethyl acetate extraction (30 mL * 4), the organic phase that merges is successively by saturated nacl aqueous solution washing (30 mL * 2), anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-cyclopropyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 226 (81 mg, yellow solid), productive rate: 49.6%.

MS m/z(ESI)：499[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.69(s，1H)，8.53(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，1H)，7.70(m，1H)，7.49(m，2H)，7.28(m，3H)，7.19(m，1H)，6.95(s，1H)，6.67(s，1H)，5.27(s，2H)，3.81(d，J＝7.2Hz，2H)，1.24(m，1H)，0.56(m，2H)，0.39(m，2H)

Embodiment 227

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-[(1r, 4r)-(4-hydroxyl-ring Hexyl]-ethanamide

The first step

2-chloro-N-[(1r, 4r)-4-hydroxyl-cyclohexyl]-ethanamide

With (1r, 4r)-4-Trans-4-Amino Cyclohexanol hydrochloride (115 mg, 0.6 mmol) be dissolved in the methylene dichloride of 10 mL dryings, add triethylamine (8.3 mL, 60 mmol), under acetone-the dry ice bath condition, be cooled to=78 ℃, drip chloroacetyl chloride (0.38 mL, 5 mmol), stir 1 hour afterreaction and finish.Reactant under reduced pressure concentrates, and adds 50 mL ethyl acetate, filters, filter cake washs with 30 mL ethyl acetate, and organic phase under reduced pressure concentrates, and obtains compound 2-chloro-N-(4-hydroxyl-cyclohexyl)-ethanamide 227a (3.55 g, the sorrel solid), productive rate: 92.7%

MS m/z(ESI)：192[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-[(1r, 4r)-(4-hydroxyl-cyclohexyl]-ethanamide

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (80 mg, 3.3 mmol), stir adding 2-chloro-N-(4-hydroxyl-cyclohexyl)-ethanamide 227a (115 mg after 30 minutes, 0.6 mmol), stirring reaction in 6 hours under the room temperature finishes.50 mL frozen water cancellation reaction will be added in the reaction solution, ethyl acetate extraction (50 mL * 3) is arranged, the organic phase that merges is washed by saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1), obtain 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-[(1r, 4r)-(4-hydroxyl-cyclohexyl]-ethanamide 227 (35 mg, yellow solid), productive rate: 11.7%.

MS m/z(ESI)：600[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.55(s，1H)，8.50(s，1H)，8.02(m，3H)，7.75(m，1H)，7.70(m，1H)，7.47(m，1H)，7.30(m，3H)，7.19(m，1H)，6.83(s，1H)，6.67(s，1H)，5.27(s，2H)，4.56(s，2H)，3.51(m，1H)，3.38(m，1H)，1.81(m，4H)1.2(m，4H)

Embodiment 228

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-tetramethyleneimine-1-base- Piperidines-1-yl)-ethyl ketone

The first step

2-chloro-1-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ethyl ketone

(350 mg, 2.27 mmol) are dissolved in the 60 mL tetrahydrofuran (THF)s with 4-pyrrolidyl piperidines, are cooled to-78 ℃ in the dry ice ethanol bath, stir down and drip chloroacetyl chloride (6 g, 53 mmol) gradually, dropwise under the ice bath cooling and stir 30 minutes, and reaction finishes.In reaction solution, add 20 mL water, boil off tetrahydrofuran (THF) under the decompression, the solution that obtains ethyl acetate extraction (100 mL * 3), the organic phase of merging is successively by water washing (100mL * 2), anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product 2-chloro-1-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ethyl ketone 228a (225 mg, brown solid), productive rate: 13%.

MS m/z(ESI)：231[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ethyl ketone

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (300 mg, 0.67 mmol) and sodium hydride (80 mg, 2 mmol) be dissolved in 10 mL N, in the dinethylformamide, stir under the room temperature and add 2-chloro-1-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ethyl ketone 228a (190mg after 30 minutes, 0.8 1 mLN mmol), dinethylformamide solution stirs 30 minutes afterreactions and finishes under the room temperature.In reaction solution, add 100 mL saturated nacl aqueous solution cancellation reaction, water ethyl acetate extraction (100 mL * 3), the organic phase that merges is passed through water successively, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ethyl ketone 228 (190 mg, yellow solid), productive rate: 44%.

MS m/z(ESI)：639[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.74(s，1H)，8.55(s，1H)，8.50(s，1H)，8.03(s，2H)，7.76(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.50(t，J＝8.8Hz，1H)，7.43(s，1H)，7.33(m，3H)，7.19(t，J＝8.8Hz，1H)，6.83(s，1H)，6.66(s，1H)，5.27(s，2H)，4.95(m，2H)，4.14(d，J＝13.2Hz，1H)，3.83(d，J＝12.0Hz，1H)，3.14(m，1H)，2.84(m，1H)，2.50(m，4H)，2.34(br，1H)，1.68(m，4H)，1.41(m，1H)，1.28(m，1H)

Embodiment 229

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-cyclopropyl amino-ethyl)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-cyclopropyl-ethanamide 217 (54 mg, 0.1 mmol) be dissolved in the 3 mL tetrahydrofuran (THF)s, stir adding lithium aluminum hydride (11.4mg, 0.3 mmol) down, afterreaction finished in 3 hours.Add methyl alcohol cancellation reaction, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(2-cyclopropyl amino-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 229 (8 mg, faint yellow solid), productive rate: 15.2%.

MS m/z(ESI)：528[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ8.467(s，1H)，8.445(s，1H)，8.057(d，J＝8.4Hz，1H)，7.920(d，J＝2Hz，1H)，7.729(d，J＝8.8Hz，1H)，7.637(t，J＝4.2Hz，1H)，7.436(m，1H)，7.319(m，3H)，7.165(d，J＝8.8Hz，1H)，7.085(t，J＝7.8Hz，1H)，6.865(s，1H)，6.708(s，1H)，5.229(s，2H)，4.124(t，J＝6.4Hz，2H)，3.134(m，2H)，2.213(m，1H)，0.532(m，2H)，0.394(m，2H)

Embodiment 230

The first step

Methylsulfonic acid (2-pyridin-4-yl) methyl esters

(536 mg, 4.92 mmol) are dissolved in the 40 mL methylene dichloride, under condition of ice bath with 2-pyridin-4-yl-methyl alcohol, be cooled to 0 ℃, add triethylamine (1.1 mg, 10.83 mmol) and methylsulfonyl chloride (668 mg successively, 5.83mmol), to stir 1 hour under the room temperature, reaction finishes.50 mL water will be added in the reaction solution, decompression steams methylene dichloride down, with ethyl acetate extraction (100 mL * 3), the organic phase that merges is filtered successively by anhydrous sodium sulfate drying, and decompression concentrates down, residue is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain methylsulfonic acid (2-pyridin-4-yl) methyl esters 230a (246 mg, white solid), productive rate: 26.7%.

MS m/z(ESI)：188[M+1]

Second step

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (203 mg, 0.46 mmol) be dissolved in the N of 2 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (46 mg, 1.15 mmol), stir and add methylsulfonic acid (2-pyridin-4-yl) methyl esters 230a (136 mg after 20 minutes, 0.73 mmol), stirring reaction in 1.5 hours under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridin-4-yl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 230 (22 mg, yellow solid), productive rate: 84%.

MS m/z(ESI)：536[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.56(m，3H)，8.51(s，1H)，8.06(d，J＝8.4Hz，1H)，8.01(d，J＝2.0Hz，1H)，7.74(m，2H)，7.49(m，2H)，7.32(m，3H)，7.21(m，3H)，7.03(s，1H)，6.77(s，1H)，5.27(s，4H)

Embodiment 231

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-piperidin-4-yl-acetyl Amine

The first step

N-(1-benzyl-piperidin-4-yl)-2-chloro-ethanamide

(2.1 mL, 10 mmol Aldrich) are dissolved in the 25 mL tetrahydrofuran (THF)s, bathe with dry ice-propanone and are cooled to-78 ℃, drip chloroacetyl chloride (0.91 mL, 12 mmol), keep this temperature, and afterreaction finished in 1 hour with 1-benzyl-piperidin-4-yl amine 231a.50 mL water and 50 mL ethyl acetate will be added in the reaction solution, separatory, posture in sleep ethyl acetate extraction (50 mL * 2), the organic phase that merges is washed by saturated nacl aqueous solution, and anhydrous sodium sulfate drying filters, decompression concentrates down, obtain N-(1-benzyl-piperidin-4-yl)-2-chloro-ethanamide 231b (2.5 g, pink solid), productive rate: 91.4%.

MS m/z(ESI)：267[M+1]

Second step

N-(1-benzyl-piperidin-4-yl)-2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanamide

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (445mg, 1 mmol) is dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (140 mg, 3 mmol), stir and add N-(1-benzyl-piperidin-4-yl)-2-chloro-ethanamide 231b (316 mg, 1.2 mmol) after 30 minutes, stir reaction in 1 hour under the room temperature and finish.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=25: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-piperidin-4-yl-ethanamide 231c (478 mg, faint yellow solid), productive rate: 70.9%.

MS m/z(ESI)：675[M+1]

The 3rd step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-piperidin-4-yl-ethanamide

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-piperidin-4-yl-ethanamide 231c (429 mg, 0.64 mmol) be dissolved in the mixed solvent of 5 mL methylene dichloride and 5 mL methyl alcohol, add Pd/C (45 mg, 0.1 mmol), under the hydrogen-pressure of 3atm, react and spend the night.Filtering reacting liquid, filtrate under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=2: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-piperidin-4-yl-ethanamide 231 (78 mg, the yellow-green colour solid), productive rate: 39.3%.

MS m/z(ESI)：585[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.73(s，1H)，8.56(s，1H)，8.50(s，1H)，8.09(s，1H)，8.07(d，J＝8.8Hz，1H)，8.03(s，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.85(s，1H)，6.67(s，1H)，5.27(s，2H)，4.58(s，2H)，4.09(s，1H)，3.62(m，1H)，3.18(s，2H)，2.93(d，J＝12.4Hz，2H)，1.71(d，J＝9.6Hz，2H)，1.32(m，2H)

Embodiment 232

(S)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-tetramethyleneimine-3-ylmethyl-1H-pyrroles-3-yl)-quinazoline -4-yl]-amine

The first step

(S)-3-methylol-tetramethyleneimine-1-t-butyl formate

(5.05 g, 50 mmol) are dissolved in the 150 mL methylene dichloride with (S)-3-methylol-tetramethyleneimine, argon shield, and ice bath is cooled to 0 ℃, adds tert-Butyl dicarbonate (11.44 g, 52.5 mmol), stirs 6 hours under the room temperature, and reaction finishes.Reaction solution is washed with saturated sodium bicarbonate, water ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying filters, and decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=1: 1), obtain (S)-3-methylol-tetramethyleneimine-1-t-butyl formate 232a (9.29 g, yellow oily liquid), productive rate: 92.4%.

MS m/z(ESI)：201[M+1]

Second step

(S)-3-methylsulfonyl oxygen methyl-tetramethyleneimine-1-t-butyl formate

With (S)-3-methylol-tetramethyleneimine-1-t-butyl formate 232a (2.01 g, 10 mmol) be dissolved in the 50 mL methylene dichloride, add triethylamine (5.6 mL under the argon atmospher, 40 mmol), stir and add methylsulfonyl chloride (1.55mL after 10 minutes, 20 mmol), stirred 1 hour under the room temperature, reaction finishes.Reaction solution is washed with saturated sodium bicarbonate, water ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying filters, and decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=4: 1), obtain (S)-3-methylsulfonyl oxygen methyl-tetramethyleneimine-1-t-butyl formate 232b (2.47 g, yellow oily liquid), productive rate: 88.5%.

The 3rd step

(S)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-tetramethyleneimine-1-t-butyl formate

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (220 mg, 0.49 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir and add sodium hydride (60 mg down, 1.47 mmol) and (S)-and 5 mLN of 3-methylsulfonyl oxygen methyl-tetramethyleneimine-1-t-butyl formate 232b (198 mg, 0.74 mmol), dinethylformamide solution, be mixed and heated to 80 ℃, afterreaction finished in 3 hours.Reaction solution is washed with water, ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: tetrahydrofuran (THF)=20: 1), obtain (S)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-tetramethyleneimine-1-t-butyl formate 232c (111 mg, yellow oily liquid), productive rate: 36.1%.

MS m/z(ESI)：629[M+1]

The 4th step

(S)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-tetramethyleneimine-3-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

With (S)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-tetramethyleneimine-1-t-butyl formate 232c (110 mg, 0.175 mmol) be dissolved in the 10 mL methylene dichloride, stir adding 3 mL hydrochloric acid methyl ether solution down, stir reaction in 1 hour under the room temperature and finish.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=20: 1, methylene dichloride: methyl alcohol: ammoniacal liquor=20: 1: 1d), obtain (S)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-tetramethyleneimine-3-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 232 (30 mg, faint yellow solid), productive rate: 32.6%.

MS m/z(ESI)：529[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(s，2H)，7.72(dd，J＝2.0Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.48(m，2H)，7.32(m，3H)，7.19(m，1H)，6.91(s，1H)，6.66(s，1H)，5.27(s，2H)，4.04(m，1H)，3.84(m，2H)，3.35(m，1H)，2.81(m，2H)，1.69(m，3H)，1.38(m，1H)

Embodiment 233

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-[4-(2-hydroxyethyl)-piperazine Piperazine-1-yl]-ethyl ketone

The first step

2-chloro-1-[4-(2-hydroxyethyl)-piperazine-1-yl]-ethyl ketone

(1.302 g, 10 mmol) are dissolved in the 20 mL tetrahydrofuran (THF)s with 2-piperazine-1-base-ethanol, under acetone-the dry ice bath condition, be cooled to-78 ℃, add 2 mL triethylamines, stir after 15 hours, drip chloroacetyl chloride (0.75 mL, 10 mmol), stir 1 hour afterreaction and finish.Reactant under reduced pressure concentrates, residue carries out separation and purification (methylene dichloride: methyl alcohol=15: 1) by silica gel column chromatography, obtain colourless oil liquid crude product 2-chloro-1-[4-(2-hydroxyethyl)-piperazine-1-yl]-ethyl ketone 233a, product directly carries out next step reaction without separating.

MS m/z(ESI)：207[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-[4-(2-hydroxyethyl)-piperazine-1-base l]-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (444 mg, 1 mmol) is dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (72 mg, 3 mmol), stir adding 2-chloro-1-[4-(2-hydroxyethyl)-piperazine-1-yl after 30 minutes]-ethyl ketone 233a (206 mg, 1 mmol), stirring reaction in 1 hour under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=8: 1), obtain 2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-[4-(2-hydroxyethyl)-piperazine-1-base l]-ethyl ketone 233 (215 mg, faint yellow solid), productive rate: 34.9%.

MS m/z(ESI)：586[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，5.0(s，2H)，3.5(m，8H)，2.4(t，J＝12Hz，4H)

Embodiment 234

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-tetramethyleneimine-1-base- Piperidines-1-yl)-propan-2-ol

4-tetramethyleneimine-1-base-piperidines (69 mg, 0.45mmol, Alfa) and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (150 mg, 0.3 mmol) be dissolved in the 10 mL methyl alcohol, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-tetramethyleneimine-1-base-piperidines-1-yl)-propan-2-ol 234 (35 mg, yellow solid), productive rate: 15%.

MS m/z(ESI)：655[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.713(s，1H)，8.546(s，1H)，8.494(s，1H)，8.034(t，J＝5.2Hz，2H)，7.764(t，J＝5.6Hz，1H)，7.703(d，J＝8.4Hz，1H)，7.484(m，1H)，7.417(s，1H)，7.319(m，3H)，7.193(t，J＝8.6Hz，1H)，6.868(s，1H)，6.655(s，1H)，5.274(s，2H)，4.896(s，1H)，4.030(d，J＝13.6Hz，1H)，3.877(m，2H)，3.486(s，2H)，3.427(m，1H)，2.848(m，2H)，2.652(m，2H)，2.245(d，J＝17.6Hz，2H)，2.000(t，J＝11.6Hz，2H)，1.815(m，2H)，1.501(m，2H)，1.254(m，4H)

Embodiment 235

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(1,1-dioxy-six hydrogen-1 λ ^* 6 ^* -thiapyran 4-base is amino)-second Base]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-(1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-yl)-and ethanamide 225 (54 mg, 0.1 mmol) is dissolved in the 3 mL tetrahydrofuran (THF)s, stirs to add lithium aluminum hydride (11.4 mg, 0.3 mmol) down, and afterreaction finished in 3 hours.Add methyl alcohol cancellation reaction, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(2-cyclopropyl amino-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 229 (8 mg, faint yellow solid), productive rate: 15.2%.

MS m/z(ESI)：528[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.68(s，1H)，8.53(s，1H)，8.50(s，1H)，8.03(m，2H)，7.76(dd，J＝8.8Hz 2.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.45(s，1H)，7.32(m，3H)，7.19(m，1H)，6.93(s，1H)，6.67(s，1H)，5.27(s，2H)，3.99(m，2H)，3.10(m，2H)，2.98(m，2H)，2.90(m，2H)，2.79(m，1H)，1.24(m，4H)

Embodiment 236

4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine Piperazine-1-yl }-cyclopropyl-ketone

The first step

Cyclopropyl-piperazine-1-base-ketone

Under the argon atmospher, piperazine-1-t-butyl formate (1.86 g, 10 mmol) and salt of wormwood (4.15 g, 30 mmol) are dissolved in the 100 mL methylene dichloride, stir adding cyclopropyl formyl chloride (1.17 g, 11.2 mmol) down, mixed solution at room temperature stirs and spends the night.Reaction solution is poured in the 30 mL water, ethyl acetate extraction (30 mL * 3), the organic phase of merging is filtered by anhydrous sodium sulfate drying, and decompression concentrates down, obtains cyclopropyl-piperazine-1-base-ketone 236a (2.5 g, white solid), productive rate: 99%.

MS m/z(ESI)：255[M+1]

Second step

Cyclopropyl-piperazine-1-base-ketone

4-cyclopropyl carbonyl-piperazine-1-t-butyl formate 236a (2.1 g, 8 mmol) is dissolved in the methylene dichloride of 10 mL dryings, stirs down to add trifluoracetic acid (14.28 g, 125 mmol), stirs 2 hours afterreactions under the room temperature and finishes.Reaction solution is under reduced pressure concentrated, add 20 mL saturated sodium carbonate solutions, separatory, concentrate water, the residue that obtains adds 20 mL methyl alcohol, stirs, filter, filter cake methanol wash three times, filtrate are filtered by anhydrous sodium sulfate drying, decompression concentrates down, obtain cyclopropyl-piperazine-1-base-ketone 236b (1.5 g, white solid), productive rate: 99%.

MS m/z(ESI)：155[M+1]

The 3rd step

4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine-1-yl }-cyclopropyl-ketone

With cyclopropyl-piperazine-1-base-ketone 236b (51 mg, 0.33 mmol) with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (150 mg, 0.3 mmol) be dissolved in the 50 mL methyl alcohol, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine-1-yl-cyclopropyl-ketone 236 (21 mg, yellow solid), productive rate: 10.7%.

MS m/z(ESI)：655[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ8.468(s，H)，8.446(s，H)，8.079(d，J＝8.8Hz，1H)，7.921(s，1H)，7.731(dJ＝8.8Hz，1H)，7.640(d，J＝9.2Hz，1H)，7.431(t，J＝7Hz，1H)，7.352(t，J＝8.6Hz，2H)，7.290(d，J＝9.2Hz，1H)，7.178(d，J＝9.2Hz，1H)，7.091(t，J＝8.6Hz，1H)，6.74(s，1H)，6.696(s，1H)，5.242(s，2H)，4.122(m，2H)，4.013(t，J＝7.2Hz，1H)，3.593(m，2H)，3.816(br，2H)，3.650(br，2H)，2.605(br，2H)，2.431(d，J＝6Hz，2H)，2.253(s，1H)，1.322(s，1H)

Embodiment 237

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-cyclopropyl methyl- Piperazine-1-yl)-propan-2-ol

The first step

1-cyclopropyl methyl-piperazine

Methylsulfonic acid cyclopropyl methyl esters 226a (1.49 g, 10 mmol) and piperazine (1.77g, 20 mmol) are dissolved in the 30 mL acetonitriles, stir adding salt of wormwood (2.07g, 15 mmol) down, the mixed solution reflux, reaction is spent the night.Reaction solution is poured in the 30 mL water, separatory, organic phase is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=5: 1), obtain 1-cyclopropyl methyl-piperazine 237a (373 mg, yellow oily liquid), productive rate: 26.8%.

MS m/z(ESI)：141[M+1]

Second step

With 1-cyclopropyl methyl-piperazine 237a (57 mg, 0.42 mmol) with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (140 mg, 0.3 mmol) be dissolved in the 25 mL methyl alcohol, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-cyclopropyl methyl-piperazine-1-yl)-propan-2-ol 237 (116 mg, yellow solid), productive rate: 30.1%.

MS m/z(ESI)：641[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.72(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(s，1H)，8.02(d，J＝8.8Hz，1H)，7.77(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.87(s，1H)，6.65(s，1H)，5.27(s，2H)，4.92(d，J＝4.0Hz，1H)，4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，2.48(br，8H)，2.25(br，2H)，2.19(br，2H)，0.80(m，1H)，0.45(d，J＝6.8Hz，2H)，0.06(d，J＝4.4Hz，2H)

Embodiment 238

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1- Piperazine-1-base-ethyl ketone

The first step

4-(2-chloracetyl)-piperazine-1-t-butyl formate

With piperazine-1-t-butyl formate (1g, 5.38 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, stir and add triethylamine (651 mg down, 6.45 mmol), reaction solution is cooled to-78 ℃ at acetone-the dry ice bath, drip chloroacetyl chloride (0.8mL, 6.45 mmol), reaction solution at room temperature stirred 24 hours, and reaction finishes.Reaction solution is under reduced pressure concentrated; residue adds 50 mL water; with ethyl acetate extraction (50 mL * 3); the organic phase that merges is filtered by anhydrous sodium sulfate drying, and decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=1: 1); obtain 4-(2-chloracetyl)-piperazine-1-t-butyl formate 238a (1.1 g, yellow solid), productive rate: 70%.

MS m/z(ESI)：264[M+1]

Second step

4-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperazine-1-t-butyl formate

In the flask of 50 mL; with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (444 mg; 1 mmol) is dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath; be cooled to 0 ℃; add sodium hydride (72 mg, 3 mmol), stir and add 4-(2-chloracetyl)-piperazine-1-t-butyl formate 238a (263 mg after 30 minutes; 1 mmol), stirring reaction in 1 hour under the room temperature finishes.In reaction solution, add saturated nacl aqueous solution; ethyl acetate extraction (100 mL * 3); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter; decompression concentrates down, the residue that obtains by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain 4-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperazine-1-t-butyl formate 238b (300 mg; faint yellow solid), productive rate: 51%.

MS m/z(ESI)：671[M+1]

The 3rd step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-piperazine-1-base-ethyl ketone

With 4-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperazine-1-t-butyl formate 238b (400mg; 0.6 mmol) be dissolved in the 10 mL methylene dichloride; stir adding 3 mL trifluoracetic acids down, stir 2 hours afterreactions under the room temperature and finish.Saturated sodium bicarbonate solution will be added in the reaction solution, regulate pH=8, with ethyl acetate extraction (100 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, residue is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-piperazine-1-base-ethyl ketone 238 (270 mg, yellow solid), productive rate: 79%.

MS m/z(ESI)：571[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.49(s，1H)，8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.95(s，2H)，3.44(br，4H)，2.72(m，4H)

Embodiment 239

N-{1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]- Piperidin-4-yl }-ethanamide

The first step

N-piperidin-4-yl-ethanamide acetate

(0.52 mL, 5 mmol) are dissolved in the 20 mL ether with piperidin-4-yl amine, drip the 20 mL diethyl ether solutions of acetic anhydride (0.57mL, 6 mmol) gradually, after dropwising, stir 1 hour under the room temperature, and reflection finishes.Filtering reacting liquid, filter cake washs with ether, and filtrate under reduced pressure concentrates, and obtains N-piperidin-4-yl-ethanamide acetate 239a (962 mg, white solid), productive rate: 95.7%.

Second step

N-piperidin-4-yl-ethanamide

N-piperidin-4-yl-ethanamide acetate 239a (500 mg, 2.48 mmol) is dissolved in the 10 mL methyl alcohol, drips the methanol solution of 20 mL saturated potassium carbonates, stirred 1 hour under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains ethyl acetate extraction (100 mL * 3), the residue of gained is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain N-piperidin-4-yl-ethanamide 239b (224 mg, colourless oil liquid), productive rate: 63.7%.

MS m/z(ESI)：143[M+1]

The 3rd step

N-{1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidin-4-yl }-ethanamide

With N-piperidin-4-yl-ethanamide 239b (60 mg, 0.42 mmol) with [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (165 mg, 0.33 mmol) be dissolved in the 30 mL methyl alcohol, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain this title product N-{1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidin-4-yl-ethanamide 239 (33 mg, yellow solid), productive rate: 22.9%.

MS m/z(ESI)：643[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ10.00(s，1H)，8.72(s，1H)，8.48(s，1H)，8.11(s，1H)，8.02(d，J＝8.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.86(s，1H)，6.73(s，1H)，5.27(s，2H)，5.17(br，1H)，4.14(d，J＝12.4Hz，1H)，4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，3.72(d，J＝13.2Hz，1H)，3.34(s，1H)，3.04(t，J＝11.6Hz，1H)，2.70(t，J＝10.8Hz，1H)，2.60(m，2H)，1.97(s，3H)，1.74(br，2H)，1.15(m，2H)

Embodiment 240

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-piperazine-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-piperazine-1-base-ethyl ketone 238 (120 mg; 0.21 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s; under argon shield; add lithium aluminum hydride (40 mg; 2.1 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=15: 1), obtain [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(2-piperazine-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine (44 mg, yellow solid), productive rate: 37.6%.

MS m/z(ESI)：557[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.49(s，1H)，8.03(d，J＝8Hz，2H)，7.76(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.33(m，3H)，7.19(t，J＝8Hz，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，4.05(t，J＝8Hz，2H)，2.92(m，4H)，2.72(m，2H)，2.53(br，4H)

Embodiment 241

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-methyl-piperazine -1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles; with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (565 mg; 1.15 mmol) be dissolved in the 30 mL methyl alcohol; add 1-methylpiperazine (461 mg under the argon shield; 4.6 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of thin layer chromatography board (methylene dichloride: methyl alcohol=7: 1), obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-methyl-piperazine-1-yl)-propan-2-ol 241 (296 mg, yellow solid), productive rate: 43.5%.

MS m/z(ESI)：591[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.83(s，1H)，8.61(s，1H)，8.44(s，1H)，8.23(s，1H)，8.17(s，1H)，8.04(d，1H，J＝8.8 Hz)，7.75(m，3H)，7.41(m，2H)，7.14(m，3H)，6.87(s，1H)，6.67(s，1H)，5.72(s，2H)，4.94(br s，1H)，4.04(m，2H)，3.94(m，1H)，3.88(m，1H)，3.18(d，2H，J＝3.6 Hz)，2.47(m，5H)，2.27(m，5H)

Embodiment 242

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-((3S, 5R)-3,5-two for 1- Methyl-piperazine-1-yl)-ethyl ketone

The first step

2-chloro-1-[(3S, 5 R)-3,5-dimethyl-piperazine-1-yl]-acetophenone hydrochloride

(2S, 6R)-2,6-lupetazin (229 mg, 2 mmol) is dissolved in the 10 mL methylene dichloride, solution is cooled to-78 ℃ under dry ice-propanone is bathed, stir to add chloroacetyl chloride (242 mg, 2.14 mmol) down, add 10 mL water after 5 minutes, rise to room temperature, reaction finishes.Reaction solution is under reduced pressure steamed methylene dichloride, and the vacuum-freeze-dry machine obtains 2-chloro-1-[(3S except anhydrating, 5R)-3, and 5-dimethyl-piperazine-1-yl]-acetophenone hydrochloride 242a (456 mg, white solid), productive rate: 100%

MS m/z(ESI)：191[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-((3S, 5R)-3,5-dimethyl-piperazine-1-yl)-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (487 mg, 1.097 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (176 mg, 4.4 mmol), stir adding 2-chloro-1-[(3S after 30 minutes, 5R)-3,5-dimethyl-piperazine-1-yl]-acetophenone hydrochloride 242a (362 mg, 1.6 mmol), stirring reaction in 1 hour under the room temperature finishes.Add 50 mL water in the reaction solution, ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-((3S, 5R)-3,5-dimethyl-piperazine-1-yl)-ethyl ketone 242 (27 mg, yellow solid), productive rate: 64.9%.

MS m/z(ESI)：599[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.54(s，1H)，8.50(s，1H)，8.03(m，2H)，7.76(d，J＝8.8Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.48(m，1H)，7.33(m，4H)，7.19(m，1H)，6.82(s，1H)，6.66(s，1H)，5.27(s，2H)，4.96(dd，J＝72.0Hz 16.4Hz，2H)，4.22(d，J＝12.8Hz，1H)，3.76(d，J＝12.0Hz，1H)，2.59(m，3H)，2.11(t，J＝12.0Hz，1H)，0.99(m，6H)

Embodiment 243

6-[1-(2-nitrogen heterocyclic heptan-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)- Phenyl]-amine

The first step

Methylsulfonic acid 2-nitrogen heterocyclic heptan-1-base-ethyl ester

2-nitrogen heterocyclic heptan-1-base-ethanol (1.43 g, 10 mmol) is dissolved in the 10 mL methylene dichloride, under condition of ice bath, be cooled to 0 ℃, add triethylamine (2.02 g, 20 mmol) and methylsulfonyl chloride (1.7 g successively, 15 mmol), stirred 1 hour under the room temperature, reaction finishes.The 20 mL shrends reaction of going out will be added in the reaction solution, to be spin-dried for methylene dichloride, water ethyl acetate extraction (30 mL * 3), the organic phase of merging is washed by saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography, obtains methylsulfonic acid 2-nitrogen heterocyclic heptan-1-base-ethyl ester 243a (2.1 g, yellow oily liquid), productive rate: 95%.

MS m/z(ESI)：222[M+1]

Second step

6-[1-(2-nitrogen heterocyclic heptan-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) be dissolved in the N of 6 mL dryings, in the dinethylformamide, stir and to add sodium hydride (60 mg, 2.5 mmol) down, add methylsulfonic acid 2-nitrogen heterocyclic heptan-1-base-ethyl ester 243a (166mg after 30 minutes, 0.75 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution adds 20 mL frozen water, with ethyl acetate extraction (30 mL * 4), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product { 6-[1-(2-nitrogen heterocyclic heptan-1-base-ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 243 (230 mg, yellow solid), productive rate: 81%.

MS m/z(ESI)：570[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.68(s，1H)，8.52(s，1H)，8.50(s，1H)，8.02(m，2H)，7.76(m，1H)，7.70(m，1H)，7.47(m，2H)，7.32(m，3H)，7.19(m，1H)，6.92(s，1H)，6.65(s，1H)，5.27(s，2H)，4.00(t，J＝6.0Hz，2H)，2.86(m，2H)，2.67(m，4H)，1.56(m，8H)

Embodiment 244

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(4-hydroxyl-1, the 1-dioxy- Six hydrogen-1 λ ^* 6 ^* -thiapyran-4-ylmethyl)-ethanamide

The first step

2-chloro-N-(4-hydroxyl-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-ylmethyl)-ethanamide

With 4-aminomethyl-1,1-dioxo-six hydrogen-1 λ ^*6 ^*-thiapyran-4-alcohol (358 mg, 2 mmol) be dissolved in the 10 mL methylene dichloride, stir triethylamine (0.55 mL, 4 mmol) down, be added under the dry ice-propanone bath condition, be cooled to-78 ℃, under the argon atmospher, add and chloroacetyl chloride (226 mg, 2 mmol), temperature rises to-30 ℃ and stirred 1 hour down, and reaction finishes.Be spin-dried for solvent under the reaction solution decompression, add 20 mL ethyl acetate, filter, filtrate under reduced pressure concentrates, and obtains 2-chloro-N-(4-hydroxyl-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-ylmethyl)-and ethanamide 244a (430 mg, sorrel solid), productive rate: 84.3%.

MS m/z(ESI)：256[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(4-hydroxyl-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-ylmethyl)-ethanamide

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (222 mg, 0.5 mmol) be dissolved in the tetrahydrofuran (THF) of 8 mL dryings, under the argon atmospher, add potassium tert.-butoxide (224 mg, 2 mmol), add 2-chloro-N-(4-hydroxyl-1,1-dioxy-six hydrogen-1 λ after 30 minutes ^*6 ^*-thiapyran-4-ylmethyl)-and ethanamide 244a (192 mg, 0.75 mmol), stir reaction in 3 hours under the room temperature and finish.Reaction solution adds 20 mL methyl alcohol, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=30: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-(4-hydroxyl-1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-ylmethyl)-and ethanamide 244 (92 mg, yellow solid), productive rate: 49%.

MS m/z(ESI)：664[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.55(s，1H)，8.50(s，1H)，8.13(m，1H)，8.03(m，2H)，7.74(m，2H)，7.49(m，1H)，7.33(m，4H)，7.19(m，1H)，6.86(s，1H)，6.68(s，1H)，5.27(s，2H)，4.68(s，2H)，3.18(m，4H)，2.98(m，2H)，1.93(m，4H)

Embodiment 245

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2-methylsulfonyl-second The oxygen base)-propan-2-ol

In 100 mL eggplant-shape bottles; with cesium carbonate (274 mg; 0.84 mmol) be dissolved in N; in the dinethylformamide; stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (140 mg down; 0.28 mmol) be dissolved in the 10 mL anhydrous methanols with 2-methylsulfonyl ethanol (104 mg, 0.84 mmol), reflux is spent the night.Reaction solution is added 100 mL water; extract with ethyl acetate (100mL * 3); the organic phase that merges is passed through anhydrous sodium sulfate drying successively; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1); obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-methylsulfonyl-oxyethyl group)-propan-2-ol 245 (42 mg; yellow solid), productive rate: 24%.

MS m/z(ESI)：625[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.67(s，1H)，8.8(s，1H)，8.5(s，1H)，8.03(d，J＝8.8Hz，2H)，7.76(dd，J＝2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.5(m，2H)，7.36(m，3H)，7.2(s，1H)，6.93(s，1H)，6.60(s，1H)，5.27(s，2H)，4.01(m，1H)，3.90(m，1H)，3.80(m，2H)，3.50(m，3H)，3.39(m，2H)，3.02(s，3H)，1.98(br，1H)

Embodiment 246

N-{1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperazine Pyridine-4-yl }-ethanamide

The first step

N-[1-(2-chloro-ethanoyl)-piperidin-4-yl]-ethanamide

N-piperidin-4-yl-ethanamide 239b (150 mg, 1.05 mmol) is dissolved in the 15 mL methylene dichloride, adds triethylamine (1 mL, 2.1 mmol), reaction solution is cooled to-78 ℃ at acetone-the dry ice bath, drips chloroacetyl chloride (119mg, 1.05 mmol), stirring reaction in 1 hour finishes.Add 50 mL water and 50 mL ethyl acetate in the reaction solution; separatory; water ethyl acetate extraction (100 mL * 2); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1); obtain this title product N-{1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperidin-4-yl-ethanamide 246a (27 mg; yellow oily liquid), productive rate: 12%.

MS m/z(ESI)：219[M+1]

Second step

N-{1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidin-4-yl }-ethanamide

In the flask of 50 mL; with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (59 mg; 0.11 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath; be cooled to 0 ℃; add sodium hydride (16 mg, 0.33 mmol), stir add N-[1-(2-chloro-ethanoyl)-piperidin-4-yl after 30 minutes]-ethanamide 246a (27 mg; 0.12 mmol), stirring reaction in 1 hour under the room temperature finishes.Add 50 mL water and 50 mL ethyl acetate in the reaction solution; separatory; water ethyl acetate extraction (100 mL * 2); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1); obtain this title product N-{1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperidin-4-yl-ethanamide 246 (18 mg; faint yellow solid), productive rate: 26.1%.

MS m/z(ESI)：627[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ10.05(s，1H)，8.76(s，1H)，8.53(s，1H)，8.50(s，1H)，8.11(s，1H)，8.02(d，J＝8.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.1 9(t，J＝8.8Hz，1H)，6.85(s，1H)，6.76(s，1H)，5.27(s，2H)，4.63(s，2H)，4.17(d，J＝12.8Hz，1H)，3.79(br，2H)，3.14(t，J＝11.6Hz，1H)，2.79(t，J＝11.4Hz，1H)，2.00(s，3H)，1.77(m，2H)，1.30(m，2H)

Embodiment 247

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[(R)-2-pyrroles Alkane-1-ylmethyl-tetramethyleneimine-1-yl]-propan-2-ol

The first step

(S)-3-methylol-tetramethyleneimine-1-t-butyl formate

(5.05 g, 50 mmol) are dissolved in the 150 mL methylene dichloride with (S)-3-methylol-tetramethyleneimine, under condition of ice bath, are cooled to 0 ℃, add diacetyl oxide (11.44 g, 52.5 mmol), and reaction solution at room temperature stirs and spends the night.Reaction solution is washed with saturated sodium bicarbonate, ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution, anhydrous sodium sulfate drying filters, and decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=3: 1), obtain (S)-3-methylol-tetramethyleneimine-1-t-butyl formate 247a (9.54 g, yellow oily liquid), productive rate: 94.9%.

MS m/z(ESI)：202[M+1]

Second step

(S)-3-methylsulfonyl oxygen methyl-tetramethyleneimine-1-t-butyl formate

With (S)-3-methylol-tetramethyleneimine-1-t-butyl formate 247a (5 g, 24.8 mmol) be dissolved in the 100 mL methylene dichloride, under argon atmospher, drip triethylamine (13.8 mL, 100 mmol), ice bath is cooled to 0 ℃, adds methylsulfonyl chloride (3.9 mL, 49.6 mmol), reaction solution at room temperature stirs to react in 1 hour and finishes.Reaction solution is washed with saturated sodium bicarbonate, ethyl acetate extraction (50 mL * 3), the organic phase that merges is by water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters, and decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=4: 1), obtain (S)-3-methylsulfonyl oxygen methyl-tetramethyleneimine-1-t-butyl formate 247b (6.14 g, yellow oily liquid), productive rate: 88.7%.

MS m/z(ESI)：280[M+1]

The 3rd step

(R)-3-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-t-butyl formate

(S)-3-methylsulfonyl oxygen methyl-tetramethyleneimine-1-t-butyl formate 247b (1.5 g, 5.37 mmol) and tetramethyleneimine (0.49 mL, 5.9 mmol) be dissolved in the mixed solvent of 55 mL ethanol and tetrahydrofuran (THF) (10: 1), stir and add salt of wormwood (1.11 g down, 8.05 mmol), heating reflux reaction spends the night.Reaction solution is under reduced pressure concentrated, residue is by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=1: 1), obtain (R)-3-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-t-butyl formate 247c (215 mg, yellow oily liquid), productive rate: 13.4%.

MS m/z(ESI)：255[M+1]

The 4th step

(S)-1-(tetramethyleneimine-3-ylmethyl) pyrrolidine hydrochloride

(R)-3-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-t-butyl formate 247c (215 mg, 0.98 mmol) is dissolved in the 10 mL methylene dichloride, stirs adding 10 mL 4N methyl ether-hydrogen chloride solutions down, stirred 3 hours under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, and the residue that obtains obtains (S)-1-(tetramethyleneimine-3-ylmethyl) pyrrolidine hydrochloride (100 mg, pale solid), productive rate: 67.6% with ethyl acetate washing (50 mL * 3).

The 5th step

(R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-propan-2-ol

(R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 186a (170 mg, 0.35 mmol) be dissolved in the 30 mL methyl alcohol, under the argon atmospher, stir and add (S)-1-(tetramethyleneimine-3-ylmethyl) pyrrolidine hydrochloride (101 mg down, 0.52 mmol) and salt of wormwood (0.071 g, 0.52mmol), mixture heating up refluxes and spends the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1,30: 1,15: 1,10: 1), obtain title product (R)-1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-propan-2-ol 247 (35 mg, yellow solid), productive rate: 24.1%.

MS m/z(ESI)：656[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.50(s，1H)，8.03(m，2H)，7.76(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.47(m，1H)，7.42(s，1H)，7.36(m，3H)，7.19(m，1H)，6.88(s，1H)，6.65(s，1H)，5.27(s，2H)，3.98(m，1H)，3.85(m，2H)，3.12(m，1H)，2.64(m，1H)，2.59(m，1H)，2.41(br，6H)，2.27(m，2H)，1.85(m，1H)，1.66(br，6H)，1.45(m，1H)

Embodiment 248

1-[3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]- Piperidines-4-alcohol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (225 g, 0.46 mmol) be dissolved in the 25 mL methyl alcohol, stir and add 4-hydroxy piperidine (186 mg down, 1.84 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-[3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidines-4-alcohol 248 (29 mg, the yellowish brown solid), productive rate: 48%.

MS m/z(ESI)：592[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.86(s，1H)，8.63(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.77(s，2H)，7.70(d，1H，J＝8.8Hz)，7.45(s，1H)，7.38(m，1H)，7.08(m，3H)，6.68(s，1H)，6.70(s，1H)，5.72(s，2H)，4.56(m，1H)，4.06(m，2H)，3.91(m，2H)，3.50(m，1H)，3.18(m，2H)，2.90(m，1H)，2.74(m，1H)，2.51(m，2H)，1.78(m，2H)，1.52(m，2H)

Embodiment 249

1-(1,1-dioxy-six hydrogen-1 λ ^* 6 ^* -thiapyran-4-base is amino)-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]- Quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol

In the 100mL eggplant-shape bottle, with 1,1-dioxy-six hydrogen-1 λ ^*6 ^*-thiapyran-4-base amine hydrochlorate (302 mg, 1.63 mmol) be dissolved in the 20 mL methyl alcohol, add triethylamine (165 mg, 1.63 mmol), stir and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 g after 30 minutes, 0.41 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, and the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(1,1-dioxy-six hydrogen-1 λ by thin-layer chromatography ^*6 ^*-thiapyran-4-base is amino)-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol 249 (45 mg, yellowish brown solid), productive rate: 17.3%.

MS m/z(ESI)：640[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.88(s，1H)，8.63(s，1H)，8.44(s，1H)，8.23(s，1H)，8.18(s，1H)，8.03(d，1H，J＝8.8Hz)，7.76(s，2H)，7.72(d，1H，J＝8.8Hz)，7.45(s，1H)，7.39(m，1H)，7.09(m，3H)，6.90(s，1H)，6.70(s，1H)，5.72(s，2H)，4.06(m，2H)，3.92(m，1H)，3.06(m，9H)，2.13(m，2H)，1.92(m，2H)

Embodiment 250

1-[1,4 '] dipiperidino-1 '] base-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrrole Cough up-the 1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with [1 (3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 g, 0.41 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 4-piperidinyl piperidine (274 mg down, 1.63 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-[1,4 '] dipiperidino-1 '-Ji-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol 250 (109 mg, the yellowish brown solid), productive rate: 41%.

MS m/z(ESI)：659[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.89(s，1H)，8.65(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.75(s，1H)，7.70(d，2H，J＝8.8Hz)，7.45(s，1H)，7.37(m，1H)，7.06(m，3H)，6.88(s，1H)，6.69(s，1H)，5.72(s，2H)，3.96(m，3H)，3.01(m，5H)，2.29(m，3H)，1.98(m，4H)，1.70(m，6H)，1.44(m，4H)

Embodiment 251

1-cyclopropyl amino-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)- Propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 g, 0.41 mmol) be dissolved in the 20 mL methyl alcohol, stir and add cyclopropylamine (93 mg down, 1.63 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-cyclopropyl amino-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-propan-2-ol 251 (95 mg, the yellowish brown solid), productive rate: 41%.

MS m/z(ESI)：548[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ8.47(s，1H)，8.43(s，1H)，8.11(s，1H)，8.09(s，1H)，8.07(d，1H，J＝8.8Hz)，7.74(s，1H)，7.70(d，2H，J＝8.8Hz)，7.43(s，1H)，7.30(m，1H)，6.97(m，3H)，6.79(s，1H)，6.63(s，1H)，5.62(s，2H)，4.02(m，3H)，2.87(m，1H)，2.74(m，1H)，2.28(m，1H)，0.57(m，4H)

Embodiment 252

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl]-pyrroles-1-yl)-3-(4-cyclopropyl-piperazine -1-yl)-propan-2-ol

The first step

1-cyclopropyl-piperazine

4-cyclopropyl-piperazine-1-t-butyl formate 252a (500mg, 2.2 mmol) is dissolved in the 20 mL methylene dichloride, stirs down and drip 3 mL trifluoroacetic acids, stirred 1 hour under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, the residue that obtains is dissolved in the 15 mL methyl alcohol, regulate pH=8～9 with saturated sodium carbonate solution, concentration of reaction solution, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=20: 2: 1d), obtain 1-cyclopropyl-piperazine 252b (277 mg, white solid), productive rate: 100%.

MS m/z(ESI)：127[M+1]

Second step

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-cyclopropyl-piperazine-1-yl)-propan-2-ol

With 1-cyclopropyl-piperazine 252b (61 mg, 0.48 mmol) be dissolved in the 25 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200mg down, 0.4 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (gradient elution: methylene dichloride: methyl alcohol=50: 1,25: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-cyclopropyl-piperazine-1-yl)-propan-2-ol 252 (46 mg, yellow solid), productive rate: 29.7%.

MS m/z(ESI)：627[M ⁺]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.70(s，1H)，8.54(s，1H)，8.38(s，1H)，8.04(m，2H)，7.77(dd，J＝2.4Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.48(m，1H)，7.41(s，1H)，7.32(m，3H)，7.19(m，1H)，6.87(s，1H)，6.65(s，1H)，5.27(s，2H)，4.03(m，1H)，3.88(br，1H)，3.81(m，1H)，2.57(br，4H)，2.40(br，4H)，2.23(br，2H)，1.58(br，1H)，0.39(m，2H)，0.27(m，2H)

Embodiment 253

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-cyclopropyl methyl- Piperazine-1-yl)-ethyl ketone

The first step

2-chloro-1-(4-cyclopropyl methylpiperazine-1-yl)-ethyl ketone

With 1-cyclopropyl methylpiperazine 237a (200 mg, 1.05 mmol) be dissolved in the mixed solvent of 10 mL methylene dichloride and 10 mL tetrahydrofuran (THF)s, add triethylamine (1 mL, 2.1 mmol), reaction solution is cooled to-78 ℃ at acetone-the dry ice bath, drip chloroacetyl chloride (0.2 mL, 1.43 mmol), stir 1 hour afterreaction and finish.Add 50 mL water and 50 mL ethyl acetate in the reaction solution, separatory, water ethyl acetate extraction (100 mL * 2), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, obtains 2-chloro-1-(4-cyclopropyl methylpiperazine-1-yl)-ethyl ketone 253a (151 mg, brown oily liquids), productive rate: 48.8%.

MS m/z(ESI)：239[M+23]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-cyclopropyl methyl-piperazine-1-yl)-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (335 mg, 0.7 mmol) be dissolved in the N of 20 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (108 mg, 2.1 mmol), stir adding 2-chloro-1-(4-cyclopropyl methylpiperazine-1-yl)-ethyl ketone 253a (150 mg after 30 minutes, 0.7 mmol), stirring reaction in 3 hours under the room temperature finishes.Add 50 mL water and 50 mL ethyl acetate in the reaction solution, separatory, water ethyl acetate extraction (100mL * 2), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=25: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(4-cyclopropyl methyl-piperazine-1-yl)-ethyl ketone 253 (215 mg, yellow solid), productive rate: 49%.

MS m/z(ESI)：625[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ10.00(s，1H)，8.72(s，1H)，8.49(s，1H)，8.10(s，1H)，8.02(d，J＝8.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.80(s，1H)，6.74(s，1H)，5.27(s，2H)，4.96(s，2H)，3.51(br，4H)，2.51(br，2H)，2.43(br，2H)，2.22(d，J＝6.0Hz，2H)，0.85(m，1H)，0.47(m，2H)，0.09(m，2H)

Embodiment 254

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[4-(2-hydroxyl second Base)-piperidines-1-yl]-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (100 g, 0.204 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 2-piperidin-4-yl ethanol (79 mg down, 0.61 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-[4-(2-hydroxyethyl)-piperidines-1-yl]-propan-2-ol 254 (105 mg, the yellowish brown solid), productive rate: 83%.

MS m/z(ESI)：620[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.85(s，1H)，8.63(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.74(m，3H)，7.44(s，1H)，7.38(m，1H)，7.08(m，3H)，6.89(s，1H)，6.70(s，1H)，5.72(s，2H)，4.36(m，1H)，4.04(m，3H)，3.91(m，1H)，3.44(m，2H)，2.51(m，6H)，1.70(m，2H)，1.24(m，5H)

Embodiment 255

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[4-(2-hydroxyl second Base)-piperazine-1-yl]-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (150 g, 0.306 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 2-piperazine-1-base ethanol (79 mg down, 0.61 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-[4-(2-hydroxyethyl)-piperazine-1-yl]-propan-2-ol 255 (95 mg, the yellowish brown solid), productive rate: 50%.

MS m/z(ESI)：621[M+1]

¹HNMR(400MHz，DMSO-d ₆)：δ9.84(s，1H)，8.62(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.43(s，1H)，7.38(m，1H)，7.12(m，3H)，6.87(s，1H)，6.67(s，1H)，5.72(s，2H)，4.94(m，1H)，4.45(m，1H)，4.07(m，2H)，4.03(m，1H)，3.87(m，1H)，3.52(m，2H)，3.18(m，2H)，2.33(m，9H)

Embodiment 256

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-the 3-[(2-hydroxyethyl)- Methyl-amino]-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (150 g, 0.306 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 2-methylethylolamine (92 mg down, 1.224 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-the 3-[(2-hydroxyethyl)-methyl-amino]-propan-2-ol 256 (49 mg, the yellowish brown solid), productive rate: 30%.

MS m/z(ESI)：566[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ8.48(s，1H)，8.23(s，1H)，7.97(s，1H)，7.88(s，1H)，7.73(d，1H，J＝8.8Hz)，7.65(m，1H)，7.53(m，1H)，7.16(m，2H)，7.05(s，1H)，6.87(m，2H)，6.77(d，1H，J＝8.8Hz)，6.57(s，1H)，6.38(s，1H)，5.42(s，2H)，3.96(m，2H)，3.69(m，3H)，2.61(m，1H)，2.52(m，1H)，2.38(m，2H).2.26(s，3H)

Embodiment 257

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-piperazine-1-base-third -2-alcohol

In the 100mL eggplant-shape bottle, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (150 g, 0.306 mmol) be dissolved in the 20 mL methyl alcohol, stir and add piperazine (105 mg down, 1.224 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-piperazine-1-base-propan-2-ol 257 (20 mg, the yellowish brown solid), productive rate: 12%.

MS m/z(ESI)：577[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ8.49(s，1H)，8.38(s，1H)，8.10(s，1H)，8.06(s，1H)，7.97(d，1H，J＝8.8Hz)，7.76(d，1H，J＝8.8Hz)，7.67(d，1H，J＝8.8Hz)，7.37(s，1H)，7.29(m，2H)，6.96(m，2H)，6.86(d，1H)，6.76(s，1H)，6.61(s，1H)，5.60(s，2H)，4.03(m，2H)，3.93(m，1H)，3.07(m，4H)，2.68(m，4H)，2.42(m，2H)

Embodiment 258

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-morpholine-4-base- Piperidines-1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (100 g, 0.203 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 4-piperidin-4-yl-morpholine (104 mg down, 0.609 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains prepares plate separation and purification (methylene dichloride: methyl alcohol=10: 1) by thin-layer chromatography, obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-morpholine-4-base-piperidines-1-yl)-propan-2-ol 258 (21 mg, the yellowish brown solid), productive rate: 16%.

MS m/z(ESI)：661[M+1]

¹HNMR(400MHz，CD3OD-d ₄)：δ8.50(s，1H)，8.36(s，1H)，8.11(s，1H)，8.06(s，1H)，7.96(d，1H，J＝8.8Hz)，7.76(d，1H，J＝8.8Hz)，7.67(d，1H，J＝8.8Hz)，7.37(s，1H)，7.28(s，2H)，6.98(s，2H)，6.86(s，1H)，6.76(s，1H)，6.61(s，1H)，5.60(s，2H)，3.95(m，3H)，3.73(m，4H)，3.09(m，2H)，2.56(m，4H)，2.46(m，2H)，2.36(m，1H)，2.24(m，2H)，1.90(m，2H)，1.61(m，2H)

Embodiment 259

1-(4-amino-piperadine-1-yl)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1- Base)-propan-2-ol

The first step

(1-benzyl-piperidin-4-yl)-t-butyl carbamate

(2.43 g, 11 mmol) are dissolved in the 20 mL methylene dichloride with acetic anhydride, slowly drip 1-benzyl-piperidin-4-yl amine 259a (2.05 mL with constant pressure funnel, 10 mmol, Aldrich) in the 20 mL dichloromethane solutions, after dropwising, stir under the room temperature and spend the night.Reaction solution is under reduced pressure concentrated, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=25: 1), obtain (1-benzyl-piperidin-4-yl)-t-butyl carbamate 259b (2.91g, white solid), productive rate: 100%.

MS m/z(ESI)：291[M+1]

Second step

Piperidin-4-yl-t-butyl carbamate

(1-benzyl-piperidin-4-yl)-t-butyl carbamate 259b (2.9 g, 10 mmol) is dissolved in the 150 mL methyl alcohol, stirs and to add Pd/C down, use the hydrogen exchange air, after 4 times, at 30 ℃ of following shortenings, afterreaction finished in 24 hours.Filtering reacting liquid, decompression is concentrated filtrate down, obtains piperidin-4-yl-t-butyl carbamate 259c (1.96g, white solid), productive rate: 98%.

MS m/z(ESI)：201[M+1]

The 3rd step

1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidin-4-yl }-t-butyl carbamate

With [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg, 0.4 mmol) be dissolved in the 20 mL methyl alcohol, stir and add piperidin-4-yl-t-butyl carbamate 259c (118 mg down, 0.5 6 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=25: 1), obtain 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidin-4-yl }-t-butyl carbamate 259d (178 mg, yellow solid), productive rate: 74.2%.

MS m/z(ESI)：701[M+1]

The 4th step

1-(4-amino-piperadine-1-yl)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol

Will 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidin-4-yl }-t-butyl carbamate 259d (58.6 mg, 0.09 mmol) be dissolved in the 15 mL methylene dichloride, under condition of ice bath, be cooled to 0 ℃, add 3 mL trifluoroacetic acids, keep this temperature to stir 3 hours afterreactions and finish.Saturated sodium bicarbonate solution will be added in the reaction solution, regulate pH=8, add 50 mL ethyl acetate and 50 mL tetrahydrofuran (THF)s, separatory, water ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methyl alcohol: ammoniacal liquor=50: 1), obtain 1-(4-amino-piperadine-1-yl)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-propan-2-ol 259 (35 mg, faint yellow solid), productive rate: 69.7%.

MS m/z(ESI)：601[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.71(s，1H)，8.55(s，1H)，8.50(s，1H)，8.11(s，1H)，8.02(d，J＝8.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.69(d，J＝8.8Hz，1H)，7.54(t，J＝8.8Hz，1H)，7.42(s，1H)，7.32(m，3H)，7.19(t，J＝8.8Hz，1H)，6.87(s，1H)，6.65(s，1H)，5.27(s，2H)，4.40(br，1H)，4.06(t，J＝12.8Hz，1H)，3.94(s，1H)，3.85(m，1H)，3.18(d，J＝3.2Hz，2H)，2.78(br，2H)，2.49(br，2H)，2.19(m，3H)，1.66(br，2H)，1.28(br，2H)

Embodiment 260

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-tetramethyleneimine-1-base-second Ketone

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(4-cyclopropyl methyl-piperazine-1-yl)-ethyl ketone 253 (53 mg, 0.08 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, stir and add lithium aluminum hydride (40 mg down, 0.08 mmol), stirring 30 minutes afterreactions under the room temperature finishes.Reaction solution methyl alcohol cancellation, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=25: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-tetramethyleneimine-1-base-ethyl ketone (8 mg, yellow solid), productive rate: 15.4%.

MS m/z(ESI)：611[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ8.64(s，1H)，8.41(s，1H)，7.97(d，J＝2.8Hz，1H)，7.90(d，J＝8.8Hz，1H)，7.84(d，J＝8.8Hz，1H)，7.70(m，1H)，7.34(m，1H)，7.22(m，3H)，7.02(m，1H)，6.94(d，J＝8.8Hz，1H)，6.69(d，J＝2.0Hz，1H)，6.56(d，J＝1.6Hz，1H)，5.13(s，2H)，4.02(t，J＝6.0Hz，3H)，2.90(m，5H)，2.80(s，4H)，2.59(d，J＝6.8Hz，2H)，0.88(m，1H)，0.62(m，2H)，0.24(m，2H)

Embodiment 261

The first step

2-chloro-1-tetramethyleneimine-1-base-ethyl ketone

Pyrroles (71 mg, 1 mmol) is dissolved in the 10 mL methylene dichloride, and solution is cooled to 0 ℃ under ice bath, stirs down to add chloroacetyl chloride (170 mg, 1.5 mmol), stirs reaction in 1 hour under the room temperature and finishes.Add 50 mL water in the reaction solution, dichloromethane extraction (50 mL * 3), the organic phase of merging is successively by water, and saturated nacl aqueous solution washs, anhydrous sodium sulfate drying filters, and decompression concentrates down, obtain 2-chloro-1-tetramethyleneimine-1-base-ethyl ketone 261a (115 mg, white solid), productive rate: 78%

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-tetramethyleneimine-1-base-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (111 mg, 0.25 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (30 mg, 0.75 mmol), stir adding 2-chloro-1-tetramethyleneimine-1-base-ethyl ketone 261a (55 mg after 30 minutes, 0.375 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution adds 50 mL water, dichloromethane extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains by the further separation and purification of silica gel column chromatography (normal hexane: ethyl acetate=2: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-tetramethyleneimine-1-base-ethyl ketone 261 (72 mg, yellow solid), productive rate: 51.9%.

MS m/z(ESI)：556[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.713(s，1H)，8.545(d，J＝1.2Hz，1H)，8.499(s，1H)，8.027(m，2H)，7.759(m，1H)，7.708(d，J＝8.8Hz，1H)，7.479(m，1H)，7.323(m，4H)，7.192(m，1H)，6.282(t，J＝2.4Hz，1H)，6.056(m，1H)，5.268(s，2H)，4.853(s，2H)，3.500(t，J＝6.8Hz，2H)，3.345(t，J＝7.2Hz，2H)，1.925(m，2H)，1.810(m，2H)

Embodiment 262

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[5-(piperidin-4-yl amino)-1H-pyrroles-3-yl]-quinazoline-4-yl }- Amine

Under argon atmospher, with 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 218a (94.4 mg, 0.2 mmol) with piperidin-4-yl amine (26 mg, 0.26 mmol) be dissolved in the 20 mL methylene dichloride, after at room temperature stirring 30 minutes, add three (acetoxyl group) sodium borohydride (212 mg, 1 mmol), mixed solution at room temperature stirs and spends the night.50 mL water will be added in the reaction solution, decompression steams methylene dichloride down, water ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=5: 1), obtain title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[5-(piperidin-4-yl amino)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 262 (8 mg, yellow solid), productive rate: 71.4%.

MS m/z(ESI)：557[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ10.919(s，1H)，9.684(s，1H)，8.533(s，1H)，8.441(d，J＝12Hz，1H)，8.143(d，J＝8.4Hz，1H)，8.044(s，1H)，7.740(m，2H)，7.461(br，1H)，7.282(m，3H)，7.179(m，1H)，6.791(s，1H)，6.452(d，J＝20.8Hz，1H)，5.244(s，2H)，3.864(s，1H)，3.480(m，2H)，3.327(br，4H)，1.913(br，2H)，1.264(br，2H)

Embodiment 263

(R)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-propylene oxide base-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline -4-yl]-amine

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (223 mg, 0.5 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 2.5 mmol), stir adding (S)-2-(2-chloroethyl) oxyethane (80 mg after 30 minutes, 0.75 mmol), stirring reaction in 1 hour under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is further by column chromatographic isolation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product (R)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-propylene oxide base-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 263 (40 mg, faint yellow solid), productive rate: 19.32%.

MS m/z(ESI)：515[M+1]

¹H NMR(400 MHz，CD3OD-d ₆)：δ9.710(s，1H)，8.552(s，1H)，8.056(s，1H)，8.026(s，1H)，7.762(d，J＝8.8Hz，1H)，7.709(d，J＝9.2Hz，1H)，7.484(m，2H)，7.323(m，3H)，7.192(m，1H)，933(s，1H)，6.696(s，1H)，5.274(s，2H)，4.989(m，1H)，4.518(m，1H)，4.336(m，1H)，4.186(m，2H)，2.666(m，1H)，2.364(m，2H)

Embodiment 264

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-((3S, 5R)-3,5-two for 3- Methyl-piperazine-1-yl)-propan-2-ol

(2S, 6R)-2,6-lupetazin (68 mg, 0.6 mmol, ABCR) be dissolved in the 25 mL Virahols, add 2 mL 1 successively under stirring, 2-ethylene dichloride and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg, 0.4 mmol), mixed solution spends the night 65 ℃ of reflux.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-((3S, 5R)-3,5-dimethyl-piperazine-1-yl)-propan-2-ol 264 (211 mg, yellow solid), productive rate: 86.1%.

MS m/z(ESI)：616[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.70(s，1H)，8.55(s，1H)，8.50(s，1H)，8.05(m，1H)，8.02(m，1H)，7.73(m，2H)，7.52(m，2H)，7.34(m，3H)，7.19(m，1H)，7.01(s，1H)，6.72(s，1H)，5.27(s，2H)，4.91(br，1H)，4.03(m，3H)，2.87(br，2H)，2.77(m，2H)，2.22(m，2H)，1.61(m，2H)，0.96(t，J＝6Hz，6H)

Embodiment 265

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-cyclopropyl-piperazine -1-yl)-ethyl ketone

The first step

2-chloro-1-(4-cyclopropyl-piperazine-1-yl)-ethyl ketone

With 1-cyclopropyl-piperazine 252b (1 g, 7.94 mmol) be dissolved in the 10 mL methylene dichloride, solution is cooled to-78 ℃ under acetone-the dry ice bath, stirs to add 1 mL triethylamine and chloroacetyl chloride (1.2 g down, 11.9 mmol), keeping this temperature stirring reaction in 40 minutes finishes.Add 50 mL water in the reaction solution, dichloromethane extraction (50 mL * 3), the organic phase that merges is passed through water successively, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters, decompression concentrates down, obtain 2-chloro-1-(4-cyclopropyl-piperazine-1-yl)-ethyl ketone 265a (115 mg, white solid), product directly carries out next step reaction without separating.

MS m/z(ESI)：203[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-cyclopropyl-piperazine-1-yl)-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (257 mg, 0.58 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (69 mg, 2.9 mmol), stir adding 2-chloro-1-(4-cyclopropyl-piperazine-1-yl)-ethyl ketone 265a (140 mg after 30 minutes, 0.69 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution adds 50 mL water, with ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(4-cyclopropyl-piperazine-1-yl)-ethyl ketone 265 (148 mg, yellow solid), productive rate: 35.2%.

MS m/z(ESI)：611[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.74(s，1H)，8.65(s，1H)，8.53(s，1H)，8.37(s，1H)，8.04(m，2H)，7.76(m，2H)，7.60(m，1H)，7.49(m，1H)，7.32(m，4H)，7.19(m，1H)，5.27(s，2H)，4.96(s，2H)，3.45(br，4H)，2.57(br，4H)，1.64(m，1H)，0.45(m，2H)，0.35(m，2H)

Embodiment 266

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-formic acid (2-diethylin-second Base)-acid amides

With two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (191 mg, 0.75 mmol) be dissolved in the 10 mL anhydrous methylene chlorides, stir and add triethylamine (0.1 mL down, 0.75 mmol), stir after 15 minutes under the room temperature, add 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino successively]-quinazoline-6-yl }-1H-pyrroles-2-formic acid 184g (244 mg, 0.5 mmol) and N ^*1 ^*, N ^*1 ^*-diethyl ethane-1,2-diamines (58 mg, 0.5 mmol) stirs reaction in 1 hour and finishes under the room temperature.Reaction solution is under reduced pressure concentrated, add 20 mL water in the residue, with ethyl acetate extraction (50mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying successively, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=15: 1), obtain title product 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-formic acid (2-diethylin-ethyl)-acid amides 266 (115 mg, yellow solid), productive rate: 39.2%.

MS m/z(ESI)：587[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ＝11.97(s，1H)，9.85(s，1H)，8.75(s，1H)，8.52(s，1H)，8.05(m，2H)，7.80(m，2H)7.68(s，1H)，7.47(m，2H)，7.31(m，3H)，7.19(m，1H)，6.98(s，1H)，6.86(s，1H)，5.27(s，2H)，3.62(m，2H)，3.33(m，2H)，3.17(m，2H)，3.05(m，2H)，1.12(m，6H)

Embodiment 267

(4-amino-piperadine-1-yl)-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2- Base)-ketone

The first step

[1-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carbonyl)-piperidin-4-yl]-t-butyl carbamate

With two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (191 mg, 0.75 mmol) be dissolved in the 10 mL anhydrous methylene chlorides, stir and add triethylamine (0.1 mL down, 0.75 mmol), stir after 15 minutes under the room temperature, add 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino successively]-quinazoline-6-yl }-1H-pyrroles-2-formic acid 184g (244 mg, 0.5 mmol) and piperidin-4-yl-t-butyl carbamate (100 mg, 0.5 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution is under reduced pressure concentrated, add 20 mL water in the residue, with ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying successively, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=30: 1), obtain title product [1-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carbonyl)-piperidin-4-yl]-t-butyl carbamate 267a (225 mg, yellow solid), productive rate: 67.2%.

MS m/z(ESI)：671[M+1]

Second step

(4-amino-piperadine-1-yl)-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-yl)-ketone

Will [1-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-carbonyl)-piperidin-4-yl]-t-butyl carbamate 267a (215 mg, 0.32 mmol) be dissolved in the 10 mL methylene dichloride, stir adding 10 mL trifluoroacetic acids down, stir reaction in 2 hours under the room temperature and finish.Reaction solution under reduced pressure concentrates, add 30 mL saturated sodium bicarbonate solutions, ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by alkali alumina column chromatographic isolation and purification (methylene dichloride: methyl alcohol=30: 1), obtain this title product (4-amino-piperadine-1-yl)-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-1H-pyrroles-2-yl)-ketone 267 (125mg, yellow solid), productive rate: 65.4%.

MS m/z(ESI)：571[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ11.78(s，1H)，9.67(s，1H)，8.63(s，1H)，8.52(s，1H)，8.18(s，1H)，8.03(d，J＝2.4Hz，1H)，7.75(m，2H)7.60(m，1H)，7.50(m，1H)，7.31(m，3H)，7.19(m，1H)，7.08(s，1H)，5.27(s，2H)，4.38(m，2H)，3.59(m，1H)，3.14(m，2H)，1.84(m，2H)，1.40(m，2H)

Embodiment 268

(3R)-1-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-third Base]-tetramethyleneimine-3-alcohol

(R)-tetramethyleneimine-3-alcohol (30 mg, 0.34 mmol) be dissolved in the 10 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (100 mg down, 0.2 mmol), 3 hours afterreactions of mixed solution reflux finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product (3R)-1-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-tetramethyleneimine-3-alcohol 268 (85 mg, yellow solid), productive rate: 43%.

MS m/z(ESI)：588[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ10.026(s，1H)，8.760(s，1H)，8.491(s，1H)，8.124(s，1H)，8.034(s，1H)，7.863(s，1H)，7.699(s，1H)，7.510(s，2H)，7.263(m，3H)，6.874(s，1H)，6.748(s，1H)，5.267(s，2H)，4.252(s，1H)，3.981(m，2H)，3.387(s，2H)，2.642(s，2H)，2.008(s，2H)，1.655(s，2H)

Embodiment 269

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(2-tetramethyleneimine-1-base- Ethyl)-ethanamide

The first step

2-chloro-N-(2-tetramethyleneimine-1-base-ethyl)-methane amide

2-tetramethyleneimine-1-base-ethamine (228 mg, 2 mmol) be dissolved in the 15 mL tetrahydrofuran (THF)s, under acetone-the dry ice bath cooling, be cooled to-78 ℃, stir and add triethylamine (0.83 mL down successively, 6 mmol) and chloroacetyl chloride (0.48mL, 6 mmol), mixed solution 1 hour afterreaction of stirring under-78 ℃ finishes.Reaction solution is under reduced pressure concentrated, obtain 2-chloro-N-(2-tetramethyleneimine-1-base-ethyl)-methane amide 310 (290 mg, yellow solid), product directly carries out next step reaction without separating.

MS m/z(ESI)：291[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(2-tetramethyleneimine-1-base-ethyl)-ethanamide

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (177 mg, 0.4 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (112 mg, 2.8 mmol), stir adding 2-chloro-N-(2-tetramethyleneimine-1-base-ethyl)-methane amide 310 (290 mg) after 30 minutes, stir reaction in 1 hour under the room temperature and finish.Reaction solution is under reduced pressure concentrated, residue is by water washing, dichloromethane extraction (100 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-(2-tetramethyleneimine-1-base-ethyl)-ethanamide 310 (45 mg, yellow solid), productive rate: 18.8%.

MS m/z(ESI)：599[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.722(s，1H)，8.563(d，J＝1.6Hz，1H)，8.504(s，1H)，8.051(s，1H)，7.766(m，1H)，7.713(d，J＝8.8Hz，1H)，7.474(m，1H)，7.344(m，3H)，7.190(m，1H)，6.868(m，2H)，6.687(s，1H)，6.633(s，1H)，5.273(s，2H)，4.622(s，2H)，3.607(m，2H)，3.243(m，2H)，2.191(s，2H)，1.765(s，2H)，1.679(s，4H)

Embodiment 270

(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-acetonitrile

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (400mg, 0.9 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 1.5 mmol), stir adding chloro-acetonitrile (82 mg after 30 minutes, 1.08 mmol), stirring reaction in 1 hour under the room temperature finishes.The reaction solution decompression concentrates down, the residue that obtains is further by column chromatographic isolation and purification (methylene dichloride: methyl alcohol=40: 1), obtain this title product (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-acetonitrile 270 (70 mg, faint yellow solid), productive rate: 16%.

MS m/z(ESI)：484[M ⁺]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.34(s，2H)，5.27(s，2H)

Embodiment 271

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[(2-hydroxyl-ethyl)- Methyl-amino]-propan-2-ol

2-methylamino--ethanol (22.5 mg, 0.3 mmol, Aldrich) be dissolved in the 10 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (150 mg down, 0.3 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-[(2-hydroxyl-ethyl)-methyl-amino]-propan-2-ol 271 (140 mg, yellow solid), productive rate: 81.2%.

MS m/z(ESI)：576[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，4.9(S，1H)，4.44(m，1H)，4.07(m，1H)，3.87(m，2H)，3.49(m，2H)，2.49(m，2H)，2.32(d，J＝5.6Hz，2H)，2.26(s，3H)

Embodiment 272

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-morpholine-4-base-piperazine Pyridine-1-yl)-propan-2-ol

The first step

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-morpholine-4-base-piperidines-1-yl)-propan-2-ol

4-(1-methyl-piperidin-4-yl)-morpholine (54.8 mg, 0.32 mmol, Aldrich) be dissolved in the 10 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (160 mg down, 0.32 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-morpholine-4-base-piperidines-1-yl)-propan-2-ol 272 (123 mg, yellow solid), productive rate: 57.4%.

MS m/z(ESI)：671[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，4.9(s，1H)，4.05(m，1H)，3.89(m，2H)，3.54(m，4H)，2.88(m，2H)，2.42(S，4H)，2.21(t，J＝4.8，3H)，2.08(t，J＝10.8，1H)，1.95(t，J＝10.4，2H)，1.72(d，J＝11.2，2H)，1.42(m，2H)

Embodiment 273

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(3-ethyl-propylene oxide-3-ylmethyl)-1H-pyrroles-3-yl]-the quinoline azoles Quinoline-4-yl }-amine

The first step

Methylsulfonic acid (3-ethyl-propylene oxide-3-yl) methyl esters

With (3-ethyl-propylene oxide-3-yl)-methyl alcohol (580 mg, 5 mmol) be dissolved in the 15 mL methylene dichloride, stir and add triethylamine (758 mg down, 7.6 mmol), reaction solution is cooled to 0 ℃ under ice bath, adds methylsulfonyl chloride (687 mg, 6 mmol) gradually, stirred 30 minutes under the room temperature, reaction finishes.Reaction solution is under reduced pressure concentrated, add 20 mL water, ethyl acetate extraction (40 mL * 3), the organic phase of merging are successively by saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain methylsulfonic acid (3-ethyl-propylene oxide-3-yl) methyl esters 273a (945 mg, colourless oil liquid), productive rate: 97.4%.

MS m/z(ESI)：195[M+1]

Second step

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-[1-(3-ethyl-propylene oxide-3-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (223 mg, 0.5 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (60 mg, 2.5 mmol), stir and add methylsulfonic acid (3-ethyl-propylene oxide-3-yl) methyl esters 273a (145 mg after 30 minutes, 0.75 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution adds 20 mL water, ethyl acetate extraction (40 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{ 6-[1-(3-ethyl-propylene oxide-3-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 273 (125 mg, faint yellow solid), productive rate: 46.1%.

MS m/z(ESI)：543[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ＝9.68(s，1H)，8.53(s，1H)，8.50(s，1H)，8.06(d，J＝8.8Hz，1H)，8.02(m，1H)，7.75(m，2H)，7.47(m，1H)，7.41(m，1H)，7.31(m，3H)，7.19(m，1H)，6.91(s，1H)，6.70(s，1H)，5.27(s，2H)，4.55(d，J＝6.0Hz，2H)，4.31(d，J＝6.0Hz，2H)，4.20(s，2H)，1.54(m，2H)，0.96(t，J＝7.2Hz，3H)

Embodiment 274

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-((R)-3-dimethylamino Base-tetramethyleneimine-1-yl)-propan-2-ol

(R)-N, N-dimethyl pyrrolidine-3-amine (52 mg, 0.46 mmol) be dissolved in the 30 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (152 mg down, 0.3 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-((R)-3-dimethylamino-tetramethyleneimine-1-yl)-propan-2-ol 274 (80 mg, yellow solid), productive rate: 54.3%.

MS m/z(ESI)：616[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，5.09(br，1H)，3.82(m，3H)，2.67(m，4H)，2.51(m，3H)，2.16(s，6H)，1.87(m，1H)，1.65(m，1H)

Embodiment 275

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(1-cyclopropyl-piperidines -4-yl)-ethanamide

The first step

(1-cyclopropyl-piperidin-4-yl)-t-butyl formate

With piperidin-4-yl-t-butyl formate (1.2 g, 5 mmol) be dissolved in the 40 mL methyl alcohol, stir and add (1-oxyethyl group-1-methyl-propoxy-)-trimethyl silane (1.52 mL down successively, 7.5 mmol), sodium cyanoborohydride (1.26g, 20 mmol) and acetic acid (2.86 mL, 50 mmol), the mixed solution heating reflux reaction spends the night.Reaction solution is under reduced pressure concentrated, add 20 mL ethyl acetate in the residue that obtains, stir the saturated sodium hydroxide solution of adding down, regulating pH is alkalescence, with ethyl acetate extraction (50 mL * 3), the organic phase that merges is filtered by anhydrous sodium sulfate drying, and decompression concentrates down, the residue that obtains silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=50: 1), obtain (1-cyclopropyl-piperidin-4-yl)-t-butyl formate 275a (1.12 g, white solid), productive rate: 80.4%.

MS m/z(ESI)：241[M+1]

Second step

1-cyclopropyl-piperidin-4-yl amine

(1-cyclopropyl-piperidin-4-yl)-t-butyl formate 275a (1 g, 4.16 mmol) is dissolved in the 50 mL methylene dichloride, stirs adding 10 mL trifluoroacetic acids down, stir reaction in 2 hours under the room temperature and finish.Reaction solution is under reduced pressure concentrated, the residue that obtains adds 5 mL methyl alcohol, add Anhydrous potassium carbonate, regulate pH=8, be spin-dried for the residue that obtains silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=20: 1), obtain 1-cyclopropyl-piperidin-4-yl amine 275b (1.317 g, white solid), productive rate: 80.4%.

MS m/z(ESI)：141[M+1]

The 3rd step

1-chloro-N-(1-cyclopropyl-piperidin-4-yl)-ethanamide

With 1-cyclopropyl-piperidin-4-yl amine 275b (350 mg, 2.5 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, solution is cooled to-78 ℃ under acetone-the dry ice bath, stirs to add 0.7 mL triethylamine and chloroacetyl chloride (339 mg down, 3 mmol), keeping this temperature stirring reaction in 40 minutes finishes.Add 20 mL tetrahydrofuran (THF)s in the reaction solution, the adularescent solid is separated out, filter, filtrate under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain 1-chloro-N-(1-cyclopropyl-piperidin-4-yl)-ethanamide 275c (297mg, white solid), productive rate: 51%.

MS m/z(ESI)：217[M+1]

The 4th step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-N-(1-cyclopropyl-piperidin-4-yl)-ethanamide

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (338 mg, 0.76 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (91 mg, 3.8 mmol), stir adding 1-chloro-N-(1-cyclopropyl-piperidin-4-yl)-ethanamide 275c (297 mg after 30 minutes, 0.91 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution adds 50 mL water, with ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N-(1-cyclopropyl-piperidin-4-yl)-ethanamide 275 (397 mg, yellow solid), productive rate: 46.3%.

MS m/z(ESI)：625[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.59(s，2H)，3.80(m，1H)，3.57(m，2H)，2.88(m，2H)，2.25(m，2H)，1.73(m，2H)，1.58(br，1H)，0.39(m，2H)，0.27(br，2H)

Embodiment 276

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(1,1-, two-1 λ ^* 6 ^* -thiophene Morpholine-4-yl)-propan-2-ol

Parathiazan 1,1-dioxide (54 mg, 0.4 mmol, Aldrich) be dissolved in the 10 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg down, 0.4 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-(1,1-, two-1 λ ^*6 ^*-thiomorpholine-4-yl)-and propan-2-ol 276 (20 mg, yellow solid), productive rate: 7.9%.

MS m/z(ESI)：636[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，5.05(s，1H)，4.06(d，J＝11.2，1H)，3.89(m，2H)，3.13(s，4H)，2.96(s，4H)，2.43(d，J＝4.8，2H)

Embodiment 277

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-((R)-3-fluoro-tetramethyleneimine -1-yl)-propan-2-ol

(R)-3-fluoropyrrolidine hydrochloride (50.4 mg, 0.4 mmol) be dissolved in the 10 mL methyl alcohol, stir successively and add 2 mL triethylamines and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (200 mg down, 0.4mmol), 2 hours afterreactions of mixed solution reflux finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-((R)-3-fluoro-tetramethyleneimine-1-yl)-propan-2-ol 277 (110 mg, yellow solid), productive rate: 46.7%.

MS m/z(ESI)：590[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，5.05(s，1H)，4.06(m，1H)，3.89(m，2H)，2.88(m，2H)，2.42(m，3H)，2.22(m，1H)，1.89(m，1H)，1.23(m，2H)

Embodiment 278

1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-3-thiazolidine-3-base-third -2-alcohol

In the 100mL eggplant-shape bottle, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 mg, 0.41 mmol) be dissolved in the 25 mL methyl alcohol, stir and add thiazolidine (43 mg down, 0.48 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=60: 1), obtain this title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-3-thiazolidine-3-base-propan-2-ol 278 (152 mg, yellow solid), productive rate: 54%.

MS m/z(ESI)：590[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，5.15(s，1H)，4.13(m，3H)，3.89(m，2H)，3.05(m，2H)，2.79(m，2H)，2.27(m，2H)

Embodiment 279

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(4-cyclopropyl-piperazine-1-yl)-ethyl]-1H-pyrroles-3-yl }-quinoline Azoles quinoline-4-yl)-amine

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(4-cyclopropyl-piperazine-1-yl)-ethyl ketone 265 (50 mg, 0.082 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, stir and add lithium aluminum hydride (31.4 mg down, 0.82 mmol), stirring is spent the night under the room temperature.Reaction solution is under reduced pressure concentrated, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=20: 1), obtain this title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(4-cyclopropyl-piperazine-1-yl)-ethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-amine 279 (48 mg, yellow solid), productive rate: 97.9%.

MS m/z(ESI)：597[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.05(m，2H)，2.67(m，2H)，2.54(br，4H)，2.42(br，4H)，1.59(br，1H)，0.38(m，2H)，0.27(m，2H)

Embodiment 280

1-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine Pyridine-4-methane amide

Piperidines-4-methane amide (80 mg, 0.63 mmol) be dissolved in the 20 mL methyl alcohol, stir adding [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (260mg, 0.52 mmol) down, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=5: 1), obtain this title product 1-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidines-4-methane amide 280 (222 mg, yellow solid), productive rate: 67.9%.

MS m/z(ESI)：629[M ⁺]

¹H NMR(400 MHz，DMSO-d6)：δ9.72(s，1H)，8.56(s，1H)，8.55(s，1H)，8.05(m，2H)，7.78(d，J＝6Hz，1H)，7.69(d，J＝6.8Hz，1H)，7.51(m，1H)，7.41(s，1H)，7.31(m，3H)，7.21(m，2H)，6.88(m，1H)，6.65(m，2H)，5.27(s，2H)，4.91(br，1H)，4.08(m，1H)，3.94(br，1H)，3.85(m，1H)，2.91(m，2H)，2.24(br，2H)，1.98(m，3H)，1.63(m，4H)

Embodiment 281

1-((3S, 5R)-3,5-dimethyl-piperazine-1-yl)-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline -6-yl }-pyrroles-1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 mg, 0.41 mmol) be dissolved in the 25 mL methyl alcohol, stir and add (2S down, 6R)-2,6-lupetazin (140 mg, 1.22 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=8: 1), obtain this title product 1-((3S, 5R)-3,5-dimethyl-piperazine-1-yl)-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol 281 (53 mg, yellow solid), productive rate: 21%.

MS m/z(ESI)：605[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.90(s，1H)，8.66(s，1H)，8.45(s，1H)，8.24(s，1H)，8.17(s，1H)，8.02(m，1H)，7.75(s，2H)，7.70(m 1H)，7.47(s，1H)，7.39(m，1H)，7.13(m，3H)，6.88(s，1H)，6.69(s，1H)，5.72(s，2H)，5.03(m，1H)，3.98(m，3H)，3.26(m，2H)，2.96(m，2H)，2.29(m，2H)，2.02(m，2H)，1.20(m，6H)

Embodiment 282

4-[3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-third Base]-piperazine-1-ethyl formate

In the 100mL eggplant-shape bottle, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 mg, 0.41 mmol) be dissolved in the 25 mL methyl alcohol, stir and add piperazine-1-ethyl formate (194 mg down, 1.22 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 4-[3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine-1-ethyl formate 282 (80 mg, yellow solid), productive rate: 30%.

MS m/z(ESI)：649[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.84(s，1H)，8.61(s，1H)，8.45(s，1H)，8.24(s，1H)，8.17(s，1H)，8.04(m，1H)，7.75(s，2H)，7.70(m 1H)，7.44(s，1H)，7.40(m，1H)，7.08(m，3H)，6.88(s，1H)，6.67(s，1H)，5.73(s，2H)，4.99(s，1H)，4.05(m，2H)，3.90(m，3H)，3.39(m，4H)，2.41(m，4H)，2.28(m，2H)，1.18(m，3H)

Embodiment 283

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2-methoxyl group-second Amino)-propan-2-ol

In the 100mL eggplant-shape bottle, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200mg, 0.41 mmol) be dissolved in the 25 mL methyl alcohol, stir and add 2-methoxyethyl amine (92 mg down, 1.22 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=8: 1), obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-methoxyl group-ethylamino)-propan-2-ol 283 (100 mg, yellow solid), productive rate: 43%.

MS m/z(ESI)：566[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.86(s，1H)，8.63(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.04(m，1H)，7.78(s，2H)，7.70(m 1H)，7.44(m，1H)，7.37(m，1H)，7.08(m，3H)，6.89(s，1H)，6.69(s，1H)，5.72(s，2H)，4.09(m，3H)，3.92(m，2H)，3.18(m，3H)，2.59(m，4H)

Embodiment 284

N-{ (3R)-1-[3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-2- Hydroxyl-propyl group]-tetramethyleneimine-3-yl }-ethanamide

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 mg, 0.41 mmol) be dissolved in the 25 mL methyl alcohol, stir and add (R)-N-(tetramethyleneimine-3-yl) ethanamide (174 mg down, 1.22 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=8: 1), obtain this title product N-{ (3R)-1-[3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-tetramethyleneimine-3-yl-ethanamide 284 (50 mg, yellow solid), productive rate: 20%.

MS m/z(ESI)：619[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.87(s，1H)，8.64(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.04(m，1H)，7.75(m，3H)，7.41(s，1H)，7.37(m，1H)，7.08(m，3H)，6.89(s，1H)，6.69(s，1H)，5.72(s，2H)，4.04(m，2H)，3.98(m，1H)，3.53(m，2H)，3.28(m，3H)，3.00(m，2H)，2.50(m，3H)，1.83(m，2H)

Embodiment 285

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-[1,2,3] triazole -1-base-propan-2-ol

In 100 mL eggplant-shape bottles, [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (100 mg, 0.23 mmol) is dissolved in the N of 5 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (22 mg, 0.92 mmol), stir and add [1,2,3] triazole (43 mg after 30 minutes, 0.63 mmol), being heated to 50 ℃ of stirrings spends the night.Add 20 mL frozen water and 20 mL methylene dichloride in the reaction solution, separatory, water dichloromethane extraction (20 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is further by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-[1,2,3] triazol-1-yl-propan-2-ol 285 (19 mg, yellow solid), productive rate: 15%.

MS m/z(ESI)：560[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.93(s，1H)，8.68(s，1H)，8.44(s，1H)，8.24(s，1H)，8.17(s，1H)， 8.11(s，1H)，8.05(m，1H)，7.74(m，4H)，7.49(s，1H)，7.37(m，1H)，7.08(m，3H)，6.89(s，1H)，6.74(s，1H)，5.72(s，2H)，4.49(m，1H)，4.35(m，1H)，4.22(m，1H)，4.09(m，1H)，3.94(m，1H)

Embodiment 286

1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(2-morpholine-4-base- Ethylamino)-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (250 mg, 0.51 mmol) be dissolved in the 30 mL methyl alcohol, stir and add 2-morpholine-4-base-ethamine (199 mg down, 1.53 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(2-morpholine-4-base-ethylamino)-propan-2-ol 286 (54 mg, yellow solid), productive rate: 17%.

MS m/z(ESI)：619[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.99(s，1H)，8.73(s，1H)，8.45(s，1H)，8.27(s，1H)，8.17(s，1H)，8.04(m，1H)，7.76(m，3H)，7.51(s，1H)，7.37(m，1H)，7.08(m，3H)，6.92(s，1H)，6.75(s，1H)，5.72(s，2H)，4.23(m，1H)，4.07(m，2H)，3.56(m，4H)，3.18(s，1H)，2.84(m，1H)，2.60(m，4H)，2.39(m，4H)

Embodiment 287

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-[1-(3-morpholine-4-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4- Base }-amine

The first step

4-(3-bromo-propyl group)-morpholine

With morpholine (4 mL, 49.36 mmol), 1,3-dibromopropyl (25 mL, 245 mmol) be dissolved in the triethylamine (27.5mL, 197 mmol), stir under the room temperature and spend the night, the adularescent solid generates, add 2 mL dissolve with methanol, mixture is by the further separation and purification of silica gel column chromatography (eluent: ethyl acetate), obtain 4-(3-bromo-propyl group)-morpholine 287a (1.2 g, faint yellow solid), productive rate: 12%.

Second step

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-[1-(3-morpholine-4-base-propyl group)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (100 mg, 0.23 mmol) be dissolved in the N of 5 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (22 mg, 0.92 mmol), stir and add 4-(3-bromo-propyl group)-morpholine 287a (79 mg after 30 minutes, 0.38 mmol), stirring reaction in 3 hours under the room temperature finishes.Add 20 mL frozen water and 20 mL methylene dichloride in the reaction solution, separatory, water dichloromethane extraction (20 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is further by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-[1,2,3] triazol-1-yl-propan-2-ol 287 (19 mg, yellow solid), productive rate: 15%.

MS m/z(ESI)：562[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.82(s，1H)，8.61(s，1H)，8.45(s，1H)，8.247(s，1H)，8.17(s，1H)，8.05(m，1H)，7.77(m，3H)，7.44(m，2H)，7.14(m，3H)，6.91(s，1H)，6.68(s，1H)，5.72(s，2H)，4.00(m，2H)，3.60(m，4H)，2.50(m，6H)，1.94(m，2H)

Embodiment 288

4-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine Piperazine-2-ketone

Piperazine-2-ketone (60 mg, 0.6 mmol) be dissolved in the 30 mL methyl alcohol, stir adding [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (250 mg, 0.51 mmol) down, the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=30: 1), obtain this title product 4-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine-2-ketone 288 (72 mg, yellow solid), productive rate: 40.1%.

MS m/z(ESI)：601[M ⁺]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，5.05(br，1H)，3.98(m，3H)，3.19(m，2H)，2.64(m，2H)，2.35(m，2H)，1.23(m，2H)

Embodiment 289

6-[5-(4-amino-piperadine-1-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)- Phenyl]-amine

The first step

(1-benzyl-piperidin-4-yl)-t-butyl carbamate

(2.05 mL, 10 mmol) are dissolved in the 20 mL methylene dichloride with 1-benzyl-piperidin-4-yl amine, slowly drip the 20 mL dichloromethane solutions of tert-Butyl dicarbonate (2.43 g, 11 mmol) with constant pressure funnel, stir under the room temperature and spend the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=25: 1), obtain (1-benzyl-piperidin-4-yl)-t-butyl carbamate 289a (2.91 g, white solid), productive rate: 100%.

MS m/z(ESI)：291[M+1]

Second step

Piperidin-4-yl-t-butyl carbamate

(1-benzyl-piperidin-4-yl)-t-butyl carbamate 289a (2.9 g, 10 mmol) is dissolved in the 150 mL methyl alcohol, stirs and to add Pd/C (0.4 g) down, with hydrogen exchange air 4 times, 30 ℃ of following catalytic hydrogenation reactions 24 hours.Filter, decompression is concentrated filtrate down, obtains piperidin-4-yl-t-butyl carbamate 289b (1.96 g, white solid), productive rate: 98%.

MS m/z(ESI)：201[M+1]

The 3rd step

4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-the 1H-pyrrole-2-aldehyde

N with 30 mL dryings, dinethylformamide, be cooled to 0 ℃ under the ice bath, add phosphorus oxychloride (918 mg, 6 mmol), stir after 1 hour, 0 ℃ adds [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (1.776 g down, 4 mmol), stirring reaction in 3 hours under the room temperature finishes.Add the 10 mL shrends reaction of going out, ethyl acetate extraction (100 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains by the silica gel main stor(e)y analyse further separation and purification (normal hexane: ethyl acetate=2: 1), obtain 4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-1H-pyrrole-2-aldehyde 289c (300 mg, yellow solid), productive rate: 15.9%.

MS m/z(ESI)：473[M+1]

The 4th step

[1-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-piperidin-4-yl]-t-butyl carbamate

With 4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrrole-2-aldehyde 289c (216mg, 0.46 mmol), piperidin-4-yl-t-butyl carbamate (183 mg, 0.92 mmol) with three (acetoxyl group) sodium borohydride (1.94 g, 9.2 mmol) be dissolved in the 20 mL methylene dichloride, stir down at 35 ℃ and spend the night.20 mL saturated sodium bicarbonate solution cancellation reaction will be added in the reaction solution, dichloromethane extraction (100 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is analysed further separation and purification (methylene dichloride: methyl alcohol=100: 1) by the silica gel main stor(e)y, obtain [1-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-piperidin-4-yl]-t-butyl carbamate 289d (210 mg, yellow solid), productive rate: 70%.

MS m/z(ESI)：657[M+1]

The 5th step

6-[5-(4-amino-piperadine-1-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine

Will [1-(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-ylmethyl)-piperidin-4-yl]-t-butyl carbamate 289d (210 mg, 0.32 mmol) be dissolved in the 10 mL methylene dichloride, stir adding 1.05 mL trifluoroacetic acids down, stir reaction in 1 hour under the room temperature and finish.Ammoniacal liquor will be added in the reaction solution, make solution be alkalescence, tell organic layer, water dichloromethane extraction (100mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is analysed further separation and purification (methylene dichloride: methyl alcohol=100: 1) by the silica gel main stor(e)y, obtain title product { 6-[5-(4-amino-piperadine-1-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 289 (170 mg, yellow solid), productive rate: 95%.

MS m/z(ESI)：557[M+1]

¹H NMR(400 MHz，CD3OD-d6)：δ8.746(s，1H)，8.677(s，1H)，8.296(d，J＝1.2Hz，1H)，7.94(S，1H)，7.823(d，J＝9.2Hz，1H)，7.661(m，1H)，7.465(m，2H)，7.398(m，1H)，7.266(s，1H)，7.237(s，1H)，7.089(m，1H)，6.968(s，1H)，5.282(s，2H)，4.399(s，2H)，3.645(d，J＝12.8Hz，2H)，3.161(m，2H)，2.309(d，J＝12.0Hz，2H)，2.018(m，2H)

Embodiment 290

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-thiazolidine-3-base-second Ketone

The first step

2-chloro-1-thiazolidine-3-base-ethyl ketone

(332 mg, 3.73 mmol) are dissolved in the 10 mL methylene dichloride with thiazolidine, and solution is cooled to-78 ℃ under acetone-the dry ice bath, stir to add 1 mL triethylamine and chloroacetyl chloride (505 mg, 4.47 mmol) down, keep this temperature stirring reaction in 40 minutes and finish.Reaction solution under reduced pressure concentrates, and the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain 2-chloro-1-thiazolidine-3-base-ethyl ketone 290a (338 mg, colourless oil liquid), productive rate: 54.6%.

MS m/z(ESI)：167[M+1]

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-thiazolidine-3-base-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (500 mg, 1.12 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (134 mg, 5.62 mmol), stir adding 2-chloro-1-thiazolidine-3-base-ethyl ketone 290a (224 mg after 30 minutes, 1.35 mmol), stirring reaction in 2 hours under the room temperature finishes.Reaction solution adds 50 mL water, with ethyl acetate extraction (50 mL * 4), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-thiazolidine-3-base-ethyl ketone 290 (442 mg, yellow solid), productive rate: 60%.

MS m/z(ESI)：574[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.98(s，2H)，4.65(s，1H)，4.51(s，1H)，3.82(m，1H)，3.71(m，1H)，3.18(m，1H)，3.04(m，1H)

Embodiment 291

1-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperazine Pyridine-3-ethyl formate

Piperidines-3-ethyl formate (61.6 mg, 0.39 mmol, Alfa) be dissolved in the 10 mL methyl alcohol, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (196 mg down, 0.39 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain title product 1-[3-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-2-hydroxyl-propyl group]-piperidines-3-ethyl formate 291 (220 mg, yellow solid), productive rate: 85.4%.

MS m/z(ESI)：658[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，5.05(s，1H)，4.06(m，1H)，3.89(m，2H)，2.83(m，1H)，2.62(m，2H)，2.27(m，4H)，1.76(m，2H)，1.50(m，2H)，1.44(m，2H)，1.24(m，3H)

Embodiment 292

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-)-1-(1,1-dioxy-1 λ ^* 6 ^* -thiophene Morpholine-4-yl)-ethyl ketone

The first step

2-chloro-1-(1,1-dioxo-1 λ ^*6 ^*-thiomorpholine-4-yl)-ethyl ketone

With thiomorpholine 1,1-dioxide (150 mg, 1.11 mmol) be dissolved in the 20 mL tetrahydrofuran (THF)s, be cooled to one 78 ℃ in the dry ice ethanol bath, stir and drip triethylamine (0.14 mL down gradually, 1.11 mmol) and chloroacetyl chloride (126mg, 1.11 mmol), dropwise and under the ice bath cooling, stir reaction in 2 hours and finish.Reaction solution under reduced pressure concentrates, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=1: 1), obtain 2-chloro-1-(1,1-dioxo-1 λ ^*6 ^*-thiomorpholine-4-yl)-and ethyl ketone 192a, product directly carries out next step reaction without separating.

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-)-1-(1,1-dioxy-1 λ ^*6 ^*-thiomorpholine-4-yl)-ethyl ketone

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (444 mg, 1 mmol) and sodium hydride (120 mg, 5 mmol) be dissolved in 10 mLN, in the dinethylformamide, stir under the room temperature and add 2-chloro-1-(1,1-dioxo-1 λ after 30 minutes ^*6 ^*-thiomorpholine-4-yl)-and ethyl ketone 292a (235mg, 1.11 mmol), reaction solution is heated to 50 ℃, and afterreaction finished in 2 hours.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-)-1-(1,1-dioxy-1 λ ^*6 ^*-thiomorpholine-4-yl)-and ethyl ketone 292 (15 mg, yellow solid), productive rate: 5.1%.

MS m/z(ESI)：620[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，3.92(s，4H)，3.15(s，2H)

Embodiment 293

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-morpholine-4-base-piperazine Pyridine-1-yl)-ethyl ketone

The first step

2-chloro-1-{4-[ethyl-(2-methoxyl group-ethyl)-amino]-piperidines-1-yl }-ethyl ketone

With ethyl-(2-methoxyl group-ethyl)-piperidines--4-base-amine (176 mg, 1.03 mmol) be dissolved in the 20 mL tetrahydrofuran (THF)s, be cooled to-78 ℃ in the dry ice ethanol bath, stir and add triethylamine (0.13 mL down successively, 1.03 mmol) and chloroacetyl chloride (115 mg, 1.02 mmol), dropwise and under ice bath cooling, stir reaction in 2 hours and finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=1: 1), obtain 2-chloro-1-{4-[ethyl-(2-methoxyl group-ethyl)-amino]-piperidines-1-yl }-ethyl ketone 293a, product directly carries out next step reaction without separating.

Second step

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(4-morpholine-4-base-piperidines-1-yl)-ethyl ketone

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (444 mg, 1 mmol) and sodium hydride (120 mg, 5 mmol) be dissolved in 10 mL N, in the dinethylformamide, stir under the room temperature and add 2-chloro-1-{4-[ethyl-(2-methoxyl group-ethyl)-amino after 30 minutes]-piperidines-1-yl }-ethyl ketone 293a (252 mg, 1.02 mmol), reaction solution is heated to 50 ℃, and afterreaction finished in 2 hours.Reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-)-1-(1,1-dioxy-1 λ ^*6 ^*-thiomorpholine-4-yl)-and ethyl ketone 292 (240 mg, yellow solid), productive rate: 36.7%.

MS m/z(ESI)：655[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.67(s，1H)，8.5(s，2H)，8.0(s，2H)，7.7(s，1H)，7.69(m，1H)，7.5(m，2H)，7.36(m，3H)，7.2(m，1H)，6.93(m，1H)，6.60(s，1H)，5.27(s，2H)，4.96(m，2H)，4.34(d，J＝8，1H)，3.92(d，J＝13.6，1H)，3.56(d，J＝4，4H)，3.18(d，J＝5.2，1H)，3.06(t，J＝12，1H)，2.67(t，J＝12.8，1H)，2.47(m，4H)，1.8(s，2H)1.3(m，2H)

Embodiment 294

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 50 mL eggplant-shape bottles, with sulfuric acid list-(2-amino-ethyl) ester (150 mg, 1 mmol) and sodium hydroxide (40mg, 1 mmol) is dissolved in the 1 mL water, stir and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (157 mg after 15 minutes successively, 0.32 2 mL dimethyl sulphoxide solutions mmol) and 20 mL methyl alcohol, the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, add 15 mL, 40% sodium hydroxide solution, continue heating reflux reaction and spend the night.Reaction solution is cooled to room temperature, regulate pH=12, mixed extractant solvent with ethyl acetate and methyl alcohol, the organic phase that merges is washed by saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of chromatographic sheet (methylene dichloride: methyl alcohol: ammoniacal liquor=120: 10: 1d), obtain this title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (92 mg, yellow solid), productive rate: 29.3%.

MS m/z(ESI)：534[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.81(s，1H)，8.59(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.38(m，2H)，7.10(m，3H)，6.87(s，1H)，6.67(s，1H)，5.72(s，2H)，3.94(m，2H)，3.76(d，1H，J＝11.2Hz)，3.65(m，1H)，3.42(m，1H)，2.76(d，1H，J＝11.2Hz)，2.66(m，2H)，2.37(m，1H)

Embodiment 295

1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidines-4- Ethyl formate

The first step

1-(2-chloracetyl)-piperidine-4-ethyl formate

With piperidine-4-ethyl formate (895 mg, 5.7 mmol) be dissolved in the 20 mL tetrahydrofuran (THF)s, stir and add triethylamine (2 mL down, 6.3 mmol), be cooled to-78 ℃ in the dry ice ethanol bath, stir and drip chloroacetyl chloride (0.78mL, 6.3 mmol) down gradually, dropwise, stir reaction in 3 hours under the room temperature and finish.In reaction solution, add 20 mL water; boil off tetrahydrofuran (THF) under the decompression; the solution that obtains ethyl acetate extraction (100 mL * 3), the organic phase of merging is successively by water washing (100 mL * 2), anhydrous sodium sulfate drying; filter; decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain 1-(2-chloracetyl)-piperidine-4-ethyl formate 295a (1.168 g; yellow oily liquid), productive rate: 87.6%.

MS m/z(ESI)：235[M+1]

Second step

1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidine-4-ethyl formate

With compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (227 mg; 0.5 mmol) and sodium hydride (78 mg; 3.25 mmol) be dissolved in 10 mLN; in the dinethylformamide; stir after 30 minutes under the room temperature and add 1-(2-chloracetyl)-piperidine-4-ethyl formate 295a (140 mg; 0.6mmol) 1 mL N, dinethylformamide solution stirs reaction in 3 hours and finishes under the room temperature.In reaction solution, add 100 mL ethyl acetate and 100 mL water; separatory; water ethyl acetate extraction (100 mL * 3); the organic phase that merges is passed through water successively; the saturated nacl aqueous solution washing; anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1); obtain title product 1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperidine-4-ethyl formate 295 (190 mg, yellow solid), productive rate: 44%.

MS m/z(ESI)：643[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.71(s，1H)，8.55(m，1H)，8.50(m，1H)，8.03(m.2H)，7.76(m.1H)，7.71(d，J＝8.8Hz，1H)，7.47(m，1H)，7.31(m，1H)，7.18(m，1H)，6.82(m，1H)，6.66(m，1H)，5.27(s，2H)，4.96(m，2H)，4.22(s，1H)4.08(m，2H)，3.85(m，1H)，3.17(m，1H)，2.77(m，1H)，6.63(m，1H)，1.87(m，2H)，1.58(m，2H)，1.22(t，J＝7.2 Hz，3H)

Embodiment 296

1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidines-4- Methane amide

The first step

1-(2-chloro-ethanoyl)-piperidines-4-methane amide

With piperidines-4-methane amide 252b (150 mg, 1.17 mmol) be dissolved in the 10 mL tetrahydrofuran (THF)s, solution is cooled to-78 ℃ under acetone-the dry ice bath, stirs to add 1 mL triethylamine and chloroacetyl chloride (159 mg down, 1.41mmol), keep this temperature stirring reaction in 40 minutes and finish.Filtering reacting liquid, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=30: 1), obtain 1-(2-chloro-ethanoyl)-piperidines-4-methane amide 296a (115 mg, white solid), productive rate: 85.4%.

MS m/z(ESI)：205[M+1]

Second step

1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidines-4-methane amide

In the flask of 50 mL; with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (327 mg; 0.74 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath; be cooled to 0 ℃; add sodium hydride (88 mg, 3.7 mmol), stir and add 1-(2-chloro-ethanoyl)-piperidines-4-methane amide 296a (180 mg after 30 minutes; 0.88 mmol), stirring reaction in 2 hours under the room temperature finishes.Reaction solution adds 50 mL water; with ethyl acetate extraction (50 mL * 3); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter; decompression concentrates down, the residue that obtains by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product 1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperidines-4-methane amide 296 (100 mg; yellow solid), productive rate: 18.5%.

MS m/z(ESI)：613[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ10.00(s，1H)，8.73(s，1H)，8.48(s，1H)，8.10(d，1H)，8.00(m，1H)，7.84(m，1H)，7.48(m，1H)，7.29(m，4H)，7.16(m，1H)，6.79(s，2H)，6.74(m，1H)，5.27(s，2H)，4.95(m，2H)，4.30(m，1H)，2.92(m，1H)，3.32(m，1H)，3.09(m，1H)，2.67(m，1H)，1.77(m，2H)，1.55(m，1H)，1.41(m，1H)

Embodiment 297

N-{ (3R)-1-[3-(3-{4-[chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-base l}-pyrroles-1-yl)-the 2-hydroxyl- Propyl group]-tetramethyleneimine-3-yl }-methane amide

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (200 mg, 0.41 mmol) be dissolved in the 25 mL methyl alcohol, stir and add (R)-N-(1-methylpyrrolidin-3-yl) ethanamide (61.4 mg down, 0.48 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=20: 1), obtain this title product N-{ (3R)-1-[3-(3-{4-[chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-base l}-pyrroles-1-yl)-2-hydroxyl-propyl group]-tetramethyleneimine-3-yl }-methane amide 297 (122 mg, faint yellow solid), productive rate: 40.5%.

MS m/z(ESI)：629[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.95(br，1H)，4.06(m，1H)，3.86(m，2H)，2.68(m，2H)，2.36(m，4H)，2.08(m，1H)，1.79(s，3H)，1.54(m，1H)

Embodiment 298

1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-the 2-hydroxypropyl]-piperazine Pyridine-4-ethyl formate

Piperazine-4-ethyl formate (94 mg, 0.6 mmol, Alfa) be dissolved in the 30 mL dehydrated alcohols, stir and add [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 187a (250 mg down, 0.5 mmol), the mixed solution reflux is spent the night.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=60: 1), obtain this title product 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-the 2-hydroxypropyl]-piperidine-4-ethyl formate 299 (260 mg, yellow solid), productive rate: 79%.

MS m/z(ESI)：658[M ⁺]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.90(s，1H)，4.05(m，3H)，3.89(m，2H)，2.81(m，2H)，2.30(m，3H)，2.06(m，2H)，1.81(m，2H)，1.64(m，2H)，1.17(t，J＝6.8Hz，3H)

Embodiment 299

1-(3-{4-[1-(3-luorobenzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-pyridin-4-yl Methyl-piperazine-1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (225 mg, 0.46 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 1-pyridin-4-yl methyl-piperazine (163 mg down, 0.92 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[1-(3-luorobenzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-pyridin-4-yl methyl-piperazine-1-yl)-propan-2-ol 299 (100 mg, the yellowish brown solid), productive rate: 33%.

MS m/z(ESI)：668[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.81(s，1H)，8.59(s，1H)，8.51(m，2H)，8.44(s，1H)，8.22(s，1H)，8.17(s，1H)，8.03(m，1H)，7.73(m，3H)，7.42(s，1H)，7.39(m，1H)，7.31(m，2H)，7.11(m，3H)，6.87(s，1H)，6.66(s，1H)，5.72(s，2H)，4.93(m，1H)，4.06(m，3H)，3.51(s，2H)，2.44(m，7H)，2.36(m，3H)

Embodiment 300

1-(3-{4-[1-(3-luorobenzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-3-(4-pyridin-3-yl Methyl-piperazine-1-yl)-propan-2-ol

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 178a (225 mg, 0.46 mmol) be dissolved in the 20 mL methyl alcohol, stir and add 2-morpholine-3-base-ethamine (163 mg down, 0.92 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by chromatographic sheet separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product 1-(3-{4-[1-(3-luorobenzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-3-(4-pyridin-3-yl methyl-piperazine-1-yl)-propan-2-ol 300 (92 mg, yellow solid), productive rate: 36%.

MS m/z(ESI)：668[M+1]

Embodiment 301

(S)-1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1- Base)-propan-2-ol

The first step

(S)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl H-indazole-5-yl)-[6-(1H-pyrroles-3-yl)-quinazoline-yl]-amine 150 (300 mg, 0.69mmol) being dissolved in the N of 5 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (60 mg, 2.76 mmol), stir after 30 minutes, add (R)-2-chloromethyloxirane (148 mg under the room temperature, 1.6 mmol), 1 hour afterreaction finishes.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (100 mL * 3), the organic phase that merges successively by organic phase successively by water washing, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters, and decompression concentrates down, the crude product that obtains (S)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 301a (yellow solid), product directly carries out next step reaction without separating.

Second step

(S)-1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol

Crude product (S)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 301a of above-mentioned steps gained is dissolved in the 25 mL methyl alcohol, stir and add diethylamine (152mg down, 2.07 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the chromatographic sheet separation and purification, obtain title product (S)-1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-propan-2-ol 301 (60 mg, the yellowish brown solid), productive rate: 15%.

MS m/z(ESI)：564[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.93(s，1H)，8.69(s，1H)，8.45(s，1H)，8.24(s，1H)，8.17(s，1H)，8.04(m，1H)，7.75(m，3H)，7.51(s，1H)，7.41(m，1H)，7.09(m，3H)，6.93(s，1H)，6.74(s，1H)，5.72(s，2H)，4.25(m，1H)，4.11(m，1H)，3.98(m，1H)，3.03(m，6H)，1.24(m，6H)

Embodiment 302

1-diethylin-3-(3-{4-[1-(3-luorobenzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-third -2-alcohol

The first step

(R)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine

In 100 mL eggplant-shape bottles, with [1-(3-fluoro-benzyl H-indazole-5-yl)-[6-(1H-pyrroles-3-yl)-quinazoline-yl]-amine 150 (300 mg, 0.69mmol) being dissolved in the N of 5 mL, in the dinethylformamide, ice bath is cooled to 0 ℃, add sodium hydride (60 mg, 2.76 mmol), stir after 30 minutes, add (S)-2-chloromethyloxirane (148 mg under the room temperature, 1.6 mmol), 1 hour afterreaction finishes.Reaction solution is poured in the 100 mL frozen water, extract with ethyl acetate (100 mL * 3), the organic phase that merges successively by organic phase successively by water washing, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters, and decompression concentrates down, the crude product that obtains (R)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 302a (yellow solid), product directly carries out next step reaction without separating.

Second step

(R)-1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-yl)-propan-2-ol

Crude product (R)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxy ethyl methyl isophthalic acid H-pyrroles-3-yl)-quinazoline-4-yl]-amine 302a of above-mentioned steps gained is dissolved in the 25 mL methyl alcohol, stir and add diethylamine (152mg down, 2.07 mmol), the reaction solution reflux is spent the night.Reaction solution is under reduced pressure concentrated, the residue that obtains is by the chromatographic sheet separation and purification, obtain title product (R)-1-diethylin-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-yl)-propan-2-ol 302 (35 mg, the yellowish brown solid), productive rate: 10%.

MS m/z(ESI)：564[M+1]

Embodiment 303

[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-6-[1-(2-methylamino--ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine

The first step

Methylsulfonic acid 2-(tertbutyloxycarbonyl-methylamino-)-ethyl ester

2-methylamino--ethanol is dissolved in the mixed solvent of 10 mL tetrahydrofuran (THF)s and 1 mL water, adds sodium bicarbonate (840 mg, 10 mmol) and tert-Butyl dicarbonate (2.18 g, 10 mmol) successively under stirring, stir under the room temperature and spend the night.Reaction solution is under reduced pressure concentrated, add 50 mL ethyl acetate in the residue, the mixed solution that obtains is successively by water washing, and saturated nacl aqueous solution washs, and anhydrous sodium sulfate drying filters, and decompression concentrates down, and (1.7 g) is standby for the residue that obtains.

The residue of above-mentioned steps is dissolved in the 20 mL methylene dichloride, and (2.1 mL 15mmol), are cooled to 0 ℃ with reaction solution under ice bath, add methylsulfonyl chloride (981 mg, 12 mmol) gradually, stir 30 minutes under the room temperature, and reaction finishes to add triethylamine under stirring.Reaction solution is under reduced pressure concentrated, add 50 mL ethyl acetate, the solution that obtains is successively by water washing, and saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=15: 1), obtain methylsulfonic acid 2-(tertbutyloxycarbonyl-methylamino-)-ethyl ester 303a (2.4 g, yellow oily liquid), productive rate: 94.8%.

MS m/z(ESI)：254[M+1]

Second step

[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl]-methyl-t-butyl carbamate

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (223 mg, 0.5 mmol) be dissolved in the N of 25 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (80 mg, 3.3 mmol), stir adding methylsulfonic acid 2-(tertbutyloxycarbonyl-methylamino-)-ethyl ester 303a (190 mg after 30 minutes, 0.75 mmol), stirring reaction in 3 hours under the room temperature finishes.Reaction solution adds 20 mL water, ethyl acetate extraction (30 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1), obtain [2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl]-methyl-t-butyl carbamate 303b (285mg, yellow solid), productive rate: 95%.

MS m/z(ESI)：602[M+1]

The 3rd step

Will [2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl]-methyl-t-butyl carbamate 303b (285 mg, 0.47 mmol) be dissolved in the 5 mL methylene dichloride, stir adding 5 mL trifluoroacetic acids down, stir reaction in 2 hours under the room temperature and finish.Reaction solution under reduced pressure concentrates, add 30 mL saturated sodium bicarbonate solutions, ethyl acetate extraction (50 mL * 3), the organic phase of merging are successively by saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, and the crude product that obtains is by re-crystallizing in ethyl acetate, obtains this title product [3-chloro-4-(3-fluorine benzyloxy)-phenyl]-{ 6-[1-(2-methylamino--ethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 303 (195 mg, yellow solid), productive rate: 83%.

MS m/z(ESI)：502[M+1]

¹H NMR(400MHz，DMSO-d6)：δ10.18(s，1H)，8.91(s，1H)，8.49(s，1H)，8.18(d，J＝2.4Hz，1H)，8.03(d，J＝8.8Hz，1H)，7.92(m，1H)，7.70(m，2H)，7.47(m，1H)，7.31(m，3H)，7.17(m，1H)，6.98(s，1H)，6.86(s，1H)，5.27(s，2H)，4.35(d，J＝6.4Hz，2H)，3.32(d，J＝6.4Hz，2H)，2.47(s，3H)

Embodiment 304

(6-{1-[4-(2-diethylin-ethyl)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-[1-(3-fluoro- Benzyl)-1H-indazole-5-yl]-amine

With [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (100 mg; 0.19 mmol) be dissolved in 2 mL dimethyl sulfoxide (DMSO); under the argon shield; add potassium hydroxide (100 mg; 1.8 mmol); stir adding (2-bromo-ethyl)-diethyl-amine (59 mg, 0.23 mmol) after 30 minutes under the room temperature, 25 ℃ are stirred reaction in 3 hours down and finish.Reaction solution is poured in the 50 mL frozen water, ethyl acetate extraction (50 mL * 4), the organic phase that merges is passed through anhydrous sodium sulfate drying successively, filter, decompression concentrates down, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain this title product (6-{1-[4-(2-diethylin-ethyl)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-amine 304 (30 mg, faint yellow solid), productive rate: 24.9%.

MS m/z(ESI)：633[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.85(s，1H)，8.62(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.74(m，3H)，7.39(m，2H)，7.08(m，3H)，6.88(s，1H)，6.68(s，1H)，5.72(s，2H)，4.00(m，2H)，3.82(d，1H，J＝11.2Hz)，3.75(m，1H)，3.49(m，1H)，2.80(d，1H，J＝11.2Hz)，2.70(m，1H)，2.55(m，3H)，2.42(m，3H)，2.06(t，2H，J＝10.4Hz)，1.83(t，2H，J＝10.4Hz)，0.98(m，6H)

Embodiment 305

(4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-1H-pyrroles-2-yl)-methyl alcohol

With 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-1-(tolyl-4-alkylsulfonyl)-1H-pyrroles-2-carboxylate methyl ester 167 (1 g; 1.5 mmol) be dissolved in the 30 mL tetrahydrofuran (THF)s; ice bath is cooled to 0 ℃; stir and add lithium aluminum hydride (470 mg down in batches; 7.5 mmol), keep 0 ℃ of stirring reaction in 1 hour to finish.Add 5 mL methyl alcohol cancellation reaction, reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain title product (4-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-1H-pyrroles-2-yl)-methyl alcohol 305 (300 mg, yellow solid), productive rate: 42.2%.

MS m/z(ESI)：475[M+1]

¹HNMR(400MHz，DMSO-d6)：δ11.02(s，1H)，9.69(m，1H)，8.55(m，1H)，8.49(m，1H)，8.05(m，2H)，7.78(m，1H)，7.69(d，J＝8.0Hz，1H)，7.47(m，1H)，7.3 1(m，4H)，7.17(m，1H)，6.60(m，1H)，5.27(s，2H)，4.45(d，J＝5.2Hz，2H)

Embodiment 306

2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanol

With 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-N, N-diethyl-ethanamide 216 (116 mg, 0.2 mmol) be dissolved in the 5 mL tetrahydrofuran (THF)s, ice bath is cooled to 0 ℃, stir and add lithium triethylborohydride tetrahydrofuran solution (2 mL down in batches, 2 mmol), stirring is spent the night under the room temperature.Add 5mL methyl alcohol cancellation reaction, reaction solution under reduced pressure concentrates, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanol 306 (26 mg, yellow solid), productive rate: 26.6%.

MS m/z(ESI)：544[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ9.70(s，1H)，8.52(m，2H)，8.04(m，2H)，7.73(m，2H)，7.49(m，2H)，7.34(m，2H)，7.29(m，1H)，7.19(m，1H)，6.90(m，1H)，6.66(m，1H)，5.27(s，2H)，4.97(t，J＝4.8Hz，1H)，3.99(m，2H)，3.72(m，2H)

Embodiment 307

(R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(3-dimethylamino Base-tetramethyleneimine-1-yl)-ethyl ketone

The first step

(R)-2-chloro-1-(3-(dimethylamino) tetramethyleneimine-1-yl) ethyl ketone

With (R)-N, N-dimethylamino tetramethyleneimine-3-amine (52 mg, 0.46 mmol) is dissolved in the 10 mL methylene dichloride, solution is cooled to-78 ℃ under acetone-the dry ice bath, stir adding 1 mL triethylamine and chloroacetyl chloride (60 mg, 0.55 mmol) down, keep this temperature stirring reaction in 40 minutes and finish.Reaction solution under reduced pressure concentrates, the residue that obtains is by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=10: 1), obtain colourless oil liquid (R)-2-chloro-1-(3-(dimethylamino) tetramethyleneimine-1-yl) ethyl ketone 307a, product directly carries out next step reaction without separating.

MS m/z(ESI)：167[M+1]

Second step

(R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-1-(3-dimethylamino-tetramethyleneimine-1-yl)-ethyl ketone

In the flask of 50 mL, with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (260 mg, 0.58 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath, be cooled to 0 ℃, add sodium hydride (101 mg, 3.48 mmol), stir adding (R)-2-chloro-1-(3-(dimethylamino) tetramethyleneimine-1-yl) ethyl ketone 307a (133 mg after 30 minutes, 0.7 mmol), stirring reaction in 3 hours under the room temperature finishes.Reaction solution adds 50 mL water, with ethyl acetate extraction (50 mL * 3), the organic phase that merges is passed through anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=40: 1), obtain this title product (R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-1-(3-dimethylamino-tetramethyleneimine-1-yl)-ethyl ketone 307 (80mg, yellow solid), productive rate: 19%.

MS m/z(ESI)：599[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ＝9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.85(m，2H)，3.65(m，4H)，3.25(m，1H)，2.68(m，1H)，2.17(s，6H)，1.72(m，1H)

Embodiment 308

(R)-N-{1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]- Tetramethyleneimine-3-yl }-ethanamide

The first step

(R)-N-[1-(2-chloro-ethanoyl)-tetramethyleneimine-3-yl]-ethanamide

With (R)-N-tetramethyleneimine-3-base-ethanamide (200 mg, 1.56 mmol) be dissolved in the 20 mL tetrahydrofuran (THF)s, solution is cooled to-78 ℃ under acetone-the dry ice bath, stirs to add 1 mL triethylamine and chloroacetyl chloride (212 mg down, 1.88mmol), keep this temperature stirring reaction in 1 hour and finish.Filtering reacting liquid; filtrate under reduced pressure concentrates, the residue that obtains by silica gel column chromatography separating purification (methylene dichloride: methyl alcohol=40: 1), obtain (R)-N-[1-(2-chloro-ethanoyl)-tetramethyleneimine-3-yl]-ethanamide 308a (205 mg; the pale yellow oily liquid body), productive rate: 21.4%.MS m/z(ESI)：205[M ⁺]

Second step

(R)-N-{1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-tetramethyleneimine-3-yl }-ethanamide

In the flask of 50 mL; with [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (472 mg; 1.06 mmol) be dissolved in the N of 10 mL dryings, in the dinethylformamide, under condition of ice bath; be cooled to 0 ℃; add sodium hydride (127 mg, 5.3 mmol), stir adding (R)-N-[1-(2-chloro-ethanoyl)-tetramethyleneimine-3-yl after 30 minutes]-ethanamide 308a (261 mg; 1.27 mmol), stirring reaction in 2 hours under the room temperature finishes.Reaction solution adds 50 mL water; with ethyl acetate extraction (50 mL * 3); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1); obtain this title product (R)-N-{1-[2-(3-{4-[3-chloro-4-(3-fluorine benzyloxy)-phenylamino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-tetramethyleneimine-3-yl-ethanamide 308 (302 mg; yellow solid), productive rate: 39%.

MS m/z(ESI)：615[M+1]

¹H NMR(400 MHz，DMSO-d6)：δ＝9.69(s，1H)，8.54(s，1H)，8.50(s，1H)，8.04(m，2H)，7.75(m，2H)，7.47(m，1H)，7.40(m，1H)，7.30(m，3H)，7.19(m，1H)，6.88(s，1H)，6.68(s，1H)，5.27(s，2H)，4.85(m，2H)，3.61(m，3H)，3.28(s，3H)，1.19(m，4H)

Embodiment 309

1-(3-amino-piperadine-1-yl)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl amino]-quinazoline-6-yl }-pyrroles -1-yl)-ethyl ketone

The first step

(S)-[1-(2-chloro-ethanoyl)-piperidines-3-yl]-t-butyl carbamate

(S)-piperidines-3-aminocarbamic acid tert-butyl ester (200 mg, 1 mmol) is dissolved in the 30 mL tetrahydrofuran (THF)s, under acetone-the dry ice bath cooling, be cooled to-78 ℃, stir and add triethylamine (0.42 mL down successively, 3 mmol) and chloroacetyl chloride (0.1 mL, 1.2 mmol), mixed solution 1 hour afterreaction of stirring under-78 ℃ finishes.Reaction solution is under reduced pressure concentrated; residue is by water washing; ethyl acetate extraction (1 00mL * 3); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter, decompression concentrates down, obtains (S)-[1-(2-chloro-ethanoyl)-piperidines-3-yl]-t-butyl carbamate 309a (271 mg; gray solid), productive rate: 98%.

MS m/z(ESI)：276[M ⁺]

Second step

(S)-1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl amino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidines-3-yl }-t-butyl carbamate

With [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 42 (317 mg; 0.71 mmol) be dissolved in the N of 10 mL dryings; in the dinethylformamide; under condition of ice bath, be cooled to 0 ℃, add sodium hydride (86mg; 3.6 mmol); stir adding (S)-[1-(2-chloro-ethanoyl)-piperidines-3-yl]-t-butyl carbamate 309a (271 mg, 0.98 mmol) after 30 minutes, stir reaction in 1 hour under the room temperature and finish.Reaction solution is under reduced pressure concentrated; residue is by water washing; ethyl acetate extraction (100 mL * 3); the organic phase that merges is passed through anhydrous sodium sulfate drying; filter; decompression concentrates down; the residue that obtains is by the further separation and purification of column chromatography (methylene dichloride: methyl alcohol=50: 1); obtain (S)-1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl amino]-quinazoline-6-yl }-pyrroles-1-yl)-ethanoyl]-piperidines-3-yl }-t-butyl carbamate 309b (100mg; pale brown look solid), productive rate: 38.5%.

MS m/z(ESI)：685[M ⁺]

The 3rd step

(S)-1-(3-amino-piperadine-1-yl)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl amino]-quinazoline-6-yl }-pyrroles-1-yl)-ethyl ketone

With (S)-1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl amino]-quinazoline-6-yl-pyrroles-1-yl)-ethanoyl]-piperidines-3-yl-t-butyl carbamate 309b (100 mg; 0.15 mmol) be dissolved in the 20 mL methylene dichloride; stir adding 5 mL trifluoroacetic acids down, stir reaction in 2 hours under the room temperature and finish.Reaction solution under reduced pressure concentrates, add 30 mL saturated sodium bicarbonate solutions, ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by alkali alumina column chromatographic isolation and purification (methylene dichloride: methyl alcohol=50: 1), obtain this title product (S)-1-(3-amino-piperadine-1-yl)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl amino]-quinazoline-6-yl-pyrroles-1-yl)-ethyl ketone 309 (60 mg, yellow solid), productive rate: 70.6%.

MS m/z(ESI)：585[M ⁺]

¹H NMR(400 MHz，DMSO-d6)：δ9.69(s，1H)，8.73(s，1H)，8.48(s，1H)，8.10(m，1H)，8.00(m，1H)，7.84(m，1H)，7.48(m，1H)，7.29(m，4H)，7.16(m，1H)，6.79(s，2H)，6.74(m，1H)，5.27(s，2H)，4.95(s，2H)，3.72(m，1H)，2.99(m，1H)，2.88(m，1H)，2.72(m，1H)，2.40(m，1H)，1.73(m，4H)

Embodiment 310

1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(2-morpholine-4-base-ethyl)-morpholine-2-ylmethyl]-1H- Pyrroles-3-yl }-quinazoline-4-yl)-amine

The first step

Methylsulfonic acid (2-morpholine-4-yl)-ethyl ester

(0.036 mL, 0.3 mmol) is dissolved in the 5 mL methylene dichloride with 2-morpholine-4-base-ethanol, stirs to add triethylamine (0.05 mL down; 0.36 mmol); mixed solution is cooled to-78 ℃ at acetone-the dry ice bath, under the argon shield, add methylsulfonyl chloride (0.06 mL; 0.33 mmol); keep-78 ℃ to react 1 hour down, thin-layer chromatography is followed the tracks of, and shows that reaction finishes; have methylsulfonic acid (2-morpholine-4-yl)-ethyl ester 310a to generate, reaction solution is not treated directly to carry out next step reaction.

MS m/z(ESI)：210[M+1]

Second step

1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(2-morpholine-4-base-ethyl)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine

In the reaction solution of above-mentioned steps, add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (80 mg, 0.15 mmol), reflux 40 hours.In reaction solution, add in the 50 mL methylene dichloride, wash with saturated sodium bicarbonate, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, the residue that obtains is by thin layer chromatography board separation and purification (methylene dichloride: methyl alcohol: ammoniacal liquor=15: 1: 1d), obtain this title product 1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(2-morpholine-4-base-ethyl)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 310 (35 mg, faint yellow solid), productive rate: 36.1%.

MS m/z(ESI)：647[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.81(s，1H)，8.60(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.39(m，2H)，7.11(m，3H)，6.88(s，1H)，6.67(s，1H)，5.72(s，2H)，4.00(m，2H)，3.81(d，1H，J＝11.2Hz)，3.74(m，1H)，3.54(m，5H)，2.80(d，1H，J＝11.2Hz)，2.71(d，1H，J＝11.2Hz)，2.41(m，4H)，2.37(m，4H)，2.06(t，1H，J＝10.4Hz)，1.82(t，1H，J＝10.4Hz)

Embodiment 311

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-[1-(4-methylsulfonyl-morpholine-2-ylmethyl)-1H-pyrroles-3-yl]- Quinazoline-4-yl }-amine

With [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (100 mg; 0.19 mmol) be dissolved in the 5 mL methylene dichloride; stir and add triethylamine (0.033mL down; 0.23 mmol); mixed solution is cooled to-78 ℃ at acetone-the dry ice bath, under the argon shield, add methylsulfonyl chloride (0.017 mL; 0.21 mmol), maintenance is reacted down for-78 ℃ to react in 3 hours and is finished.Reaction solution is added in the 50 mL methylene dichloride; wash by saturated sodium bicarbonate successively; the saturated nacl aqueous solution washing; anhydrous sodium sulfate drying; filter; decompression concentrates down; residue is by thin layer chromatography board separation and purification (methylene dichloride: methyl alcohol=15: 1); obtain this title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-{ 6-[1-(4-methylsulfonyl-morpholine-2-ylmethyl)-1H-pyrroles-3-yl]-quinazoline-4-yl }-amine 311 (50 mg; faint yellow solid), productive rate: 43%.

MS m/z(ESI)：612[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.84(s，1H)，8.61(s，1H)，8.46(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.72(m，3H)，7.44(s，1H)，7.39(m，1H)，7.11(m，3H)，6.92(s，1H)，6.69(s，1H)，5.72(s，2H)，4.12(m，3H)，3.83(m，1H)，3.55(m，2H)，3.35(m，1H)，2.92(s，3H)，2.84(t，1H，J＝11.2Hz)，2.59(m，1H)

Embodiment 312

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(2-methylsulfonyl-ethyl)-morpholine-2-ylmethyl]-the 1H-pyrrole Cough up-the 3-yl-quinazoline-4-yl)-amine

The first step

Methylsulfonic acid (2-methylsulfonyl)-ethyl ester

With 2-methylsulfonyl-ethanol (47 mg; 0.38 mmol) be dissolved in the 5 mL methylene dichloride; stir and add triethylamine (0.065 mL down; 0.46 mmol); mixed solution is cooled to-78 ℃ at acetone-the dry ice bath, under the argon shield, add methylsulfonyl chloride (0.027 mL; 0.34 mmol), rose to room temperature reaction 1 hour.Reaction solution is under reduced pressure concentrated, and the crude product methylsulfonic acid that obtains (2-methylsulfonyl)-ethyl ester 312a directly carries out next step reaction without separating.

MS m/z(ESI)：203[M+1]

Second step

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(2-methylsulfonyl-ethyl)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine

Crude product methylsulfonic acid (2-methylsulfonyl)-ethyl ester is dissolved in the 5 mL acetonitriles; stir and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (100mg down; 0.19 mmol) and salt of wormwood (105 mg; 0.76 mmol), heating reflux reaction spends the night.In reaction solution, add in the 50 mL methylene dichloride, suction filtration, filtrate under reduced pressure concentrates, the residue that obtains is by thin layer chromatography board separation and purification (methylene dichloride: methyl alcohol=12: 1), obtain this title product 1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(2-morpholine-4-base-ethyl)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine 312 (75 mg, faint yellow solid), productive rate: 61.7%.

MS m/z(ESI)：640[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.81(s，1H)，8.60(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.38(m，2H)，7.08(m，3H)，6.88(s，1H)，6.67(s，1H)，5.72(s，2H)，4.02(m，2H)，3.79(m，2H)，3.49(m，1H)，3.28(m，2H)，3.03(s，3H)，2.75(m，4H)，2.07(t，1H，J＝10.4Hz)，1.88(t，1H，J＝10.4Hz)

Embodiment 313

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(3-methoxyl group-propyl group)-morpholine-2-ylmethyl]-1H-pyrroles -3-yl }-quinazoline-4-yl)-amine

The first step

Methylsulfonic acid 3-methoxyl group propyl ester

With 3-methoxyl group-third-1-alcohol (34 mg; 0.38 mmol) be dissolved in the 5 mL methylene dichloride; stir and add triethylamine (0.065 mL down; 0.46 mmol); mixed solution is cooled to-78 ℃ at acetone-the dry ice bath, under the argon shield, add methylsulfonyl chloride (0.027 mL; 0.34 mmol), rose to room temperature reaction 1 hour.Reaction solution is under reduced pressure concentrated, and the crude product methylsulfonic acid 3-methoxyl group propyl ester 313a that obtains directly carries out next step reaction without separating.

MS m/z(ESI)：203[M+1]

Second step

[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(3-methoxyl group-propyl group)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl }-quinazoline-4-yl)-amine

313a is dissolved in the 5 mL acetonitriles with crude product methylsulfonic acid 3-methoxyl group propyl ester, stir and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (100mg down, 0.19 mmol) and salt of wormwood (105 mg, 0.76 mmol), heating reflux reaction spends the night.In reaction solution, add in the 50 mL methylene dichloride, suction filtration, filtrate under reduced pressure concentrates, the residue that obtains is by thin layer chromatography board separation and purification (methylene dichloride: methyl alcohol=12: 1), obtain this title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-(6-{1-[4-(3-methoxyl group-propyl group)-morpholine-2-ylmethyl]-1H-pyrroles-3-yl-quinazoline-4-yl)-amine 313 (40 mg, faint yellow solid), productive rate: 34.8%.

MS m/z(ESI)：606[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.81(s，1H)，8.59(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s，1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.39(m，2H)，7.06(m，3H)，6.88(s，1H)，6.67(s，1H)，5.72(s，2H)，4.02(m，2H)，3.82(d，1H，J＝10.4Hz)，3.74(m，1H)，3.50(m，1H)，3.33(m，2H)，3.21(s，3H)，2.75(d，1H，J＝10.4Hz)，2.67(d，1H，J＝10.4Hz)，2.30(m，2H)，2.00(m，1H)，1.75(t，1H，J＝10.4Hz)，1.66(m，2H)

Embodiment 314

2-[2-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-morpholine -4-yl]-ethanol

The first step

2-(tertiary butyl-dimethyl-siloxy)-ethanol

(800 mg, 20 mmol) are dissolved in the 20 mL tetrahydrofuran (THF)s with sodium hydride, and under the argon shield, ice bath is cooled to 0 ℃, drip ethylene glycol (1.24 g, 20 mmol), stir reaction in 1 hour under the room temperature and finish.Reaction solution is poured in the 100 mL frozen water, ethyl acetate extraction (50 mL * 3), the organic phase that merges is washed by saturated sodium bicarbonate solution successively, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying filters, decompression concentrates down, obtain crude product 2-(tertiary butyl-dimethyl-siloxy)-ethanol 314a (3.8 g, colourless oil liquid), product directly carries out next step reaction without separating.

Second step

Methylsulfonic acid 2-(tertiary butyl-dimethyl-siloxy)-ethyl ester

Crude product 2-(tertiary butyl-dimethyl-siloxy)-ethanol 314a (3.8 g) is dissolved in the 30 mL methylene dichloride; stir and add triethylamine (4 g down; 30 mmol); mixed solution is cooled to-78 ℃ at acetone-the dry ice bath; under the argon shield; add methylsulfonyl chloride (3.4 g, 30 mmol), rose to room temperature reaction 1 hour.Reaction solution is poured in the 100mL frozen water, ethyl acetate extraction (50 mL * 3), by the saturated sodium bicarbonate solution washing, saturated nacl aqueous solution washs the organic phase that merges, anhydrous sodium sulfate drying successively, filter, decompression concentrates down, and residue is by silica gel column chromatography separating purification (normal hexane: ethyl acetate=4: 1), obtain methylsulfonic acid 2-(tertiary butyl-dimethyl-siloxy)-ethyl ester 314b (3.5 g, colourless oil liquid), productive rate: 68.8%.

MS m/z(ESI)：255[M+1]

The 3rd step

[6-(1-{4-[2-(tertiary butyl-dimethyl-siloxy)-ethyl]-morpholine-2-ylmethyl }-1H-pyrroles-3-yl)-quinazoline-4-yl]-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine

With methylsulfonic acid 2-(tertiary butyl-dimethyl-siloxy)-ethyl ester 314b (84 mg, 0.33 mmol) be dissolved in the 5 mL acetonitriles, stir and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-morpholine-2-ylmethyl-1H-pyrroles-3-yl)-quinazoline-4-yl]-amine 294 (60 mg down, 0.11 mmol) and salt of wormwood (61 mg, 0.44 mmol), heating reflux reaction spends the night.In reaction solution, add in the 20 mL methylene dichloride, suction filtration, filtrate under reduced pressure concentrates, the residue that obtains is by thin layer chromatography board separation and purification (methylene dichloride: methyl alcohol=12: 1), obtain [6-(1-{4-[2-(tertiary butyl-dimethyl-siloxy)-ethyl]-morpholine-2-ylmethyl }-1H-pyrroles-3-yl)-quinazoline-4-yl]-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 314c (40 mg, faint yellow solid), productive rate: 39.4%.

MS m/z(ESI)：692[M+1]

The 4th step

2-[2-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl }-pyrroles-1-ylmethyl)-morpholine-4-yl]-ethanol

Will [6-(1-{4-[2-(tertiary butyl-dimethyl-siloxy)-ethyl]-morpholine-2-ylmethyl }-1H-pyrroles-3-yl)-quinazoline-4-yl]-[1-(3-luorobenzyl)-1H-indazole-5-yl]-amine 314c (30 mg, 0.043 mmol) be dissolved in the 2 mL tetrahydrofuran (THF)s, stir and add tetrabutyl ammonium fluoride (50 mg down, 0.16 mmol), stirring reaction in 1 hour under the room temperature finishes.Reaction solution is poured in the 20 mL frozen water, add 2 mL saturated sodium bicarbonate solutions, ethyl acetate extraction (20 mL * 3), the organic phase that merges is washed by saturated sodium bicarbonate solution successively, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, decompression concentrates down, residue is by thin layer chromatography board separation and purification (methylene dichloride: methyl alcohol=10: 1), obtain 2-[2-(3-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base is amino]-quinazoline-6-yl-pyrroles-1-ylmethyl)-morpholine-4-yl]-ethanol 314 (19 mg, faint yellow solid), productive rate: 76.5%.

MS m/z(ESI)：578[M+1]

¹HNMR(400MHz，DMSO-d6)：δ9.81(s，1H)，8.60(s，1H)，8.45(s，1H)，8.23(s，1H)，8.17(s.1H)，8.03(d，1H，J＝8.8Hz)，7.73(m，3H)，7.38(m，2H)，7.08(m，3H)，6.88(s，1H)，6.67(s，1H)，5.72(s，2H)，4.40(t，1H，J＝5.2Hz)，4.00(m，2H)，3.83(m，2H)，3.51(m，3H)，2.79(d，1H，J＝10.4Hz)，2.70(d，1H，J＝10.4Hz)，2.39(m，2H)，2.08(t，1H，J＝10.4Hz)，1.85(t，1H，J＝10.4Hz)

Experimental example:

Biological assessment

Example 1 EGFR suppresses the cell proliferation test

Following in vitro tests is to measure The compounds of this invention for the cell strain inhibition proliferation activity of human tumor cell A431 EGFR high expression level.

Cell in vitro described below test can determine test-compound to the anti-angiogenesis activity of the tumour cell of high expression level EGFR and suppress proliferation activity, its active available IC ₅₀Value is represented.The general approach of this type of test is as follows: the human tumor cell who at first selects high expression level EGFR, be seeded on 96 well culture plates with (5000 cells of exp/ml medium) under the suitable cell concn, then cell is cultivated in carbon dioxide incubator, when growing to 85%, they converge, change substratum for being added with the substratum of a series of concentration degree of passing (general 6 to 7 concentration) test-compound solution, culture plate is put back to incubator again, cultured continuously 72 hours.After 72 hours, available sulphonyl rhodamine B (SRB) method is carried out test compounds for suppressing cell-proliferation activity.IC ₅₀Value can be by under a series of different concns, and test-compound calculates for cell inhibiting numerical value.Material and method:

A. dimethyl sulfoxide (DMSO) (Sinophma chemical reagent company, catalogue T20050806 number)

B.A431 cell (purchasing the biology in Institute of biochemistry and cell)

C.Falcon 100 mm Tissue Culture Plates (Baton Dickison Labware, Baton Dickison andcompany, No. 18677, catalogue)

D. healthy and free from worry (corning) 96 well culture plates (Corning Incorporated, No. 3599, catalogue)

E. Fei Shi transfer pipet (Fisher scientific, catalogue 03-692-164 number)

F. DMEM/F12 cell culture medium (Gibco, catalogue 12400-024 number)

G. Australian foetal calf serum (Gibco, catalogue 10099-141 number)

H. phosphate buffered saline (PBS) (Gibco, catalogue 10010-072 number)

I.0.25% Regular Insulin-EDTA (Gibco, catalogue 25200-056 number)

J. sulphonyl rhodamine B (Sigma, catalogue 3520-42-1 number)

K. acetic acid (Sinophma chemical reagent company, catalogue T20060508 number)

L. Tricholroacetic Acid (Sinophma chemical reagent company, catalogue T20060305 number)

M.Tris alkali (Amresco, No. 0826, catalogue)

N.II level A/B3 type biological safety cabinet (ThermoForma catalogue .HB0053-03 number)

O. serial II water-jacket typ CO2gas incubator (ThermoForma model: 3111)

P. whizzer (Fisher Scientific Marathon 8 k, catalogue 0027-02 number)

Q.Novastar plate reader (BMG Labtech, catalogue 700-0081 number)

R. orbital shaker (Qilinbeier, catalogue TS-1 number)

Scheme:

Following scheme is used for testing test-compound of the present invention for A431 cell inhibiting cell proliferation IC ₅₀Value.

1. the A431 cell is grown in the healthy and free from worry culture plate of 100mm in growth substrate (be nutrient solution with the DMEM/F12+10% foetal calf serum), cultivate (37 ℃, 5%CO ₂), fully converge until cell;

In 100 mm culture plates with foetal calf serum washing A431 cell, behind trypsin digestion and cell, again with cell inoculation on healthy and free from worry 96 porocyte culture plates, concentration is 50000 cells/ml, each plate empty 6 holes, hole in contrast.;

3. at 37 ℃, 5%CO ₂Under the condition, cell is cultivated in 96 orifice plates, converged until reaching about 85%;

4. dissolve test-compound with DMSO, dispose 20 mM mother liquors, mother liquor is diluted with DMSO in the back, obtains the solution of the test-compound of a series of concentration, i.e. 2 mM, 1 mM, 0.2 mM, 20 μ M, 2 μ M, 0.2 μ M;

5. use the compound solution that disposes above cell culture medium (the DMEM/F12+10% foetal calf serum the is nutrient solution) dilution.20 times of each DMSO series concentration compound solution dilutions add 5 μ l DMSO compound solutions and 95 μ l nutrient solutions at every turn in cell culture medium, guarantee that the concentration of A431 cellular exposure in DMSO solution is no more than 0.5%, use vortex mixed;

6. when the A431 cell attachment, growth reach 85% converge after, substratum is changed to the new substratum that is added with DMEM/F12+10% foetal calf serum nutrient solution, every Kong Zhongzai adds 180 μ l nutrient solutions and 20 μ l prepared test-compound solution in the 5th step.The negative control cell group adds the 20 μ l nutrient solutions that contain 0.5%DMSO, and the ultimate density of A431 cellular exposure in test-compound solution is 100 μ M like this, 10 μ M, 5 μ M, 1 μ M, 0.1 μ M, 0.01 μ M, and 0.001 μ M;

7. culture plate is put into thermostat container, at 37 ℃, 5%CO ₂Under the condition, cultured continuously 72 hours;

8.72 after hour, culture plate is transferred to aseptic working spaces from thermostat container;

9. reagent level pure water is joined prepare among the TCA fixing agent (50% Tricholroacetic Acid-TCA), with cell at leisure layering be placed in the cold TCA solution of 50 μ l;

10. under 4 ℃, cultivated 1 hour, after wash with water for several times to remove TCA, serum protein etc.Culture plate is stored stand-by at air drying.Blank is the numerical value that incubation is cultivated gained in the substratum that does not have the cell growth by the mensuration of scape optical density (OD) value.

11. prepare 0.4% sulphonyl rhodamine B solution with 10% acetum, and in every hole, add 50 μ l sulphonyl rhodamine B solution;

12. painted 30 minutes of cell;

13. prepare 10% acetic acid washing soln.When painted will finishing, discard tinting material, get cell express developed with 10% acetum.Repeat above-mentioned operation till tinting material is cleaned, reduce washing time with the go absorption of minimizing with protein bound tinting material as far as possible.The flushing finish after, with culture plate at air drying;

14. the tinting material that mixes is dissolved in the sulphonyl rhodamine B of certain volume, (10 mM Tris) is identical with the substratum original volume for solubilising solution, and culture plate was at room temperature placed 5 minutes, slowly stirs mixing of quickening and dyestuff with shaking table;

15. use spectrophotometry, under wavelength 565 nm, read absorbance.Absorbancy numerical value is that absorbancy deducts under 690 nm 96 orifice plates by the numerical value of scape absorbancy gained under 565 nm;

16. make and calculate inhibiting rate ratio with the following method:

IR=100 * (control group absorbance-medication group absorbance)/control group absorbance %.

IC ₅₀Value can obtain by compound inhibiting rate ratio calculation under the different concns.

The activity of The compounds of this invention

The biochemical activity of The compounds of this invention is measured by above test, the IC that records ₅₀Value sees the following form.

Example 2.EGFR kinase activity is measured

External EGFR kinase activity is tested by following method.

Material and reagent:

A. lavation buffer solution (PBS-T damping fluid): 1x PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mMNa ₂HPO ₄, 1.4 mM KH ₂PO ₄, transfer pH to 7.2) and 0.05% tween 20

B.1% bovine serum albumin (BSA, Calbiochem#136593) PBS-T damping fluid

C. stopping of reaction damping fluid: 50 mM EDTA, pH 8.0.

D.

The anti-mouse IgG of europium mark (PerkinElmer Life Sciences#AD0124)

E.

Signal multiplication liquid (PerkinElmer Life Sciences#1244-105)

F.

Streptavidin wraps the yellow plate (PerkinElmer Life Sciences#AAAND-0005) in 96 holes

G.EGFR kinases (50 mM Tris-HCl (pH 8.0), 100mM NaCl, 5 mM DTT, 15 mM glutamylcystyl-glycines and 20% glycerine, Cell signaling technology#7908)

H.10 mM ATP solution (Cell signaling technology#9804).

I.PTP1B (Tyr66) biotinylation albumen (Cell signaling technology#1325).

J. phosphorus-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology#9411).

K.HTScanTM Tyrosylprotein kinase damping fluid (4x)

1x kinase buffer liquid:

60 mM HEPES

5 mM MgCl ₂

5 mM MnCl ₂

3μMNa ₃VO ₄

(cell signalling technology #9805).

L.1.25 M DTT (1000x) (cell signalling technology).

Scheme:

Use following scheme to test:

1. reach the ultimate density value with DMSO dilution test-compound;

In each test, add 1 μ l test-compound, negative control and blank (not accepting any test-compound), only add 1 μ l DMSO;

2. use dH ₂O1: 1 dilution, 6 μ M substrate proteins (Tyr589), and add 15 μ l to each test;

3. enzyme is directly transferred on ice from-80 ℃, the EGFR enzymolysis freezes on ice;

4. get 3 μ gEGFR enzymes in each test;

5. add 10 μ l DTT (1.25 M) to 2.5 ml 4x HTScan ^TMTyrosylprotein kinase damping fluid (240 mMHEPES pH, 7.5,20 mM MgCI ₂, 20 mM MnCI ₂, 12 μ M Na ₃VO ₄) in, make DTT/ kinase buffer liquid;

6. transferase 10 .75 ml DTT/ kinase buffer liquid makes the 4x reaction mixture in each each test, and adds 7.5 μ l 4x reaction solutions in each test;

7. add 2 μ lATP (10 mM) to 496 μ l dH ₂Among the O, and in each test, add 7.5 μ l; 30 μ l reaction final test condition is:

60 mM HEPES pH 7.5

5 mM MgCl ₂

5 mM MnCl ₂

3μM Na ₃VO ₄

1.25 mM DTT

20μMATP

1.5 μ M peptide substrate

30 ngEGFR kinases

8. under 25 ℃, with reaction tubes incubation 45 minutes;

9. add 30 μ l stopped reaction damping fluid (50 mM EDTA, pH 8.0) stopped reactions in each test;

10. in the every hole of culture plate of 96 pore chain avidin bag quilts, add 25 μ l reaction solutions and 75 μ l dH ₂O, at room temperature, and jolting 60 minutes;

11. every hole pats to remove remaining liquid with 200 μ lPBS-T damping fluids washing 3 times at paper handkerchief;

12. with 1% bovine serum albumin PBS-T damping fluid dilution in 1: 1000 antibody phosphorus-tyrosine mAb (P-Tyr-100), in every hole, add the antibody of 100 μ l dilution;

13. at room temperature, the jolting incubation is 60 minutes;

14. by the described method washing of the 11st step;

15. with the anti-mouse IgG of 1% bovine serum albumin PBS-T damping fluid dilution in 1: 500 europium mark, and in every hole, add 100 μ l dilution antibody;

16. at room temperature, the jolting incubation is 30 minutes;

17. every hole pats to remove remaining liquid with PBS-T damping fluid 200 μ l washing 5 times at paper handkerchief;

18. add 100 μ in every hole

Signal multiplication liquid;

19. at room temperature, the jolting incubation is 5 minutes;

20. at 615 nm places, read fluorescence intensity with suitable temporal resolution plate reader.。

Calculate inhibiting rate ratio: IR (%)=100-100* (X-B)/(N-B)

X=test-compound fluorescent value

The N=negative control

The B=blank

IC ₅₀Value can obtain by the inhibiting rate ratio calculation under the test-compound different concns degree of passing.

The activity of The compounds of this invention

The embodiment numbering	IC50(EGFR/BIO)(μM)
		1	0.003
2	0.012
		3	0.0225
5	0.05
		6	0.031
7	0.028
		8	0.004
9	0.006
		10	0.005
11	0.018
		12	0.0026
13	0.0036
		14	0.008
15	0.003
		16	0.002
17	0.005
		18	0.02
21	0.009
		22	0.042
23	0.053
		24	0.0075
25	0.003
		26	0.015
27	0.008
		28	0.054
29	0.007
		30	0.004
31	0.009
		32	0.008

33	0.032
		34	0.032
35	0.01
		36	0.049
37	0.016
		38	0.043
39	0.055
		40	0.091
41	0.016
		42	0.004
43	0.006
		44	0.006
45	0.005
		46	0.013
47	0.008
		48	0.061
49	0.011
		50	0.008
52	0.066
		53	0.025
54	0.03
		55	0.078
56	0.108
		57	0.096
58	0.049
		59	0.06
60	0.03
		61	0.026
62	0.011
		63	0.197
64	0.004
		65	0.032
67	0.005
		68	0.095
69	0.032

70	0.007
		86	0.04
88	0.022
		99	0.105
111	0.276
		112	0.127
113	0.376
		114	0.291
115	0.056
		116	0.071
117	0.031
		118	0.102
119	0.014
		123	0.037
124	0.039
		125	0.019
126	0.024
		127	0.011
128	0.025
		129	0.072
130	0.015
		131	0.057
132	0.05
		133	0.062
134	0.156
		135	0.115
136	0.023
		137	0.016
138	0.012
		141	0.065
142	0.076
		143	0.127
145	0.016
		148	0.042
149	0.021

150	0.003
		151	0.012
152	0.015
		153	0.025
154	0.047
		155	0.017
156	0.072
		157	0.086
158	0.094
		159	0.387
164	0.006
		165	0.004
166	0.007
		169	0.006
170	0.074
		172	0.012
173	0.009
		174	0.006
177	0.131
		178	0.005
179	0.001
		180	0.027
182	0.039
		183	0.022
184	0.024
		185	0.031
186	0.018
		187	0.022
188	0.021
		189	0.023
190	0.079
		191	0.079
192	0.006
		193	0.036
194	0.011

195	0.02
		196	0.116
197	0.017
		213	0.019
214	0.008
		215	0.066
216	0.14
		217	0.013
218	0.47
		219	0.092
220	0.011
		221	0.03
222	0.049
		223	0.06
224	0.166
		225	0.14
227	0.263
		228	0.106
229	0.239
		230	0.08
231	0.034
		232	0.638
233	0.051
		234	0.039
235	0.492
		236	0.197
237	0.079
		238	0.041
239	0.001
		240	0.002
241	0.002
		242	0.012
243	0.027
		244	0.017
245	0.038

246	0.102
		247	0.095
248	0.024
		251	0.012
252	0.117
		253	0.443
260	0.094
		285	0.058
299	0.598
		300	0.282
301	0.038
		302	0.071
303	0.073
		304	0.248
306	0.052
		307	0.133
308	0.129
		309	0.038
310	0.276
		311	0.257
312	0.236
		313	0.291
314	0.205

The determination of activity of example 3:HER-2 kinase inhibitor

This test is measured external HER-2 kinase inhibitor activity with enzyme-linked immunosorbent assay (ELISA).Material and reagent:

A. lavation buffer solution (PBS-T damping fluid): 1x PBS (137mM NaCl, 2.7mM KCl, 4.3mMNa ₂HPO ₄, 1.4mM KH ₂PO ₄, regulate pH7.2) and 0.05% tween 20

B.1% bovine serum albumin (BSA, Calbiochem#136593) PBS-T damping fluid

C. seal damping fluid: 50mM EDTA, pH 8.0

D. The anti-mouse IgG of europium mark (PerkinElmer Life Sciences#AD0124)

E. Signal multiplication liquid (PerkinElmer Life Sciences#1244-105)

F.

Streptavidi wraps the yellow plate (PerkinElmer Life Sciences#AAAND-0005) in 96 holes.

G.HER-2/ErbB2 kinases (Invitrogen corporation#PV3366).

H.10mM ATP solution (Cell signaling technology#9804).

I.FLT3 (Tyr589) biotinylation protein (Cell signaling technology#1305).

J. phosphorus-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology#9411).

K.HTScan ^TMTyrosylprotein kinase damping fluid (4x)

1x kinase buffer liquid

60mM HEPES

5mM MgCl ₂

5mM MnCl ₂

3μMNa ₃VO ₄

(cell signalling technology #9805).

L.1.25M DTT (1000x) (cell signalling technology).

Scheme:

Use following scheme to test:

1. reach the ultimate density value with DMSO dilution test-compound;

In each test, add 1 μ l test-compound, negative control (not accepting any test-compound) and 1 μ lDMSO;

2. use dH ₂O dilutes 1: 16 μ M substrate protein (Tyr87), and adds 15 μ l in each test;

3. the HER-2 enzyme is directly transferred on ice from-80 ℃, the HER-2 enzymolysis freezes on ice;

4. get 4.5 μ gHER-2 enzymes in the enzyme pipe;

5. add 10 μ l DTT (1.25M) to 2.5ml 4x HTScan ^TMTyrosylprotein kinase damping fluid (240mM

HEPES pH 7.5,20mM MgCI ₂, 20mM MnCI ₂, 12 μ M Na ₃VO ₄) in, make DTT/ kinase buffer liquid;

6. transferase 10 .75ml DTT/ kinase buffer liquid makes the 4x reaction mixture in each enzyme pipe, and adds 7.5 μ l 4x reaction solutions in each test;

7. add 2 μ l ATP (10mM) to 496 μ l dH ₂Among the O, and in each test, add 7.5 μ l; 30 μ l react final test conditions:

60mM HEPES pH 7.5

5mM MgCl ₂

5mM MnCl ₂

3μM Na ₃VO ₄

1.25mM DTT

20μM ATP

1.5 μ M substrate protein

45ng HER-2 kinases

8. under 25 ℃, with reaction tubes incubation 60 minutes;

9. add 30 μ l sealing damping fluid (50mM EDTA, pH 8.0) termination reaction in each test;

10. in the every hole of culture plate of 96 pore chain avidin bag quilts, add 25 μ l reaction solutions and 75 μ l dH ₂O at room temperature, and followed jolting 60 minutes;

11. every hole pats to remove excessive liquid with 200 μ l PBS-T damping fluids washing 3 times at paper handkerchief;

12. with 1% bovine serum albumin PBS-T damping fluid dilution in 1: 1000 main antibody phosphorus-tyrosine mAb (P-Tyr-100), and in every hole, add the main antibody that 100 μ l dilute;

13. under the room temperature, followed under the jolting incubation 60 minutes;

14. wash by described method of the 11st step;

15. with the anti-mouse IgG of 1% bovine serum albumin PBS-T damping fluid dilution in 1: 500 europium mark, and in each hole, add the antibody that 100 μ l dilute;

16. under the room temperature, followed under the jolting incubation 30 minutes;

17. every hole pats to remove excessive liquid with PBS-T damping fluid 200 μ l washing 5 times at paper handkerchief;

18. add 100 μ in every hole Signal multiplication liquid;

19. under the room temperature, followed under the jolting incubation 5 minutes;

20. under wavelength 615nm, read absorbancy with suitable temporal resolution plate reader.Calculate inhibiting rate ratio: IR (%)=100-100* (X-B)/(N-B)

X=test-compound fluorescent value

The N=negative control

The B=blank

The IC ₅₀Value can obtain by the inhibiting rate ratio calculation under the different tonsure concentration of test-compound.

The activity of The compounds of this invention

The biochemical activity of The compounds of this invention is measured by above test, the IC that records ₅₀Value sees the following form

Example 4:HER-2 suppresses the cell proliferation test

Following in vitro tests is to measure The compounds of this invention for the cell strain inhibition proliferation activity of human tumor cell SK-BR-3HER-2 high expression level.

Cell in vitro described below test can determine test-compound to the anti-angiogenesis activity of the tumour cell of highly expressing HER-2 and suppress proliferation activity, its active available IC ₅₀Value is represented.The general approach of this type of test is as follows: the human tumor cell who at first selects highly to express HER-2, to be seeded on 96 well culture plates under the suitable cell concn, then cell is cultivated in carbon dioxide incubator, when growing to 60%, they converge, change substratum for being added with the substratum of a series of concentration degree of passing (general 6 to 7 concentration) test-compound solution, culture plate is put back to incubator again, cultured continuously 96 hours.After 96 hours, available sulphonyl rhodamine B (SRB) method is carried out test compounds for suppressing cell-proliferation activity.IC ₅₀Value can be by under a series of different concns, and test-compound calculates for cell inhibiting numerical value.

Material and method:

A dimethyl sulfoxide (DMSO) (Sinophma chemical reagent company, catalogue T20050806 number)

B.SK-BR-3 cell (purchasing the biology in Institute of biochemistry and cell)

D. healthy and free from worry 96 well culture plates (Corning Incorporated, No. 3599, catalogue)

E. Fei Shi transfer pipet (Fisher scientific, catalogue 03-692-164 number)

F.RPMI1640 cell culture medium (Gibco, catalogue 12400-021 number)

G. Australian foetal calf serum (Gibco, catalogue 10099-141 number)

H. phosphate buffered saline (PBS) (Gibco, catalogue 10010-072 number)

I.0.25% Regular Insulin-EDTA (Gibco, catalogue 25200-056 number)

J. sulphonyl rhodamine B (Sigma, catalogue 3520-42-1 number)

K. acetic acid (Sinophma chemical reagent company, catalogue T20060508 number)

M.Tris alkali (Amresco, No. 0826, catalogue)

O. serial II water-jacket typ CO2gas incubator (ThermoForma model: 3111)

P. whizzer (Fisher Scientific Marathon 8 k, catalogue 0027-02 number)

Q.Novastar plate reader (BMG Labtech, catalogue 700-0081 number)

R. orbital shaker (Qilinbeier, catalogue TS-1 number)

Scheme:

Following scheme is used for testing test-compound of the present invention for SK-BR-3 cell inhibiting cell proliferation IC ₅₀Value.

1. the SK-BR-3 cell is grown in the healthy and free from worry culture plate of 100mm in growth substrate (be nutrient solution with the RPMI1640+10% foetal calf serum), cultivate (37 ℃, 5%CO ₂), fully converge until cell;

In 100 mm culture plates with foetal calf serum washing SK-BR-3 cell, behind trypsin digestion and cell, again with cell inoculation on healthy and free from worry 96 porocyte culture plates, concentration is 50000 cells/ml, each plate empty 6 holes, hole in contrast.;

3. at 37 ℃, 5%CO ₂Under the condition, cell is cultivated in 96 orifice plates, converged until reaching about 60%;

4. dissolve test-compound with DMSO, dispose 20 mM mother liquors, mother liquor is diluted with DMSO in the back, obtains the solution of the test-compound of a series of concentration, i.e. 2mM, 1mM, 0.2mM, 20 μ M, 2 μ M, 0.2 μ M;

5. use the compound solution that disposes above cell culture medium (the RPMI1640+10% foetal calf serum the is nutrient solution) dilution.20 times of each DMSO series concentration compound solution dilutions add 5 μ l DMSO compound solutions and 95 μ l nutrient solutions at every turn in cell culture medium, guarantee that the concentration of SK-BR-3 cellular exposure in DMSO solution is no more than 0.5%, uses vortex mixed;

6. when the SK-BR-3 cell attachment, growth reach 60% converge after, substratum is changed to the new substratum that is added with RPMI1640+10% foetal calf serum nutrient solution, every Kong Zhongzai adds 180 μ l nutrient solutions and 20 μ l prepared test-compound solution in the 5th step.The negative control cell group adds the 20 μ l nutrient solutions that contain 0.5%DMSO, and the ultimate density of SK-BR-3 cellular exposure in test-compound solution is 100 μ M like this, 10 μ M, 5 μ M, 1 μ M, 0.1 μ M, 0.01 μ M, and 0.001 μ M;

7. culture plate is put into thermostat container, at 37 ℃, 5%CO ₂Under the condition, cultured continuously 96 hours;

8.96 after hour, culture plate is transferred to aseptic working spaces from thermostat container;

12. painted 30 minutes of cell;

16. make and calculate inhibiting rate ratio with the following method:

The activity of The compounds of this invention

The biochemical activity of The compounds of this invention is measured by above test, the IC that records ₅₀Value sees the following form:

Claims

A quinazoline compounds or its salt, wherein this compound is selected from:
2. compound or its salt according to claim 1, wherein said salt are described compound and be selected from the salt that following acid forms: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, tosic acid, sulfuric acid, phosphoric acid, citric acid, tartrate, acetic acid or trifluoroacetic acid.
3. medicinal compositions, it contains the compound or its salt according to claim 1 and 2 for the treatment of effective dose, and pharmaceutically acceptable carrier or vehicle.
4. the purposes of compound or its salt according to claim 1 and 2 in the medicine of preparation treatment and protein kinase diseases associated.
5. the purposes of composition according to claim 3 in the medicine of preparation treatment and protein kinase diseases associated.