CN104768952A - PI3Kdelta inhibitor - Google Patents

Abstract

Disclosed are a PI3Kdelta inhibitor compound of formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof, preparation methods of these compounds, a pharmaceutical preparation containing these compounds, and the use thereof for preparing a medicine for treating inflammatory disorders or tumours.

Description

PI3Kdelta inhibitor

PI3K6 inhibitor ι, technical field

The invention belongs to pharmaceutical technology field, specifically related to Ρ Β Κ δ inhibitor, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing, the preparation method of these compounds, pharmaceutical preparation containing these compounds, and purposes of these compounds in the medicine for the treatment of inflammatory disease or tumour is prepared.

2nd, background technology

Tumour is body under the effect of the various tumorigenesis factors, causes cellular genetic material to change, causes gene expression not normal, neoformation formed by abnormal cell proliferation.Tumour cell loses normal growth regulatory function, with autonomous or relative autonomous growth ability, when remaining to continued growth after the stopping of the tumorigenesis factor, largely the nutriments of consumption human bodies.If it find that with treatment not in time, cancer cell also can be transferred to whole body growth and breeding everywhere, and discharge a variety of toxin, cause human body to be become thin, anaemia, organ function are damaged to death.

The method of oncotherapy, it is main to include three aspects：Drug therapy, operative treatment and radiotherapy.Because operative treatment, radiotherapy are difficult to thorough tumor eradication, and the effect of centering patients with advanced cancer is not obvious, therefore status of the drug therapy in oncotherapy is more and more obvious.Traditional anti-tumor medicine cannot be distinguished by tumour cell and normal tissue cell, often result in serious side effect, targeted drug is used as specific target spot using cancer cell, tumour can accurately be acted on, greatly improve treatment level, and adverse reaction rate is alleviated, for example making the median survival time of advanced CRC increases by 66.7%, and the treated effect of advanced breast cancer improves 71.3%.

Because each drugmaker accelerates to the development for targetting class antineoplastic, along with market is in strong demand to the antineoplastic of this classification, molecular targeted agents have become fastest-rising unit in global antineoplastic market.Phosphatidyl-inositol 3-kinase (phosphoinositide 3-kinase, PBK) signal transduction path is one of system of topnotch mutation in human cancer, PI3K signal transductions are also the key factor in the various other diseases of the mankind, PBK signal transductions participate in various disease conditions, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, the inflammatory complication such as acute coronary syndrome of the obstacle for being related to diabetic complication and cardiovascular system.

PI3K is the 3'-OH on the member of unique and conservative lipid within endothelial cells kinase families, its phosphorylation phosphatidylinositols or phosphoinositide.PI3K families include 15 kinds of kinases with different substrate specificities, expression pattern and regulative mode.The Κ of I class Ρ Ι 3 (ρ 110 α, ρ 110 110 10 γ of δ, pi of β, ρ) generally by EGFR-TK or g protein coupled receptor activation to produce PIP3, and PIP3 combination downstream effect things effector as in Akt/PDKl approach, mTOR, Tec family kinase and Rho families GTP enzymes.II classes and Π Ι classes PI3K play crucial in transporting in the cell by synthesizing PI (3) P and PI (3,4) P2 Effect.PIKK is the protein kinase (mTORCl) for controlling cell growth or the protein kinase (ATM, ATR, DNA-PK and hSmg-l) for monitoring genomic integrity.

It is related to I classes PI3K δ hypotypes in a variety of diseases and bioprocess.The Κ δ of Ρ Ι 3 are main to express in hematopoietic cell includes leucocyte such as Τ cells, dendritic cells, neutrophil cell, mast cell, Β cells and macrophage.It is essential in immune system function such as Τ cell functions, Β cell activations, Mast cell activation, Dendritic Cell Function and neutrophil activity to be related to the Κ δ of Ρ Ι 3.Due to the effect that the Κ δ of Ρ Ι 3 are essential in function of immune system, the Κ δ of Ρ Ι 3 also assist in a variety of related diseases corresponding to abnormal immune, such as allergy, inflammatory disease, inflammation mediated angiogenesis, rheumatoid arthritis, autoimmune pathologies such as lupus, asthma, wind-puff and other breathing problems.

The downstream media of the Κ signal transduction pathways of Ρ Ι 3 includes the mammal target (mTOR) of Akt and rapamycin.Akt has blood platelet leucocyte C kinase substrates homology (PH) domain for combining PIP3, wherein and PIP3 combination cause the activation of Akt kinases.The a variety of substrates of Akt sulphations, and be PI3K for the corresponding core downstream effect thing of various kinds of cell.A kind of Akt critical function is to strengthen mTOR activity by phosphorylation TSC2 and other mechanism.MTOR is the serine-threonine kinase related to PI3K families lipid kinases.MTOR participates in a variety of bioprocess, including cell growth, cell propagation, cell mobility and survival.The imbalance of mTOR approach has been reported in polytype cancer.MTOR is to integrate growth factor and trophic signals with the translation of regulatory protein matter, nutrition intake, from thermophilic and mitochondrial function multi-functional kinases.Therefore, kinases, particularly PI3K, are the major targets of drug development.

CAL-101 is the specific inhibitor of Κ δ of Ρ Ι 3, Yuan Yan companies are Calistoga drugmakers, bought by Gilead companies within 2011, it is the medicine that the Κ δ target spots of Ρ Ι 3 study forefront, being currently in the clinical III phases studies, and clinical principal indication is chronic lymphocytic leukemia, NHL, acute myeloid leukaemia, allergic rhinitis etc..Structure is as follows：

In Intellikine patent WO2009088990 and Icos patents US6667300, validity of the Κ δ inhibitor of Ρ Ι 3 in tumour and inflammation treatment is reported.At present, temporarily listed without the Κ δ inhibitor classes medicines of Ρ Ι 3, accordingly, it would be desirable to more Κ δ inhibitor structure types of Ρ Ι 3, effectiveness of selection and the preferable compound of security be researched and developed, for the treatment of cancer and inflammation, to meet clinical needs.

3rd, the content of the invention The invention provides following technical proposals：

Technical scheme 1:

A kind of formula（I salt, its stereoisomer or its deuterated thing shown in):

( I )

Wherein-

X¹, X², X³, X⁴, Y is separately N or CR³, R³For hydrogen, halogen, hydroxyl, carboxyl, trifluoromethyl, Cw alkyl, CL₆Protective embankment epoxide ,-N (R^a)(R^a'), cyano group, C₂.₆Alkenyl, C₂.₆Alkynyl, carbamoyl, alkyl formyl radical, amino-sulfonyl, 3-14 yuan of rings protective embankments base, 6-14 members aryl, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases；

L is covalent bond or-N (R^a)-_;

When L is covalent bond, R¹For benzo ring mono alkenyl, benzo C₄_₈Cycloalkadienyl, C₃.₈Ring monoene and phenyl and Ο μ₈Cyclic diolefine and phenyl, by（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃.₈Ring mono alkenyl, C₄_₈Cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

L is-N (R^a)-when, R¹For Q.₆Alkyl, Q.6 alkyl formyl radical, Cw alkyl sulphonyls, 3-14 members cycloalkyl, 6-14 members aryl, 6-14 member aryl CM protective embankments base, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

R^a、 R^a' independently represent hydrogen,₆Protective embankment base, alkenyl, C₂.₆Alkynyl, 3-14 yuan of rings protective embankment bases, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

Z is -0-,-C (R⁴'R⁴)-or-N (R⁴)-;

W is -0-,-C (R⁵'R⁵)-or-N (R⁵)-;

R⁴, R⁴', R⁵, R⁵' it is separately hydrogen, that is unsubstituted or being replaced by least one hydroxyl or at least one halogen₆Alkyl or 3-14 yuan of rings protective embankment bases；

R²To be unsubstituted or by least one R^bSubstituted 6-10 membered bicyclics Heterocyclylalkyl, by（Phenyl or 5-6 unit monocycle heteroaryls）With（5-6 unit monocycle heteroaryls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases；

R^bFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino, C_1-6Alkyl amine group, two (C_1-6Alkyl) amido, carboxyl, Amino-sulfonyl, carbamoyl, C^ protective embankment bases, protective embankment epoxide, halo protective embankment base, halo .6 protective embankment epoxides, hydroxyl C^ protective embankment bases, amino C_1-6Alkoxy, carboxyl protective embankment base, carbamoyl .6 alkyl, d-₆Protective embankment base carbonyloxy group, C_1-6Alkoxy carbonyl, C_1-6Protective embankment base carbonyl, C_2-6Alkenyl, C₂Alkynyl, 3-14 yuan of rings protective embankment bases, 3-14 yuan of rings protective embankment base epoxides, 6-14 member aryl, 6-14 member aryloxies, 3-14 circle heterocycles bases, 3-14 circle heterocycles base epoxides, 7-12 member loop coil bases or 7-12 member bridged ring bases.

Technical scheme la:

A kind of formula（I salt, its stereoisomer or its deuterated thing shown in)：

( I )

Wherein:

X¹, X², X³, X⁴, Y is separately N or CR³, R³For hydrogen, halogen, trifluoromethyl, C^ protective embankments base, d.₆Alkoxy ,-N (R^a)(R^a'), cyano group, C₂.₆Alkenyl, C₂.₆Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases；

L is covalent bond or-N (R^a)-_;

When L is covalent bond, R¹For benzo ring mono alkenyl, benzo C₄_₈Cycloalkadienyl, C₃_₈Ring monoene and phenyl and.₄.₈Cyclic diolefine and phenyl, by（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃.₈Ring mono alkenyl, C₄.₈Cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

L is-N (R^a)-when,！^ is.^ protective embankments base .6 protective embankment bases formoxyl .6 protective embankment bases sulfonyl, 3-14 yuan of rings protective embankments base, 6-14 members aryl, 6-14 member aryl C^ protective embankments base, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

R^a、 R^a' independently represent hydrogen, d.₆Protective embankment base, C₂_ e alkenyls, C₂_₆Alkynyl, 3-14 member cycloalkyl, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

Z is -0-,-C (R⁴'R⁴)-or-N (R⁴)-;

W is -0-,-C (R⁵'R⁵)-or-N (R⁵)-;

R⁴, R⁴', R⁵, R⁵' it is separately hydrogen, Cw protective embankments base or 3-14 yuan of rings protective embankment bases unsubstituted or replaced by least one hydroxyl or at least one halogen；

R²To be unsubstituted or by least one R^bSubstituted 6-10 membered bicyclics Heterocyclylalkyl, by（Phenyl or 5-6 members are single Ring heteroaryl）With（5-6 unit monocycle heteroaryls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases；

R^bFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino,₆Alkyl amine group, two (Cw protective embankments base) amidos, carboxyl, amino-sulfonyl, carbamoyl, Cw protective embankment bases, C^ protective embankment epoxides, halo Cw protective embankment bases, halo C₆Alkoxy, hydroxyl.^ alkyl, aminoalkoxy, carboxyl d.₆Protective embankment base, carbamoyl C₆Alkyl, Q_₆Protective embankment base carbonyloxy group, Ci_₆Alkoxy carbonyl, alkyl-carbonyl, C₂_₆Alkenyl, C alkynyls, 3-14 member cycloalkyl, 3-14 member cycloalkyl oxies, 6-14 member aryl, 6-14 member aryloxies, 3-14 circle heterocycles bases, 3-14 circle heterocycles base epoxides, 7-12 member loop coil bases or 7-12 member bridged ring bases.

Technical scheme 2:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to technical scheme la or technical scheme 1：

Wherein-

X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, C^ protective embankments base, Cw alkoxies ,-N (R^a)(R^a'), cyano group, C₂.₆Alkenyl, C₂_₆Alkynyl, 3-8 unit monocycle ring protective embankments base, phenyl or 3-8 unit monocycles Heterocyclylalkyl, 3-8 circle heterocycles alkenyl, 5-6 unit monocycle heteroaryls；

Y is N;

When L is covalent bond, R¹For benzo₈Ring mono alkenyl, benzo C^₈Cycloalkadienyl, C₃_₈Ring monoene and phenyl and C₄.₈Cyclic diolefine and phenyl, by（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃.₈Ring mono alkenyl, C₄.₈Cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

L is-N (R^a)-when,！^ is.^ protective embankments base, _₆Alkyl formyl radical, Cw alkyl sulphonyls, 3-14 yuan of rings protective embankments base, 6-14 members aryl, 6-14 member aryl CM protective embankments base, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

R^a、 R^a' independently represent hydrogen, C^ protective embankment bases, C₂_ 6 alkenyls, C^₆Alkynyl, 3-14 yuan of rings protective embankment bases, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

Z is-C (R⁴'R⁴)-;

W is-N (R⁵)-;

R⁴, R⁴', R⁵It is separately hydrogen, C that is unsubstituted or being replaced by least one hydroxyl or at least one halogen!_₆Alkyl or 3-14 member cycloalkyl；

R²To be unsubstituted or by least one R^bSubstituted 6-10 membered bicyclic heterocycle protective embankments base, by（Phenyl or 5-6 members are single Ring heteroaryl）With（5-6 unit monocycle heteroaryls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases；

R^bFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino, Q.6 alkyl amine group, two (Cw protective embankments base) amidos, carboxyl, amino-sulfonyl, carbamoyl, C_1-6Protective embankment base, C_1-6Wash epoxide, halo d.₆Protective embankment base, halo CM protective embankment epoxides, hydroxyl₆Protective embankment base, amino C^ protective embankment epoxides, carboxyl .6 protective embankment bases, carbamoyl protective embankment base, d_₆Protective embankment base carbonyloxy group, -6 protective embankment Epoxide carbonyls, C₆Alkyl-carbonyl, C₂.₆Alkenyl, C₂.₆Alkynyl, 3-8 yuan of rings protective embankment bases, 3-8 yuan of rings protective embankment base epoxides, phenyl, phenyl epoxide, 3-8 unit monocycle heterocycle protective embankments base, 3-8 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 3-8 unit monocycle Heterocyclylalkyls epoxide, 3-8 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

Technical scheme 3:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-2,

There is following structure：

Wherein X¹ , X², X³, X⁴, Y, L, R¹, R², R⁴And R⁵With such as technical scheme 1, the implication described in la or 2.

Technical scheme 4:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-3,

In：

X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, C_1-6Alkyl, _ 6 alkoxy or amino；

Y is N;

L is covalent bond, R¹Serve as reasons（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃_₈Ring mono alkenyl or C₄.₈Cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl or 7-12 member spiro heterocyclic radicals, and R¹Optionally by 1-3 R^bSubstitution,

Z is-CH (R⁴)-; W is-N (R⁵)-;

R⁴, R⁵It is separately hydrogen, C bases that are unsubstituted or being replaced by least one hydroxyl or at least one halogen or 3-5 member cycloalkyl；

R^bFor hydrogen, oxo, halogen, cyano group, Cw alkyl, d_₃Alkoxy, trifluoromethyl, amino or 3-8 unit monocycle heterocycle protective embankments base, 3-8 circle heterocycles alkenyl, 5-6 unit monocycle heteroaryls.

Technical scheme 5_:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-4：

Wherein-

X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, fluorine, chlorine, trifluoromethyl or methyl；

Y is N;

L is covalent bond, R¹Serve as reasons（Phenyl or 5-6 unit monocycle heteroaryls）With（C^ rings mono alkenyl or C₅.₆Cycloalkadienyl or 5-6 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl or 7-12 member spiro heterocyclic radicals, and R¹Optionally by 1-3 R^bSubstitution,

Z is-CH (R⁴)-, R⁴For hydrogen, d. that is unsubstituted or at least being replaced by a hydroxyl or fluorine₃Protective embankment base or cyclopropyl;W is-N R⁵)-, R⁵It is separately hydrogen or methyl；

R^bFor halogen.

Technical scheme 6:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-5：

Wherein-

X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, d.₆Alkyl, protective embankment epoxide ,-N (R^a)(R^a') or cyano group；

Y is N; L is-N (R^a)-, R¹For C_1-6Protective embankment base, C^ protective embankment bases formoxyl, C₆Protective embankment base sulfonyl, 3-6 members cycloalkyl, 6-14 members aryl, 6-14 member aryl C_1-3Protective embankment base, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

R^a、 R^a' independently represent hydrogen, C^ protective embankment bases, alkenyl, alkynyl, 3-14 yuan of rings protective embankment bases, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

Z is-CH (R⁴)-;

W is-N (R⁵)-;

R⁴, R⁵It is separately hydrogen, that is unsubstituted or being replaced by least one hydroxyl or at least one halogen₃Protective embankment base or 3-5 yuan of rings protective embankment bases；

R^bFor hydrogen, oxo, element, cyano group, hydroxyl, amino, d.₆Alkyl amine group, two (d_₆Protective embankment base) amido, carboxyl, amino-sulfonyl, carbamoyl, Cw protective embankment epoxides, C^ alkyl, halo₆Protective embankment base, 3-6 yuan of rings protective embankment bases, 3-6 member cycloalkyl oxies, 3-8 unit monocycle heterocycle protective embankments base, 3-8 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 3-8 unit monocycle Heterocyclylalkyls epoxide, 3-8 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

Technical scheme 7:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-6-wherein：

X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, C^ protective embankments base or C_1-6Baked epoxide；

Y is N;

L is-N (R^a)-, ^ is₃Protective embankment base, d.₃Protective embankment base formoxyl, d_₃Alkyl sulphonyl, 3-6 yuan of rings protective embankments base, 6-14 members aryl, 6-14 members aryl _₃Protective embankment base, 5-6 unit monocycle heterocycle protective embankments base, 5-6 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 6-10 membered bicyclic heterocycle protective embankments base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

R^aRepresent hydrogen, C_1-6Alkyl, 3-14 yuan of rings protective embankment bases or 6-14 member aryl；

Z is-CH (R⁴)-, R⁴For hydrogen, Cw alkyl that is unsubstituted or being replaced by least one hydroxyl or at least one halogen or cyclopropyl； W is-N (R⁵)-, R⁵It is separately hydrogen or methyl;

R²For ；

R^bFor hydrogen, oxo, element, cyano group, hydroxyl, amino, d.₆Protective embankment base amido, two (d.₆Protective embankment base) amido, d.₆Protective embankment epoxide, C_1-6Alkyl, halo C_1-6Alkyl, 3-6 member cycloalkyl, 3-6 yuan of rings protective embankment base epoxides, 5-6 unit monocycle heterocycle protective embankments base, 5-6 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 5-6 unit monocycle heterocycle protective embankment bases epoxide, 5-6 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

Technical scheme 8:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-7：

Wherein-

X¹, X², X^s, X⁴It is separately CR³, R³For hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl；Y is N;

L is-N (R^a)-,！^ is.^ protective embankments base, acetyl group, methyl sulphonyl, phenyl, pyridine radicals, pyrimidine radicals, furyl, thienyl, pyrrole radicals, thiazolyl, imidazole radicals, pyrazolyl, imidazoles protective embankment base, pyrazolidinyl, indyl, isoindolyl, indazolyl, benzimidazolyl, pyrido pyrazolyl, purine radicals, piperazinyl, quinolyl, THP trtrahydropyranyl, piperidyl, morpholinyl, pyrazinyl, pyridin-2-ones base, cyclohexyl, cyclopenta or benzyl, and R¹Optionally by 1-3 R^bSubstitution,

R^aRepresent hydrogen, C_wProtective embankment base, 3-8 members cycloalkyl or 6-14 member aryl；

Z is-CH (R⁴)-, R⁴For hydrogen, d_ that is unsubstituted or being replaced by least one hydroxyl or at least one fluorine₃Protective embankment base or cyclopropyl；

W is-N (R⁵)-, R⁵It is separately hydrogen or methyl；

R²For ；

R^bFor hydrogen, oxo, element, cyano group, hydroxyl, amino, _₆Protective embankment base amido, two (Cw protective embankments base) amidos, Q.₆Alkoxy, C^ alkyl, halo protective embankment base, 3-6 yuan of rings protective embankment bases, 3-6 member cycloalkyl oxies, 5-6 unit monocycle heterocycles are washed base, 5-6 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 5-6 unit monocycle Heterocyclylalkyls epoxide, 5-6 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides. Technical scheme 9:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-8：

Wherein：

X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl；Y is N;

L is-N (R^a)-, 1^ is._1-3Protective embankment base, acetyl group, methyl sulphonyl, phenyl, pyridine radicals, pyridin-2-ones base, cyclohexyl, cyclopenta or benzyl, and R¹Optionally by 1-3 R^bSubstitution,

R^aRepresent hydrogen, methyl, ethyl, cyclopropyl or phenyl；

Z is-CH (R⁴)-, R⁴For hydrogen, protective embankment base that is unsubstituted or being replaced by least one hydroxyl or at least one fluorine or cyclopropyl；

W is-N R⁵)-, R⁵It is only respectively

R²

R^bFor hydrogen, oxo, element, cyano group,₃Protective embankment base,₃Protective embankment epoxide or trifluoromethyl.

Technical scheme 10:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-9, the compound are selected from：

11

The ο ε Please Ο Ζ OA of ε 8

£1

The ο ε Please Ο Ζ OA of ε 8

PI

^C6000/ClOZIS[3/X3d ε8οεζο/ θζ OAV

Technical scheme 11:

Compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing according to any of technical scheme la or technical scheme 1-10, the compound be selected from-

91

The ε Please IOZ OAV of ^C6000/C10ZN3/X3d ￡ 80

LI

The ο ε Please ο ζ OA of ε 8

8ΐ

l7C6000/ClOZM3/I3d C80Ci0/M0Z O/W

61

The ο ε Please Ο Ζ OA of ε 8 Upper acceptable salt, its stereoisomer or its deuterated thing, and one or more pharmaceutical carriers.

Technical scheme 13:

The composition described in compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing or technical scheme 12 described in any of technical scheme la or technical scheme 1-11 prepare be used to treat and/or prevent inflammatory disease and/or the medicine of tumour in purposes.

Technical scheme 14:

It is a kind of treat and/or prevention inflammatory disease and/or tumour method, methods described includes giving the composition described in the technical scheme 12 of compound described in any of technical scheme la or technical scheme 1-11 for needing its subject's effective dose, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing or therapeutically effective amount.

Technical scheme 15:

The composition described in compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing or technical scheme 12 described in any of technical scheme la or technical scheme 1-11, it is used to treat and/or prevents inflammatory disease and/or tumour.

Technical scheme 16:

In technical scheme 13,14 and 15, described inflammatory disease is selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, chronic obstructive pulmonary disease（COPD), lupus erythematosus, psoriasis, multiple sclerosis and end-stage renal disease, and the tumour is selected from leukaemia, lymthoma, myelosis disease, non Hodgkin lymphom and Chronic Spontaneous myelofibrosis.

4th, embodiment

Definition

In the present invention, term " halogen " refers to fluorine atom, chlorine atom, bromine atoms or iodine atom.

In the present invention, term " institute's base " refers to straight or branched, hydrocarbyl group without double or triple bonds.The example of alkyl includes₆Protective embankment base, d_₅Protective embankment base, alkyl and d_₃Protective embankment base, it each has 1-6 carbon atom, 1-5 carbon atom, 1-4 carbon atom and 1-3 carbon atom.The instantiation of protective embankment base includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- methyl-propyls, 1- methyl-propyls, 1, 1- dimethyl ethyls, n-pentyl, 3- methyl butyls, 2- methyl butyls, 1- methyl butyls, 1- ethyl propyls, n-hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3, 3- dimethylbutyls, 2, 2- dimethylbutyls, 1, 1- dimethylbutyls, 1, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2, 3- dimethylbutyls, 2- ethyl-butyls, with 1, 2- dimethyl propyls.

In the present invention, term " ring protective embankment base " refers to the hydrocarbyl group of the ring-type without double or triple bonds.From the point of view of the atomicity of the ring carbons of ring protective embankment base, cycloalkyl include 3-14 yuan of rings protective embankments base, 3-12 yuan of rings protective embankments base, 3-10 yuan of rings protective embankments base, 3-8 yuan of rings protective embankments base, 3-6 yuan of rings protective embankments base, 5-10 yuan of rings protective embankments base, 5-8 yuan of rings protective embankment bases and 4-6 yuan of rings protective embankment bases, it each has 3-14 ring carbons, 3-12 ring carbons, 3-10 ring carbons, 3-8 ring carbons, 3-6 ring carbons, 5-10 ring carbons, 5-8 ring carbons and 4-6 ring carbons.From the point of view of the number of rings of cycloalkyl, ring protective embankment base includes monocyclic ring protective embankment base and condensed ring cycloalkyl.Monocyclic cycloalkyl only has a ring.Condensed ring ring protective embankment base refers to share the group that two adjacent carbon atoms are formed each other by two or more monocyclic ring protective embankment bases.Monocyclic ring protective embankment base includes 3-8 unit monocycle ring protective embankments base, 3-6 unit monocycle ring protective embankments base, 5-8 unit monocycles cycloalkyl and 5-6 unit monocycle ring protective embankment bases.The instantiation of monocyclic ring protective embankment base includes the third protective embankment of ring base, cyclobutane base, the protective embankment base of ring penta, hexamethylene protective embankment base, cycloheptyl protective embankment base and cyclooctane base.Monocyclic ring protective embankment base can also be further substituted, such as by₆Alkyl-substituted 3-8 unit monocycles ring protective embankment base includes but is not limited to：The third protective embankment of methyl ring base, the third protective embankment of diformazan basic ring base, methyl ring fourth protective embankment base, diformazan basic ring fourth protective embankment base, methyl cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl and dimethyleyelohexane protective embankment base.Condensed ring ring protective embankment base includes 6-14 member condensed ring ring protective embankments base, 6-12 member condensed ring ring protective embankments base, 8-12 member condensed ring ring protective embankments base, 7-10 member condensed ring ring protective embankment bases, such as 6-14 members bicyclic cycloalkyl, 6-12 member bicyclic ring protective embankments base, 8-12 member bicyclic ring protective embankments base, 7-10 member bicyclic cycloalkyls.The example of condensed ring ring protective embankment base includes but is not limited to：The own protective embankment base of two rings [3.1.0], two rings [4 Shang 0] protective embankment base in heptan, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, the pungent protective embankment base of two rings [4.2.0], octahydro -1H- indenyls, decahydronaphthalene naphthyl and ten tetrahydrochysene phenanthryl.

In the present invention, term " alkenyl " refers to the hydrocarbyl group of the straight or branched containing at least one double bond.Alkenyl includes₆Alkenyl, C₂.₅Alkenyl, C_MAlkenyl and C₂.₃Alkenyl, it each has 2-6 carbon atom, 2-5 carbon atom, 2-4 carbon atom and 2-3 carbon atom.The example of alkenyl includes but is not limited to vinyl, 1- acrylic, 2- acrylic, 1- methyl ethylenes, 1- cyclobutenyls, 2- cyclobutenyls, 3- cyclobutenyls, 1- methyl-1-propylene bases, 2- methyl-1-propylene bases, 1- methyl -2- acrylic, 2- methyl -2- acrylic, 1- pentenyls, 2- pentenyls, 3- pentenyls, 4- pentenyls, 1- methyl isophthalic acids-cyclobutenyl, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 1- methyl-2-butene bases, 2- methyl-2-butene bases,₃- methyl _₂_ cyclobutenyl, 1- methyl -3- cyclobutenyls, 2- methyl -3- cyclobutenyls, 3- methyl -3- cyclobutenyls, 1, 1- dimethyl -2- acrylic, 1, 2- dimethyl -1- acrylic, 1, 2- dimethyl -2- acrylic, 1- ethyl -1- acrylic, 1- ethyl -2- acrylic, 1- hexenyls, 2- hexenyls, 3- hexenyls, 4- hexenyls, 5- hexenyls, 1- methyl-1-pentene alkenyls, 2- methyl-1-pentene alkenyls, 3- methyl-1-pentene alkenyls, 4-methyl-1-pentene base, 1- methyl -2- pentenyls, 2- methyl -2- pentenyls, 3- methyl -2- pentenyls, 4- methyl -2- pentenyls, 1- methyl-3-pentenyls, 2- methyl-3-pentenyls, 3- methyl-3-pentenyls, 4- methyl-3-pentenyls, 1- methyl -4- pentenyls, 2- methyl -4- pentenyls, 3- methyl -4- pentenyls, 4- methyl -4- pentenyls,

1.1- dimethyl -2- cyclobutenyls, 1,1- dimethyl -3- cyclobutenyls, 1,2- dimethyl -1- cyclobutenyls, 1,2- dimethyl -2- cyclobutenyls,

1.2- dimethyl -3- cyclobutenyls, 1, the small cyclobutenyl of 3- dimethyl, 1, 3- dimethyl -2- cyclobutenyls, 1, 3- dimethyl -3- cyclobutenyls, 2, 2- dimethyl -3- cyclobutenyls, 2, the small cyclobutenyl of 3- dimethyl, 2, 3- dimethyl -2- cyclobutenyls, 2, 3- dimethyl -3- cyclobutenyls, 3, the small cyclobutenyl of 3- dimethyl, 3, 3- dimethyl -2- cyclobutenyls, 1- ethyl -1- cyclobutenyls, 1- ethyl -2- cyclobutenyls, 1- ethyl -3- cyclobutenyls, 2- ethyl -1- cyclobutenyls, 2- ethyl -2- cyclobutenyls, 2- ethyl -3- cyclobutenyls, 1, 1, 2- trimethyl -2- propylene Small methyl-2- the acrylic of base, 1-ethyl, the small acrylic of 1-Ethyl-2-Methyl, 1-Ethyl-2-Methyl-2- acrylic, 1,3- butadiene, 1,3- pentadienes, 1,4- pentadienes and 1,4- hexadiene.

In the present invention, term " cycloalkenyl group " refers to the alkyl of the ring-type containing at least one double bond.Cycloalkenyl group includes C₃.₈Ring mono alkenyl, C₃_₇Ring mono alkenyl and C₃.₆Ring mono alkenyl, it each has 3-8 carbon atom, 3-7 carbon atom and 3-6 carbon atom.Cycloalkenyl group also includes C₄.₈Cycloalkadienyl, C₄-₇Cycloalkadienyl and C₄.₆Cycloalkadienyl, it each has 4-8 carbon atom, 4-7 carbon atom and 4-6 carbon atom.Cycloalkenyl group also includes ring trialkenyl and ring apos etc..The instantiation of cycloalkenyl group includes but is not limited to cyclopropanyl, cyclobutane base, cyclopentenyl, 1,3- cyclopentadienyl groups, cyclohexenyl group, 1,4- cyclohexadienyls and cyclooctatetraenyl.

In the present invention, term " alkynyl " refers to the alkyl of the straight or branched containing at least one three key.Alkynyl includes C₂.₆Alkynyl, C₂_₅Alkynyl, C₂Alkynyl and C₂.3 alkynyl, it each has 2-6 carbon atom, 2-5 carbon atom, 2-4 carbon atom and 2-3 carbon atom.The instantiation of alkynyl includes but is not limited to acetenyl, 2-propynyl, 2- butynyls, 3- butynyls, 1-methyl-2-propynyl, valerylene base, 3- pentynyls, 4- pentynyls, 1- methyl -2- butynyls, 1- methyl -3- butynyls, 2- methyl -3- butynyls, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2- hexin bases, 3- hexin bases, 4- hexin bases, 5- hexin bases, 1-methyl-valerylene base, 1- methyl -3- pentynyls, 1-methyl-4- pentynyls, 2- methyl -3- pentynyls, 2- methyl -4- pentynyls, 3- methyl -4- pentynyls, 4- methyl-valerylene base, 1, 1-dimethyl-2- butynyls, 1, 1-dimethyl-3- butynyls, 1, 2- dimethyl -3- butynyls, 2, 2- dimethyl -3- butynyls, 1- ethyl -2- butynyls, 1-ethyl-3- butynyls, 2- ethyl -3- butynyls, with 1-ethyl-1-methyl-2-propynyl.

In the present invention, term " alkoxy " refers to " alkyl oxy " or " institute base -0- ", and wherein alkyl is as defined hereinabove.Burning epoxide includes .6 protective embankments epoxide, C_MProtective embankment epoxide, CM alkoxies and.^ protective embankment epoxides, it each has 1-6 carbon atom, 1-5 carbon atom, 1-4 carbon atom and 1-3 carbon atom.The instantiation of protective embankment epoxide includes but is not limited to methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen and hexyloxy.

In the present invention, term " aryl " refers to aromatic hydrocarbyl group.From the point of view of the atomicity of the ring carbons of aryl, aryl includes 6-14 members aryl, 8-14 members aryl, 6-10 members aryl and 6-8 member aryl, and it each has 6-14 ring carbons, 8-14 ring carbons, 6-10 ring carbons, 6-8 ring carbons.From the point of view of the number of rings of aryl, aryl includes monocyclic aryl and fused ring aryl.Monocyclic aryl only has a ring.The example of monocyclic aryl is phenyl.Fused ring aryl refers to that wherein at least one single ring architecture is armaticity by two or more single ring architectures group that shared two adjacent carbon atoms are formed each other.Fused ring aryl includes " complete armaticity fused ring aryl " and " partial aromatic fused ring aryl ".Whole rings that complete armaticity fused ring aryl refers to form fused ring aryl are armaticity.The example of complete armaticity fused ring aryl includes but is not limited to naphthalene and phenanthrene.Partial aromatic fused ring aryl refers to that the ring for the part to form fused ring aryl is not armaticity, that is to say, that partial aromatic fused ring aryl be by aromatic carbon ring and non-aromatic carbocyclic such as formed by ring mono alkenyl or cycloalkadienyl condense.Partial aromatic fused ring aryl includes benzo C_3-8Ring mono alkenyl, benzene And C^ cycloalkadienyls, ring monoene and phenyl and C₄.₈Cyclic diolefine and phenyl.The instantiation of partial aromatic fused ring aryl includes but is not limited to 2,3- dihydro -1H- indenyls, 1H- indenyls, 1,2,3,4- tetralyls, Isosorbide-5-Nitrae-ihydro naphthyl etc..

In the present invention, " heterocyclic radical " refers to that containing at least one hetero atom for being selected from nitrogen, oxygen and sulphur is used as the cyclic group of ring member nitrogen atoms.Heterocyclic radical can have 3-14 ring member nitrogen atoms（Abbreviation 3-14 circle heterocycles bases, similarly hereinafter）, 3-10 ring member nitrogen atoms, 3-8 ring member nitrogen atoms, 4-12 ring member nitrogen atoms, 5-10 ring member nitrogen atoms, 5-8 ring member nitrogen atoms or 5-6 ring member nitrogen atoms.Heterocyclic radical includes monocyclic heterocycles protective embankment base, bicyclic heterocycle protective embankment base, heterocycloalkenyl, bicyclic heteroaryl and bicyclic heteroaryl.

Monocyclic heterocycloalkyl refers to such monocyclic cycloalkyl, and the hetero atom that wherein at least one carbon atom is selected from N, 0 and S is replaced.Monocyclic heterocycles protective embankment base can have 3-8 ring member nitrogen atoms（Abbreviation 3-8 unit monocycle Heterocyclylalkyls, similarly hereinafter）, 3-6 ring member nitrogen atoms, 5-6 ring member nitrogen atoms or 5-8 ring member nitrogen atoms, and monocyclic heterocycles protective embankment base has 1-2, the 1-3 or 1-4 hetero atoms selected from N, 0 and S as ring member nitrogen atoms.The example of 3-8 unit monocycle heterocycle protective embankment bases includes：The third protective embankment of azacyclo- base, azetidin protective embankment base, Thietane base, tetrahydrofuran base, nafoxidine base, imidazoles protective embankment base, pyrazoles protective embankment base, 1,4- dioxa hexamethylene protective embankments base, 1,3- dioxa hexamethylene protective embankments base, 1,3- dithia hexamethylene protective embankments base, piperidyl, morpholinyl, piperazinyl etc..Further, as the CH of annular atom₂It can be oxidized, in addition, monocyclic heterocycles protective embankment base can be by oxo, such as piperidines -2- ketone.

Bicyclic heterocycloalkyl refers to such condensed ring ring protective embankment base with two rings, and the hetero atom that wherein at least one carbon atom is selected from N, 0 and S is replaced.Bicyclic heterocycle protective embankment base includes 6-10 membered bicyclic heterocycle protective embankment bases, and it includes 6-10 ring member nitrogen atoms, and 1-2, the 1-3 or 1-4 hetero atoms for selecting g N, 0 and S as ring member nitrogen atoms.The example of 6-10 membered bicyclic heterocycle protective embankment bases includes：Cyclobutane and nafoxidine base（Such as 3- azabicyclos [3.2.0] protective embankment in heptan), the protective embankment of ring penta and nafoxidine base (such as octahydro cyclopentadiene [c] and pyrroles）And azetidin protective embankment and imidazolidinyl（Such as the azabicyclos of 2,4,6- tri- [3.2.0] heptane).

Heterocycloalkenyl refers to such cycloalkenyl group, and the hetero atom that wherein at least one carbon atom is selected from N, 0 and S is replaced.Heterocycloalkenyl can have 3-8 ring member nitrogen atoms（Abbreviation 3-8 circle heterocycles alkenyls, similarly hereinafter）, 5-8 ring member nitrogen atoms or 5-6 ring member nitrogen atoms, and with 1-2,1-3 or 1-4 as being selected from of ring member nitrogen atoms, 0 and S hetero atom.The example of 3-8 circle heterocycles alkenyls includes：2,5- dihydro-thiophenes base, 4,5- pyrazolines base, 1,2- dihydropyridine bases, 3,4- dihydro -2H- pyranoses, 5,6- dihydros -4H--oxazinyl, oxepin base, thia cycloheptatriene base, azepine cycloheptatriene base, 1,3- diazas cycloheptatriene base, azepine cyclooctatetraenyl etc..In addition, heterocycloalkenyl can be by oxo, such as pyridin-2-ones and pyrans -4- ketone.

Bicyclic heteroaryl refers to 5-6 unit monocycle heteroaryls, and it has armaticity and including 5-6 ring member nitrogen atoms and the 1-4 hetero atoms for selecting β Ν, 0 and S as ring member nitrogen atoms.The example of bicyclic heteroaryl includes：Furyl, thienyl, pyrrole radicals, thiazolyl, thiadiazolyl group, oxazolyl, oxadiazolyls, imidazole radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, 1,4- Dioxins base, 2H-1,2- oxazinyls, 4H-1,2- oxazinyls, 6H-1,2- oxazinyls, 4H-1,3- oxazinyls, 6H-1,3- oxazinyl, 4H-1,4- oxazinyls, pyridazinyl, pyrazinyl, 1,2,3- triazine radicals, 1,2,4- triazine radicals, 1,3,5- triazine radicals and 1,2,4,5- tetrazine bases.

In the present invention, bicyclic heteroaryl include by（Phenyl or 5-6 unit monocycle heteroaryls）With（5-6 unit monocycles heteroaryl) condense obtained bicyclic heteroaryl, Yi Jiyou（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃.₈Ring mono alkenyl, C₄.₈Cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl, for example by（Phenyl or 5-6 unit monocycle heteroaryls）With（C^ rings mono alkenyl, C₅_ 6 cycloalkadienyls or 5-6 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl.

By（Phenyl or 5-6 unit monocycle heteroaryls）With（5-6 unit monocycle heteroaryls）Condensing the example of obtained bicyclic heteroaryl includes：Benzofuranyl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl, indazolyl, BTA base, quinolyl, isoquinolyl, pyrido pyrazolyl, pyrido pyrrole radicals, pyrimido pyrazolyl, pyrimido pyrrole radicals, pyridazine and pyrazolyl, pyridazine and pyrrole radicals, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, pteridine radicals, purine radicals and naphthyridines base.

By（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃_₈Ring mono alkenyl, C₄.₈Cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condensing the example of obtained bicyclic heteroaryl includes：1,3- dihydro benzo furyls, benzo [[1.3] dioxa cyclopentenyl, isoindoline base, indoline base, Chromanyl, 1,2,3,4- nafoxidines simultaneously [3,4- (] pyrrole radicals, pyrrolin and pyridine radicals, pyrrolin and pyrimidine radicals, pyrrolin and pyridazinyl, nafoxidine and pyridine radicals, nafoxidine and pyrimidine radicals, nafoxidine and pyridazinyl etc..

In the present invention, term " bridged ring base " refers to such cyclic group, and two of which ring shares two ring member nitrogen atoms not being joined directly together.Ring member nitrogen atoms can contain hetero atom with all carbon atoms or ring member nitrogen atoms, and described hetero atom is selected from nitrogen, oxygen and sulphur.Bridged ring base can include unsaturated bond.The example of bridged ring base includes " 7-12 member bridged rings base " or " 7-12 member bridges heterocyclic radical "（Abbreviation 7-12 members bridge (miscellaneous) ring group）, wherein 7-12 members bridge (miscellaneous) ring group contains 7-12 ring member nitrogen atoms, and the ring member nitrogen atoms can contain hetero atom with all carbon atoms or the ring member nitrogen atoms, and described hetero atom is selected from nitrogen, oxygen and sulphur." 7-12 members bridge (miscellaneous) ring group " includes " 7-12 member saturation bridge (miscellaneous) ring group " and " unsaturated bridge (miscellaneous) ring group of 7-12 members ".All rings that " 7-12 member saturation bridge (miscellaneous) ring group " refers in bridge (miscellaneous) ring group are the cyclic group of saturation, including such as " 7-10 member saturation bridge (miscellaneous) ring group " and " 7-8 member saturation bridge (miscellaneous) ring group ".Described " unsaturated bridge (miscellaneous) ring group of 7-12 members " refers to have at least one ring to be undersaturated cyclic group in bridge (miscellaneous) ring group, including such as " unsaturated bridge (miscellaneous) ring group of 7-10 members " and " unsaturated bridge (miscellaneous) ring group of 7-8 members ".

The instantiation for constituting bridge (miscellaneous) ring of 7-12 member saturation bridge heterocyclic radicals includes but is not limited to：

Unsaturated bridge (miscellaneous) the ring instantiation of 7-12 members is constituted to include but is not limited to:

In the present invention, term " loop coil base " refers to such cyclic group, and wherein at least two ring shares a ring member nitrogen atoms.Ring member nitrogen atoms can contain hetero atom with all carbon atoms or ring member nitrogen atoms, and described hetero atom is selected from nitrogen, oxygen and sulphur.Loop coil base can include unsaturated bond.The example of loop coil base includes " 7-12 member loop coils base " and " 7-12 members spiro heterocyclic radical "（Abbreviation 7-12 members spiral shell (miscellaneous) ring group）, it contains 7-12 ring member nitrogen atoms, and ring member nitrogen atoms can contain hetero atom with all carbon atoms or ring member nitrogen atoms, and described hetero atom is selected from nitrogen, oxygen and sulphur；" 7-11 members spiral shell (miscellaneous) ring group ", " 8-11 members spiral shell (miscellaneous) ring group " and " 9-10 members spiral shell (miscellaneous) ring group "." 7-12 members spiral shell (miscellaneous) ring group " includes " 7-12 member saturation spiral shell (miscellaneous) ring group " and " unsaturated spiral shell (miscellaneous) ring group of 7-12 members ".All rings that " 7-12 member saturation spiral shell (miscellaneous) ring group " refers in spiral shell (miscellaneous) ring group are the cyclic group of saturation, including such as " 7-11 member saturation spiral shell (miscellaneous) ring group ", " 8-11 member saturation spiral shell (miscellaneous) ring group ", " 9-10 member saturation spiral shell (miscellaneous) ring group ".Described " unsaturated spiral shell (miscellaneous) ring group of 7-12 members " refers to that at least one ring is undersaturated cyclic group in spiral shell (miscellaneous) ring group, including such as " unsaturated spiral shell (miscellaneous) ring group of 7-11 members ", " unsaturated spiral shell (miscellaneous) ring group of 8-11 members ", " unsaturated spiral shell (miscellaneous) ring group of 9-10 members ".

The instantiation for constituting spiral shell (miscellaneous) ring of 7-12 member saturation spiral shell (miscellaneous) ring group includes but is not limited to：

The instantiation for constituting spiral shell (miscellaneous) ring of unsaturated spiral shell (miscellaneous) ring group of 7-12 members includes but is not limited to: In the present invention, " pharmaceutically acceptable salt " includes alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkali salt, such as calcium salt, magnesium salts；Other metal salts, such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt；Inorganic base salts, such as ammonium salt；Organic alkali salt, such as t-octyl amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine protective embankment base ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N ,-dibenzyl ethylenediamine salt, chloroprocanine salt, procaine salt, diethanolamine salt, N- benzyls-phenethyl amine salt, piperazine salt, tetramethyl amine salt, three (methylol) amido first protective embankment salt；Halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate；Inorganic acid salt, such as nitrate, perchlorate, sulfate, phosphate；Rudimentary alkyl sulfonate, such as mesylate, fluoroform sulphonate, esilate；Arylsulphonate, such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt；Acylate, such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalates, maleate；Amino-acid salt, such as glycinate, trimethylglycine salt, arginine salt, ornithine salt, glutamate, aspartate.

In the present invention, compound also includes its " stereoisomer ".When there is one or more asymmetric carbon atoms in compound structure, enantiomter can be produced；When compound contains alkenyl or cyclic structure, cis/trans isomers can be produced；When compound there are ketone or oxime, dynamic isomer etc. can be produced.All these isomers and mixture all scope of the invention.

In the present invention, compound also includes its " deuterated thing ".When the hydrogen atom in compound is by its isotope deuterium（Symbol is D) some or all of replacement when, produced material falls within scope of the invention.

Currently preferred compound-

HZ

The ο ε Please ο ζ OA of ε 8

οε

The ο ε Please ο ζ OA of ε 8 31

Preferred compound of the invention:

Compile

Structural formula structural formula number number

1 2

™

The ο ε Please Ο Ζ OA of ε 8

Present invention also offers pharmaceutical composition.Described pharmaceutical composition includes formula（I) compound, its is deuterated Thing, its pharmaceutically acceptable salt or its stereoisomer, and one or more pharmaceutical carriers（Such as excipient, binder, humidizer, disintegrant, thickener).

Formula（I) pharmaceutical preparation can be made with one or more pharmaceutical carriers in compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer.The pharmaceutical preparation refers to the conventional formulation clinically used, and can be applied in modes such as oral and parenteral administrations needs the patient of this treatment.Such as tablet, particle, capsule, powder, injection, inhalant, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, eye drops, spray, preparation capable of permeating skin.These preparations can be added pharmaceutical carrier such as excipient, binder, humidizer, disintegrant, thickener etc. and be prepared from by conventional method.

Present invention also offers formula（I the purposes of compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing in the medicine for preparing treatment and/or prevention inflammatory disease or tumour shown in).Described inflammatory disease is selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, chronic obstructive pulmonary disease（COPD), lupus erythematosus, psoriasis, multiple sclerosis and end-stage renal disease etc..Described tumor disease is selected from leukaemia, lymthoma, myelosis disease, non Hodgkin lymphom and Chronic Spontaneous myelofibrosis etc..Present invention also offers the preparation method of above-claimed cpd：

With in subsequent embodiment in terms of following preparation, Shrink abbreviations Xia Ru have been used：

DIEA:DIPEA

HATU:2- (7- azos BTA)-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester

DMF:Ν, Ν-dimethylformamide

Et:Ethyl

EtOH:Ethanol

Bu:Butyl

BuOH:Butanol

Boc:Tertbutyloxycarbonyl

DCM:Dichloromethane

DMAP:DMAP

TLC:Thin-layer chromatography

TFA:Trifluoroacetic acid

THF:Tetrahydrofuran

Me:Methyl Py=pyridine

EA:Ethyl acetate

PE:Petroleum ether

Ac:Acetyl group

HOAc:Acetic acid

LS-MS:Liquid chromatography-mass spectrography

Ts:P-toluenesulfonyl

TsCl:Paratoluensulfonyl chloride

THP:Oxinane scheme 1

The formula of 3 intermediate of intermediate 4（ I )

Reactions steps

(1) (1 equivalent of raw material 1）It is dissolved in dichloromethane, is added dropwise under a small amount of DMF, ice bath and oxalyl chloride is added dropwise（For example, 1.1-1.5 equivalents）, reaction a few hours concentration is stirred at room temperature, adds the dioxane and the mixed solution of water that raw material 2 and sodium acid carbonate are slowly added dropwise under dioxane dissolving, ice bath, is raised to and is stirred at room temperature, after reaction terminates, extracts, concentration, column chromatography obtains intermediate 1.

(2) intermediate 1 is dissolved in appropriate solvent（Such as methanol or ethanol）, Pd/C is added thereto, leads to hydrogen, reacts at room temperature, reaction terminates, and filters out Pd/C, intermediate 2 is obtained after organic phase concentration.

(3) in the reaction bulb dried, by intermediate 2 (1 equivalent), raw material 3 (for example, 1.2-2 equivalents）, tertiary amine（Such as DIEA or triethylamine）（For example, 1.2-2 equivalents) and condensing agent（Such as HATU or EDCI）（For example, 1-1.2 equivalents) it is added to dichloromethane protective embankment（Or the mixed solvent of dichloromethane protective embankment and DMF or DMA), it is stirred at room temperature, reaction terminates After extract, be concentrated under reduced pressure, column chromatography obtains intermediate 3.

(4) intermediate 3 is dissolved in appropriate solvent（Such as ethanol）In, concentrated hydrochloric acid is added dropwise under ice bath or hydrogen chloride gas are passed through, reaction is heated for a period of hours, is concentrated after cooling, obtains intermediate 4.

(5) by (1 equivalent of intermediate 4）It is dissolved in appropriate solvent（Such as the tert-butyl alcohol）, raw material 4 is added (for example, 1-1.5 equivalents）, alkali（Such as triethylamine or diisopropyl (ethyl) amine）（For example, 2-5 equivalents）, heating（Generally solvent refluxing）Reaction to intermediate 4 disappears, and concentrates, and silica gel column chromatography or preparation liquid phase purify to obtain formula（I) compound.

X in upper reaction equation¹、 X²、 X³、 X⁴、 Z、 W、 L、 R¹, R²As defined hereinabove.In raw material 4, X represents halogen, such as chlorine, bromine, iodine.If necessary, blocking group can be sloughed thereafter through conventional method with conventional protective agent to needing functional group to be protected to protect；If necessary, some compounds can also be prepared, for example the preparation of raw material 1.Scheme 2

It can also be prepared with reference to following preparation method:

Reactions steps

(1) by raw material Γ (1 equivalents）, raw material 2'(is for example, 1-1.5 equivalents）, triphenyl phosphite（For example, 1-1.5 equivalents）Mixing, adds the pyridine of quantity of solvent, heating（45 °C to 85 Γ) under react a few hours, produce intermediate 1, directly carry out next step reaction.

(2) by raw material 3,（For example, 1-1.5 equivalents）It is added directly into the reaction system of previous step, heats（100 °C) reaction a few hours, after cooling, concentration, column chromatography obtains intermediate 2'.

(3) by intermediate 2, (1 equivalent）It is dissolved in appropriate solvent（Such as dichloromethane, ether or methanol）, room temperature or ice-water bath cooling add trifluoroacetic acid, or are passed through hydrogen chloride gas, and reaction to intermediate 2' disappears, concentration, obtains intermediate 3,.

(4) by intermediate 3'(1 equivalents）It is dissolved in appropriate solvent（Such as the tert-butyl alcohol）, raw material 4'(is added for example, 1-1.5 equivalents）, alkali（Such as triethylamine or diisopropyl (ethyl) amine）（For example, 2-5 equivalents）, heating（Generally solvent refluxing）Reaction disappears to intermediate 3', and concentration, silica gel column chromatography or preparation liquid phase purify to obtain formula（I) compound.

X in upper reaction equation¹、 X²、 X³、 X⁴、 Y、 Z、 W、 L、 R¹, R²As defined hereinabove.In raw material 4, X represents halogen, such as chlorine, bromine, iodine.If necessary, blocking group can be sloughed thereafter through conventional method with conventional protective agent to needing functional group to be protected to protect；If necessary, some compounds can also be prepared.Scheme 3

The intermediate of intermediate 3₄ ^ '

Reactions steps：

(1) in the reaction bulb dried, raw material 1 (is generally methyl esters or ethyl ester）（1 equivalent）, raw material 2 is (for example, 1.2-2 equivalents）, tertiary amine（Such as DIEA or triethylamine）（For example, 1.5-3 equivalents）With condensing agent（Such as HATU or EDCI) (for example, 1-1.2 equivalents) be added to dichloromethane protective embankment（Or the mixed solvent of dichloromethane and DMF or DMA）, it is stirred at room temperature, reaction is extracted after terminating, and is concentrated under reduced pressure, column chromatography obtains intermediate 1.

(2) ester group of intermediate 1 is hydrolyzed in the basic conditions, it is usually added into the aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide, or the mixed solvent of tetrahydrofuran, methanol and water, after reaction terminates, it is faintly acid with dilute acid for adjusting pH, product is separated out, aqueous phase is extracted once, merges to obtain intermediate 2.

(3) in the reaction bulb dried, by (1 equivalent of intermediate 2）, raw material 3 is (for example, 1-1.5 equivalents）, tertiary amine（Such as DIEA or triethylamine）（For example, 1.5-3 equivalents）With condensing agent（Such as HATU or EDCI) (for example, 1-1.2 equivalents）It is added to dichloromethane（Or the mixed solvent of dichloromethane protective embankment and DMF or DMA）, it is stirred at room temperature, reaction is extracted after terminating, and is concentrated under reduced pressure, column chromatography obtains intermediate 3. The step 4 and step 5 of step 4 and step 5 with preparation method 1.

X in upper reaction equation¹、 X²、 X³、 X⁴、 Y、 Z、 W、 L、 R R²As defined hereinabove.In raw material 4, X represents halogen, such as chlorine, bromine, iodine.If necessary, blocking group can be sloughed thereafter through conventional method with conventional protective agent to needing functional group to be protected to protect；If necessary, some compounds can also be prepared.Embodiment

The embodiment of form, is described in further detail to the above of the invention by the following examples.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following examples.All technologies realized based on the above of the present invention belong to the scope of the present invention.The beneficial effect of the compounds of this invention is expanded on further below by way of the biological activity test of the compounds of this invention for biological activity test, other compounds of the invention have identical beneficial effect with the compounds of this invention cited in experiment, but this should not be interpreted as to the compounds of this invention only with following beneficial effect.The external zymetology inhibitory activity of the compounds of this invention of experimental example 1

Test sample：The compounds of this invention, is prepared according to embodiment method is prepared；

Experimental method：

1. the mother liquor that compound is formulated as into ImM with DMSO is preserved, during experiment, mother liquor is diluted 100 times to 10 μ Μ with 100% DMSO.Ι Ο μ Μ are the maximum concentration of this experiment, then continuous 4 times of dilutions, totally 10 concentration, respectively 25 μ Μ, 0.625 μ Μ, 0.156 μ Μ, 0.039 μ Μ, 0.009 μ Μ, 0.00244 μ Μ, 0.61 η Μ, 0.15 η Μ, 0.04 η Μ;

2. the good compound solution of 4 dilutions is taken in 96 orifice plates；

3. take 1 μ Ι l x kinase buffer liquids to be added in 96 orifice plates.L x kinase buffer liquids： 50mM HEPES, pH 7.5; 3mM MgCl₂, ImM EGTA, lOOmM NaCl, 0.03% CHAPS, 2mM DTT;

4. by step 2 and the mixed hook of step 3 liang solution, it is incubated lOmin;

5. taking the above-mentioned mixed liquors of 2.5 μ in 384 orifice plates, multiple holes are standby；

6. taking 2.5 L kinase solutions in 384 orifice plates, shake, the ultimate density of the Κ δ enzymes of Ρ Ι 3 is 5.7nM;

7. take substrate solutions of 5 μ in 384 orifice plates（ΡΙΡ₂) and Α Τ Ρ reaction buffers in 384 orifice plates, concussion；

8. 2h is incubated at room temperature;

9. taking Ι Ο μ reaction solutions terminating reaction in 384 orifice plates, 15min, Caliper readings are shaken. 10. IC_5QCalculate

Calculate inhibiting rate（%)=(maximum conversion ratio-conversion ratio）I (maximum conversion ratios-minimum transition rate）χ ι ο ο, are carried out curve fitting using XL fit softwares, draw IC₅.Value.

Experimental result：

The external zymetology inhibitory activity of the compounds of this invention of table 1

Test sample Ρ Β Κ δ zymetology inhibitory activity IC₅。 (nM)

Compound 1 100

Compound 2 52

Compound 4 13

Compound 5 86.52

Compound 6 33.5

Compound 7 26.2

Compound 8 28.8

Compound 9 14.3

Compound 12 47.5

Compound 13 86

Compound 19 45

Compound 22 16.8

Compound 23 29

Compound 24 11.58

Compound 25 34.5

Compound 28 36.7

Compound 29 27.4

Compound 30 5.4

Compound 31 28

Compound 32 13.6

Compound 33 6.5

Compound 34 7.2

Compound 35 14.3

Compound 36 10

Compound 37 33

Compound 38 27

Compound 41 39 Test sample Ρ Β Κ δ zymetology inhibitory activity IC_5Q (nM)

Compound 42 11

Compound 43 4.5

Compound 44 85.92

Compound 53 27

Compound 57 9.3

Compound 59 3.3

Compound 60 3.7

Compound 61 4.5

Compound 62 43

Compound 63 8.3

Compound 64 11

Compound 65 44.6

The experiment conclusion of compound 71 3.6：As can be seen from Table 1, the compounds of this invention has good inhibitory activity to the Κ δ enzymes of Ρ Ι 3.

Inhibitory activity of the compounds of this invention of experimental example 2 to external Β cells

Test sample：The compounds of this invention, self-control, its chemical name and structural formula are shown in the preparation embodiment of each compound；Experimental method：

1. separate Balb/c mouse Β cells

(1) Balb/c mouse spleens are taken, is smashed to pieces in MACS (Miltenyl Biotec) buffer solution, single cell suspension is obtained with 40 μ π ι Nylon cell screen filtration.

(2) obtained cell suspension 4 °C, is centrifuged five minutes in 400 g, removes supernatant, 1 ml erythrocyte cracked liquid is added at room temperature and cell mass has lightly been resuspended.After two minutes, the MACS buffer solutions of precooling are added.With 40 μ ι η cell screen clothes filtration cell suspension into a new centrifuge tube, 4.C, 400 g centrifuge 5 minutes to collect cell.

(3) before magnetic bead is added, cell density is adjusted to 10 with MACS buffer solutions⁷The μ 1 of individual cell/40.Every 10⁷10 μ biotinylated mixtures of antibodies is added in individual cell.20 minutes, every 10 are being incubated on ice after mixing⁷The magnetic bead of 30 μ MACS buffer solutions and 20 μ biotinylated mixtures of antibodies is added in individual cell and is incubated 20 minutes on ice.Cell is resuspended with 500 μ MACS buffer solutions after centrifugation.The MACS sorting posts of precooling are placed in MACS sorters, cell suspension is added in MACS sorting posts.Collect the cell of the uncombined antibody flowed down.

(4) cell of the flow cytometry before PE anti-biotin antibody and CD45R (B220) antibody test grouping system and after sorting is passed through. 2. cytotoxicity experiment and IC_5QDetermine

(1) mouse B cell of fresh separated is counted with blood counting chamber（Step 1-4), Tong Guo Yi expect that blue decoration method detection Cell viability should be more than 98%.

(2) cell density is adjusted to every milliliter of 3.89X10 with culture medium⁵Individual cell, 90 μ cell suspensions are taken with multichannel pipettor into 96 orifice plates, obtain final cell density for 3.5X10⁴Individual cell per well.

(3) with DMSO dissolved dilutions test compound and positive compound formation storing liquid, in a series of compound solutions that 10 μ of addition are prepared to 96 orifice plates（Each concentration of each compound does 3 points of repetitions）.In 37 V, 5% C0₂It is incubated 30 minutes in incubator, then adds 50 μ Β cytositimulation mixed liquors：The ng/ml recombined small-mouses IL-4 (final concentration) of 3 μ § η LPS+5.

(4) by cell plates in 37 V, 5% C0₂Continue to be detected with CTG method after being incubated 72 hours in incubator.

(5) melt CTG reagents and balance to room temperature, it is transferred to multichannel pipettor in 96 orifice plates, 5 (^1 CTG reagents/hole, on the quick oscillator of microwell plate shake 2 minutes after place in the dark 10 minutes, with Envision detect luminescence readings

3. data analysis

Obtained data can be analyzed with Excel 2007 and the softwares of GraphPad Prism 5.0, in order to calculate IC_5Q, will be returned using non-linear S curve and draw a dose-effect curve come fitting data, the softwares of GraphPad Prism 5.0 can provide IC automatically₅O values.Cell survival rate is calculated with below equation：V sample V2 solvent controls X 100%, V samples are the readings that compound handles hole, and V2 solvent controls are the average value of solvent control hole (V2) readings.

Inhibitory activity of the compounds of this invention to external B cell

The inhibitory activity IC of the external B cell of test sample₅.（ μ Μ)

Compound 8 0.75

Compound 9 0.65

Compound 30 0.016

Compound 33 0.034

Compound 34 0.12

Compound 53 0.111

Compound 57 0.01

Compound 60 0.032

Compound 61 0.05

Compound 63 0.04

The experiment conclusion of compound 72 0.32：As can be seen from Table 2, the compounds of this invention has good inhibitory activity to Β cells.

The internal pharmacological activity of the compounds of this invention of experimental example 3

Test sample：The compounds of this invention, self-control, its chemical name and structural formula are shown in the preparation embodiment of each compound；Investigate this Drug effect of the invention compound in lipopolysaccharide-induced tumor necrosis factor α release test.

Experimental method：

BALB/C mice, male, 22-25 g.Model group, 30 groups of compound, 33 groups of compound, 53 groups of compound, CAL-101 groups are randomly divided into by body weight, every group 5, dosage is 30 mg/kg.Model group gavage solvent, administration group gavage give relative medicine, 30 min pneumoretroperitoneums injection lipopolysaccharides（LPS after) 15 mg/kg, LPS induction l h, mouse intraocular corner of the eyes venous sinus takes the μ 1 of blood 500, it is put into 1.5 ml of anticoagulant heparin agent-secondary property centrifuge tube and mixes, with the rpm of eppendorf 5424R centrifuges 3500,4 °C of 10 min of centrifugation, blood plasma is stored in -80.The content of TNF-α in C, Mouse TNF-alpha Elisa Ready-set-go kits detection blood plasma.

TNF-α inhibiting rate=(model class mean-administration class mean in blood plasma）/ model class mean X 100%

Experimental result and conclusion：

Inhibitory action of the compounds of this invention of table 3 to TNFa

Test sample TNFa inhibiting rates（%)

Compound 30 52.4

Compound 33 52.0

Compound 53 51.7

CAL-101 41.2 is compared from table 3 with model group, and test sample CAL-101, compound 30, compound 33, compound 53 can significantly reduce TNFa contents in mice plasma, and its inhibiting rate is respectively 41.2% (p<0.01 ) , 52.0% (p<0.001), 52.4% (p<0.001), 51.7% (p<0.001), compared with CAL-101 groups, the compounds of this invention has more significant inhibitory action to the TNFa in mice plasma.Prepare embodiment

It is commercially available to prepare raw materials used in embodiment, for example, light science and trade (chemical reagent) Co., Ltd is opened purchased from Jinan, Shanghai Da Rui fine chemicals Co., Ltd, upper seascape face Chemical Industry Science Co., Ltd, Beijing lark prestige Science and Technology Ltd., Shanghai De Mo Chemical Co., Ltd.s, AlfaAesar (Tianjin) Chemical Co., Ltd., Nanjing remedies medicament research and development Co., Ltd etc..The f5 of embodiment 1) and -2- " l-f9H- purine -6- bases amino) propyl group " -3- phenylaminos) quinazoline -4f3H>The preparation of -one (compound 1)

(1) preparation of (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] ethyl benzoate

In dry single port bottle, add (5) -2- (t-butoxycarbonyl amino) butyric acid (18.33 g, 90.2 mmol), DIEA (31.3 mL, 180 mmol), HATU (23 g, 60.5 mmol), 150 mL dichloromethanes protective embankments and 2 mL DMF dissolvings, 30 π ι are stirred at room temperature, add 2- benzocaines (10 g, 60.5 mmol), 16 h are stirred at room temperature, rotary evaporation is washed except dichloromethane, adds water, ethyl acetate extraction, sample, silica gel column chromatography are mixed in concentration（Petroleum ether:Ethyl acetate=4:1) g of white solid 12.5, the % of yield 59.0 are obtained.

(2) preparation of (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] benzoic acid

In dry reaction bulb, add (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] ethyl benzoate (2.94 g, 8.4 mmol), 10 mL methanol, 10 mL tetrahydrofurans and 20 mL water, add hydronium(ion) lithia (0.806 g, 19.2 mmol), it is stirred overnight at room temperature, TLC monitoring reactions are finished, rotary evaporation removes methanol and tetrahydrofuran, pH to 3-4 is adjusted with 2 N aqueous hydrochloric acid solutions, there is white solid precipitation, it is extracted with ethyl acetate, it is spin-dried for obtaining the g of white solid 2.52, yield is 92.9 %.

(3) preparation of (5) -1- oxos -1- [2- (2- phenylhydrazinos formoxyl) phenylamino] butyl- 2- carbamates

In dry reaction bulb, add (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] benzoic acid (2 g, 6.2 mmol), DIEA (3.24 mL, 18.6 mmol), HATU (2.61 g, 6.86 mmol), 40 mL dichloromethanes protective embankments and 2 mL DMF make solvent, and 30 min are stirred at room temperature, and power B enters phenylhydrazine (0.675 g, 6.24 mmol), 48 h are stirred at room temperature, stop reaction, rotary evaporation removes dichloromethane, add water, ethyl acetate is extracted, and sample, silica gel column chromatography are mixed in concentration（Petroleum ether:Ethyl acetate=5:1) g of white solid 1.18, the % of yield 46.1 are obtained.

(4) preparation of (5) -2- (1- aminopropyls) -3- (phenylamino) quinazoline -4 (3H) -one hydrochloride

In thousand dry reaction bulbs; weigh (5) -1- oxos -1- [2- (2- phenylhydrazinos formoxyl) phenylamino] butyl- 2- carbamates (1.0 g; 2.42 mmol); the dissolving of 40 mL ethanol is added, 4 mL concentrated hydrochloric acids is added dropwise under ice-water bath stirring, stirs 30 min; it is warming up to 85 °C of 16 h of stirring; LC-MS display reactions are completed, and are concentrated after cooling, are obtained white solid straight Connect for next step.

(5) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (phenylamino) quinazoline -4 (3H) _ ketone

Previous step product (5) -2- (1- aminopropyls) -3- (phenylamino) quinazoline -4 (3H) -one hydrochloride; dissolved with the 20 mL tert-butyl alcohols; add DIEA (2.1 mL; 12.1 mmol); half an hour is stirred under ice bath; then chloro- 9H- purine (376 mg of 6- are added thereto; 2.43 mmol); under 85 °C, nitrogen protection, lucifuge reacts 6 h; cooling; concentration, it is anti-phase to be prepared into the mg of white solid 116, the % of two step yield 11.6.

Mass spectrum (Μ+Η): 413.2

1H-NMR( ₆-DMSO, 400 ΜΗζ):δ 12.9 (1 Η, br s), 9.10 (1H, s), 8.23-8.12 (1H, m), 8.11-8.02 (2H, m), 7.85-7.76 (1H, m), 7.76-7.68 (1H, m), 7.61 (1H, d), 7.50 (1H, t), 7.26-7.15 (2H, m), 6.94 (2H, d), 6.84 (1H, t), 5.53 (1H, m), 2.22-2.11 (1H, m), 2.05-1.92 (1H, m), 0.995 (3H, t) 2-KS of embodiments 2)-:9H- purine -6- bases amino) propyl group " -5- fluoroanilinos) quinazoline ~ (3H) -one（Compound 2) preparation

(1) preparation of the fluoro- 6- nitros-N'- phenylbenzohydrazides of 2-

2- fluoride-6-nitrobenzoic acids (7.4 g, 40.0 mmol) are dissolved in 50 mL CH₂Cl₂With 0.4 mL DMF, oxalyl chloride (7.61 g are slowly added dropwise thereto, 60.0 mmol), it is stirred at room temperature after two hours, concentration removes solvent, 8 mL dioxane are then dissolved in, phenylhydrazine (4.32 g, 40.0 mmol), NaHC0 are added dropwise under cooling₃(6.72 g, 80.0 mmol) dioxane (20 mL) and water (20 mL) solution in, completion of dropping, which is raised to, is stirred at room temperature half an hour, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, concentrate organic phase, silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) g of white solid 4.7, yield 42.8% are obtained.

(2) preparation of the fluoro- N'- phenylbenzohydrazides of 2- amino -6-

The fluoro- 6- nitros-N'- phenylbenzohydrazides of 2- (1.5 g, 5.45 mmol) are dissolved in 20 mL methanol, added thereto S3

0.5 g 10% Pd/C, leads to hydrogen, 36 h is reacted at room temperature, reaction terminates, and filters out Pd/C, 1.3 g, yield 97.2% are obtained after organic phase concentration.

(3) preparation of (5) -1- [the fluoro- 2- of 3- (2- phenylhydrazines formoxyl) phenylamino] -1- oxo butyl- 2- carbamates

In dry reaction bulb, by (5) -2- (t-butoxycarbonyl amino) butyric acid (166 mg, 0.817 mmol), the fluoro- T ' of 2- amino -6--phenylbenzohydrazide (100 mg, 0.408 mmol), DIEA (0.093 mL, 0.533 mmol) and HATU (170 mg, 0.448 mmol) it is added in 12 mL dichloromethane protective embankments, 48 h are stirred at room temperature, add water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=3:1) mg of white solid 153, yield 87.0%, are obtained.

(4) (the preparation of 5-2- (1- aminopropyls)-5- fluoro- 3- (phenylamino) quinazoline-4 (3H) -one hydrochloride

By (5) -1- [the fluoro- 2- of 3- (2- phenylhydrazines formoxyl) phenylamino] -1- oxo butyl- 2- carbamates (421 mg; 0.978 mmol) it is dissolved in 20 mL ethanol; 2 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into oil bath and reacts 16 h under 85 °C; concentrated after cooling, obtain white solid and be directly used in next step.

(5) preparation of 2- [(5)-l- (9H- purine -6- bases amino) propyl group] -5- fluoro- 3- (phenylamino) quinazoline -4 (3H) -one

Obtained (S) -2- (l- aminopropyls) -5- fluoro- 3- (phenylamino) quinazoline -4 (3H)-keto hydrochloride (about 0.978 mmol) and DIEA (0.68 mL is walked on being added into the 20 mL tert-butyl alcohols, 3.91 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (152 mg of 6- are added thereto, 0.98 mmol), it is warming up to 85 °C of 24 h of reaction, cooling, concentration, silica gel column chromatography (ethyl acetate), obtain the mg of white solid 178, two step yields 42.3%.

Mass spectrum (M+H): 431

1H-NMR(DMSO-i/₆, 400 MHz, 80°C):δ 12.74 (1 Η, s), 8.86 (1 Η, s), 8.19-8.00 (2H, m), 7.83-7.74 (1H, m), 7.48 (1H, d), 7.29-7.13 (4H, m), 6.93-6.78 (3H, m), 5.78 (1H, s), 2.24-1.88 (2H, m), 1.03-0.91 (3H, m)

(the S of embodiment 3>- 2- " l-i9H- Piao Ling -6- bases amino) propyl group 1-5- chloro- 3- (phenylamino) quinazoline ~ 4 (3ff) -one compound 4) preparation

(1) preparation of 2- amino -6- chloro benzoic ethers

2- amino -6- chlorobenzoic acids (10 g are added in dry reaction bulb, 58.3 mmol), 120 mL DMF, potassium carbonate (12 g are added under ice bath, 86.8 mmol), iodine first protective embankment (9.88 g, 69.6 mmol), room temperature lucifuge stirring reaction is stayed overnight.Solvent is spin-dried for, column chromatography obtains 10.3 g colorless oils, yield 95.2%.

The preparation of (2) 0-2- [2- (t-butoxycarbonyl amino) butyrylamino]-6- chloro benzoic ethers

100 mL DMF are separately added into reaction bulb, 100 mL DCM, 2- amino -6- chloro benzoic ethers (10.3 g, 55.5 mmol), (5) -2- (t-butoxycarbonyl amino) butyric acid (18.0 g, 88.6 mmol), DIEA (12.6 mL, 72.4 mmol), HATU (23.3 g, 61.3 mmol), be stirred overnight at room temperature reaction.Partial solvent is removed in rotation, is added water, ethyl acetate extraction, washing, and thousand is dry, and column chromatography obtains the g of weak yellow liquid 15.8, yield 76.8%.

(3) preparation of (S) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chlorobenzoic acids

By (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chloro benzoic ethers (15.7g, 42.3 mmol) dissolved with 200 mL tetrahydrofurans and 60 mL methanol, the 200 mL IM multiple lithia aqueous solution is added, be stirred overnight at room temperature reaction.Partial solvent is removed in rotation, is added water, and watery hydrochloric acid, which is adjusted to pH, is equal to 4, and ethyl acetate extraction is multiple, dries, is spin-dried for obtaining the g of light yellow oil 15.0, yield 99.3%.

(4) 0S)-l- [the chloro- 2- of 3- (2- phenylhydrazinos formoxyl) phenylamino] -1- oxo butyl- 2- carbamates preparation

(5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chlorobenzoic acids (7.48 g are separately added into dry reaction bulb, 21.0 mmol), 50 mL DCM and 50 mL DMF, DIEA (9.1 mL, 52.3 mmol), hydrazinobenzene hydrochloride salt (4.48 g, 31.0 mmol), HATU (10.37 g, 27.3 mmol), is stirred overnight at room temperature.Rotary evaporation removes partial solvent, adds water, Ethyl acetate is extracted, and washing, column chromatography obtains the g of white solid 7.96, yield 84.8%.

(5) preparation of (5) -2- (1- aminopropyls) -5- chloro- 3- (phenylamino) quinazoline -4 (3H) -one hydrochloride

() -1- [the chloro- 2- of 3- (2- phenylhydrazinos formoxyl) phenylamino] -1- oxo butyl- 2- carbamates (500 mg are added in reaction bulb; 1.12 mmol); 10 mL ethanol, 3 mL concentrated hydrochloric acids, heating reflux reaction is stayed overnight.Room temperature is cooled to, white solid, suction filtration, ice ethanol and ether washing filter cake is separated out.Obtain the mg of white solid 200, yield 48.8%.

(6) preparation of (S) -2- [l- (9H- purine -6- bases amino) propyl group] -5- chloro- 3- (phenylamino) quinazoline -4 (3H) -one

(5) -2- (1- aminopropyls) -5- chloro- 3- (phenylamino) quinazoline -4 (3H) -one hydrochlorides (200mg is separately added into dry reaction bulb, 0.547 mmol), the 15 mL tert-butyl alcohols, 2 mL DIEA, chloro- 9 Η of 6--purine (113 mg, 0.73 mrnol), heating reflux reaction 3 days.Solvent is spin-dried for, column chromatography obtains white solid llO mg, yield 45.7%.

Mass spectrum (Μ+Η): 447.2

1H-NMR( ₆-DMS0, 400 ΜΗζ):δ 12.97 (H, br s), 8.99 (IH, s), 8.22-8.12 (IH, m), 8.09 (IH, m), 7.80-7.61 (2H, m), 7.52 (2H, t), 7.28-7.15 (2H, m), 6.99 (2H, d), 6.71 (IH, d), 5.47 (IH, m), 2.21-2.10 (1H, m), 2.04-1.92 (IH, m), 0.999 (3H, t)

Embodiment 4 (5V2- " l- (7-pyrrolo- " 2,3-dl pyrimidine-4-yls amino) propyl group 1-5- chloro- 3- (phenylamino) quinazolines-4f3H)-ketone（Compound 5) preparation

By (5) -2- (1- aminopropyls) -5- chloro- 3- (phenylamino) (3H) -one of quinazoline -4 hydrochloride (600 mg, 1.64 mmol) it is dissolved in the mL of the tert-butyl alcohol 10, add the chloro- 7H- pyrrolo-es [2 of 4-, 3- ^ pyrimidines (300 mg, 1.95 mmol), add DIEA (0.8 mL, 4.59 mmol), back flow reaction 7 days, it is spin-dried for solvent, cross preparation liquid phase and obtain the mg of product 200, yield 27.3%.Mass spectrum (Μ+Η): 446.2

1H-NMR( <i-DMS0, 400 ΜΗζ):δ 11.51 (IH, s), 8.93 (IH, s), 7.98 (1H, s), 7.82 (IH, d), 7.66 (1H, t), 7.47 (2H, t), 7.27 (2H, t), 7.16-7.08 (2H, m), 6.87 (IH, t), 6.80-6.75 (IH, m), 6.74-6.65 (1H, m), 5.45-5.35 (IH, m), 2.20-2.08 (IH, m), 1.95-1.80 (1H, m), 1.06 (3H, t)

The tf of embodiment 5) and -2- " l- (9H- purine -6- bases amino) propyl group 1-3- phenylamino -5- trifluoromethyl quinazolines -4f3H) -one（Compound 6) preparation

(1) preparation of 2- oxyiminos-N- (3- trifluoromethyls) acetamide

In 2 L reaction bulb, chloral hydrate (100 g, 0.605 mol) and anhydrous sodium sulfate（700 g, 4.93 mol) it is dissolved in 1.4 L water, and it is heated to 35 °C, by 3-Aminotrifluorotoluene (87 g, 0.54 mol) be dissolved in 400 mL water after be added in above-mentioned reaction solution, 56 mL concentrated hydrochloric acids then are added dropwise and keeping temperature is constant, will be dissolved with the light amine of hydrochloric acid（135 g, 1.94 mol) 200 mL solution be added in system, finish rear reaction solution and be warming up to 90 ' C reactions, 2 h, then cooling down, filtered when temperature is down to 50, flaxen filter cake, which is washed with water, to be put into vacuum drying chamber after three times and is dried overnight, and obtains 112 g, yield 89.3%.

(2) preparation of 4- (trifluoromethyl) indoline -2,3- diketone

In dry reaction bulb, the 86 % concentrated sulfuric acid (430 mL) is heated to 60 °C, by dry 2- oxyiminos-N- (3- trifluoromethyls) acetamide（100 g, 431 mmol) add in batches in upper reaction bulb, feed time continues 1 h, keeps system temperature to be no more than 65 Γ, and 85 °C are warming up to after finishing and is reacted 20 minutes, room temperature is then cooled to.It is poured into 2 L frozen water and stirs half an hour, yellow solid is separated out, is dried after filtering, obtain 20 g products, the % of yield 21.6.

(3) preparation of 2- amino -6- (trifluoromethyl) benzoic acid

220 mL 5 % sodium hydroxide solutions (275 mmol) and 220 mL 30 % hydrogen peroxide solutions are added in dry reaction bulb, 4- (trifluoromethyl) indoline -2,3- diketone is added in batches（17 g, 79 mmol) after be warming up to 50 °C reaction l h, then cool, filter, filtrate adjust pH to 4, have solid precipitation, filter, dry, obtain the g of faint yellow solid 11, the % of yield 67.8.

(4) preparation of (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- (trifluoromethyl) benzoic acid

In dry reaction bulb, by 2- amino -6- (trifluoromethyl) benzoic acid (5.2_&25.3 11∞01)、 （5) -2- (tertbutyloxycarbonyls Amino) butyric acid (5.2 g, 25.6 mmol), DIEA (3.44 g, 26.6 mmol) and HATU (10.16 g, 26.7 mmol) it is added in 50 mL DMF, it is stirred at room temperature 7 days, adds water and dichloromethane protective embankment, dichloromethane extraction, merge organic phase, washing, saturated common salt washing paint, organic layer anhydrous sodium sulfate drying, the g of white solid 2.6, the % of yield 26.3 are obtained after being concentrated under reduced pressure with preparation chromatographic isolation.

(5) (5) -1- (4- oxo -5- trifluoromethyl -4H- benzos [[1,3] oxazine -2- bases) propylcarbamate the dry reaction bulb of preparation in, it is separately added into (5) -2- [2- (tertiary fourth oxygen Henan base amino) butyrylamino] -6- (trifluoromethyl) benzoic acid (2.6 g, 6.66 mmol), the 50 mL tert-butyl alcohols, acetic anhydride（3.15 g, 30.9 mmol), heating reflux reaction is stayed overnight.Solution decompression distills, and products obtained therefrom is directly used in next step.

(6) preparation of (5) -1- (4- oxo -3- phenylamino -5- trifluoromethyl -3,4- dihydroquinazoline -2- bases) propylcarbamate

Upper step product is dissolved in 15 mL pyridines, phenylhydrazine is added（756 tng, 6.99 mmol), it is heated to 100 °C and reacts 8 hours.Solvent is spin-dried for, column chromatography obtains the g of light yellow solid 1.5, in summary the % of two step yield 48.7.

(7) preparation of (5) -2- (1- aminopropyls) -3- phenylaminos -5- (trifluoromethyl) quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb, by (5) small (4- oxo -3- phenylamino -5- trifluoromethyl -3,4- dihydroquinazoline -2- bases) propylcarbamate（1.5 g, 3.24 mmol) it is dissolved in absolute ethyl alcohol（30 mL) in, hydrogen chloride gas is led into system until reaction is complete, 1.2 g solids are obtained after revolving（Hydrochloride）, the % of yield 92.9.

(8) in the dry reaction bulb of the preparation of (5 2- [the fast cry of certain animals -6- bases amino of 9H-) propyl group 1-3- anilino-s -5- (trifluoromethyl) quinazoline -4 (3/) -one, (5) -2- (1- aminopropyls) -3- phenylaminos -5- (trifluoromethyl) (3H) the -one hydrochloride of quinazoline -4 (800 mg are added into the 30 mL tert-butyl alcohols, 2.01 mmol) and DIEA (1.4 mL, 8.04 mmol), then fast cry of certain animals (619 1^, 4.00 of 6- chloro- 9 are added thereto：1^101), reaction reacts 24 h at 85 times, cools down, concentration, prepares chromatographic isolation and obtains the mg of white solid 194, the % of yield 20.1.

Mass spectrum（M+H): 481.2

1H-NMR(^-DMS0, 400 MHz):(1 Η of δ 12.92, br s), 9.13 (1H, s), 8.22-8.11 (1H, m), 8.10 (1H, s), 8.02-7.84 (3H, m), 7.84-7.63 (1H, m), 7.29-7.15 (2H, t), 6.99 (1H, d), 6.86 (1H, t), 6.69 (1H, d), 5.48 (1H, m), 2.25-2.10 (1H, m), 2.02-1.89 (1H, m), 1.01, 0.87 (3H, two triplets) 6 i5 of embodiments) -2-U- (9ff- purine -6- bases amino) propyl group l-3- μ-fluoroanilino) -5- (trifluoromethyl) quinazolines -40g)-ketone（Compound 7) preparation

(1) (5)-l- [4- oxos-⁵- (trifluoromethyl) -4H- benzos [] [l, 3] oxazine -2- bases] propylcarbamate the dry reaction bulb of preparation in, by 2- amino -6- (trifluoromethyl) benzoic acid (1.5 g, 7.31 mmol) it is dissolved in 50 mL pyridines, successively add (5) -2- (t-butoxycarbonyl amino) butyric acid (1.5 g, 7.38 mmol), triphenyl phosphite (2.3 g, 7.41 mmol) after reacting 24 h under 60 °C, until raw material disappears.

(2 ) (5)-1-[3-(⁴- fluoroanilino) -4- oxos -5- (trifluoromethyl) -3,4- dihydroquinazoline -2- bases] propylcarbamate preparation

Added into above-mentioned reaction solution to fluorophenyl hydrazine hydrochloride (1.5 g, 9.23 mmol), and be warming up to 100 °C of 8 h of reaction, until raw material disappears.Organic solvent and column chromatography are spun off after cooling（PE:EA=6:1) g of faint yellow solid 1.5, the % of two step yield 42.7 are obtained.

(3) in the dry reaction bulb of the preparation of (5) -2- (1- aminopropyls) -3- (4- fluoroanilinos) -5- (trifluoromethyl) quinazoline -4 (3H) -one hydrochloride, by (5) -1- [3- (4- fluoroanilinos) -4- oxos -5- (trifluoromethyl) -3,4- dihydroquinazoline -2- bases] propylcarbamate (1.5 g, 3.12 mmol) it is dissolved in 30 mL absolute ethyl alcohols, lead to hydrogen chloride gas into system until reaction is complete, 1.2 g solids are obtained after revolving（Hydrochloride）, the % of yield 92.3.

(4) (5-2- [l- (9H- purine-6- bases amino) propyl group]-3- (4- fluoroanilinos)-5- (trifluoromethyl) (preparation of 3H ketone of quinazoline-4

In dry reaction bulb, (5 2- (1- aminopropyls) -3- (4- fluoroanilinos) -5- (trifluoromethyl) quinazoline -4 (3H) _ keto hydrochloride (1.0 g are added into the 30 mL tert-butyl alcohols, 2.40 mmol) and DIEA (2.0 mL, 11.5 mmol), chloro- 9H- purine (700 mg of 6-, 4.53 mmol), 24 h are reacted in reaction under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of white solid 600, the % of yield 50.

Mass spectrum（Μ+Η): 499.2 S9

'H-NMR^-DMSO, 400 MHz):δ 12.98 (1H, s), 9.12 (1H, s), 8.22-8.10 (2H, m), 8.00-7.81 (4H, m), 7.16-7.00 (4H, m), 5.44 (1H, m), 2.21-1.80 (2H, m), 1.02 (3H, t)

Embodiment 7 (S) -2- " W9 purine -6- bases amino) the fluoro- 3- of propyl group 1-5- (4- fluoroanilinos)-quinazoline -4 (3^) -one f compounds 8) preparation

(1) the fluoro- NH4- fluorophenyls of 2-) -6- nitrobenzoyl hydrazides preparation

2- fluoride-6-nitrobenzoic acids (5.5 g, 29.7 mmol) are dissolved in 50 mL CH₂C1₂With 0.4 mL DMF, oxalyl chloride (5.66 g are slowly added dropwise thereto, 44.6 mmol), it is stirred at room temperature after two hours, concentration removes solvent, 8 mL dioxane are then dissolved in, are added dropwise under cooling to fluorophenyl hydrazine hydrochloride (4.829 g, 29.7 mmol), NaHC0₃(6.72 g, 80 mmol) the mL of dioxane 20 and the mL solution of water 20 in, completion of dropping, which is raised to, is stirred at room temperature half an hour, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, organic phase is concentrated, Diethyl ether recrystallization obtains the g of light yellow product 4.4, the % of yield 50.5.

(2) preparation of the fluoro- N'- of 2- amino -6- (4- fluorophenyls) benzoyl hydrazine

By the fluoro- N- of 2- (4- fluorophenyls) -6- nitrobenzoyls hydrazides (4.4 g, 15.0 mmol) it is dissolved in 60 mL methanol, 0.5 g l0% Pd/C is added thereto, logical hydrogen, 36 h are reacted at room temperature, and reaction terminates, and filters out Pd/C, 3.8 g, yield 96.3% are obtained after organic phase concentration.

(3) in the dry reaction bulb of the preparation of (5) -1- [the fluoro- 2- of 3- [2- (4- fluorophenyls) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates, by (5) -2- (t-butoxycarbonyl amino) butyric acid (5.8 g, 28.6mmol), the fluoro- N'- of 2- amino -6- (4- fluorophenyls) benzoyl hydrazines (3.8 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) it is added in 200 mL dichloromethane protective embankments, 48 h are stirred at room temperature, add water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, with preparation chromatogram point after being concentrated under reduced pressure From obtaining the g of white solid 3.4, yield 52.6%.

(4) preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (4- fluoroanilinos) quinazoline -4 (3H) -one hydrochloride

By (5) -1- [the fluoro- 2- of 3- [2- (4- fluorophenyls) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates (3.4 g; 7.58 mmol) it is dissolved in 60 mL ethanol; 10 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into 85 times 16 h of reaction in oil bath; concentration prepares chromatographic isolation and obtains 1.6 g white solids, yield 57.5% after cooling.

(5) CS) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- (4- fluoroanilinos)-quinazoline -4 (3H) -one preparation

(5) -2- (1- aminopropyls) -5- fluoro- 3- (4- fluoroanilinos) (3H) the -one hydrochloride of quinazoline -4 (600 mg are added into the 20 mL tert-butyl alcohols, 1.64 mmol) and DIEA (0.71 mL, 4.08 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (378 mg of 6- are added thereto, 2.45 mrnol), 24 h are reacted in reaction under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of white solid 140, yield 19.0%.

Mass spectrum (Μ+Η): 449.2

1H-NMR( ₆-DMS0, 400 ΜΗζ):δ 12.96 (1 Η, br s), 8.99 (1H, s), 8.22-8.08 (2H, m), 7.66-7.47 (1H, m), 7.38 (1H, d), 7.24 (1H, t), 7.13-6.99 (4H, m), 6.78-6.69 (1H, m), 5.47 (1H, m), 2.20-2.07 (1H, m), 2.06-1.85 (1H, m), 1.01 (3H, t)

The i5 of embodiment 8) -2-ll-i9H- purine -6- bases amino) propyl group " the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3^) -one（Chemical combination

(1) 1.50 g (4.20 mmol) (S) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chlorobenzoic acids are separately added into the dry reaction bulb of the preparation of (5) -1- [the chloro- 2- of 3- [2- (4- fluorophenyls) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates; 20 mL DCM and 10 mL DMF; 1.8 mL (10.33 mmol) DIEA; 1.03 g (6.33 mmol) are to fluorophenyl hydrazine hydrochloride; 2.08 g (5.47 mmol) HATU, is stirred overnight at room temperature.Partial solvent is removed in rotation, is added water, second Acetoacetic ester is extracted, washing, column chromatography（Petroleum ether:Ethyl acetate=3:1) g of light yellow solid 1.95, yield 99.8% are obtained.

(2) (>S) the preparation of the chloro- 3- of -2- (l- aminopropyls) -5- (4- fluoroanilinos) quinazoline -4 (3H) -one hydrochloride

(5) -1- [the chloro- 2- of 3- [2- (4- fluorophenyls) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates (640 mg are added in reaction bulb; 1.38 mmol); 10 mL ethanol; 3 mL concentrated hydrochloric acids, heating reflux reaction is stayed overnight.Room temperature is cooled to, white solid, suction filtration, ice ethanol and ether washing filter cake is separated out.Obtain the mg of white solid 200, yield 37.8%.

(3) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one

(5) -2- (1- aminopropyls) -5- chloro- 3- (4- fluoroanilinos) (3H) the -one hydrochloride of quinazoline -4 (200 mg are separately added into dry reaction bulb, 0.522 mmol), the 15 mL tert-butyl alcohols, 2 mL DIEA, the chloro- 9H- purine of 155 mg (1.0 mmol) 6-, heating reflux reaction 3 days.It is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=1:1-1 :3) mg of white solid 200, yield 82.4% are obtained.

Mass spectrum (Μ+Η): 465.2

1H-NMR( ₆-DMS0, 400 ΜΗζ):δ 12.97 (IH, br s), 8.98 (IH, s), 8.30-8.08 (2H, m), 7.90-7.59 (2H, m), 7.57-7.46 (2H, m), 7.16-6.98 (4H, m), 5.44 (IH, m), 2.20-2.05 (IH, m), 2.05-1.92 (IH, m), 1.01 (3H, t)

Embodiment 9 (S) -2-fl-f3H ~ imidazo【4,5-W pyridin-7-yls amino) the chloro- 3- 4- fluoroanilinos of propyl group 1-5-) (3 -one of quinazoline-4（Compound 10) preparation

(1) preparation of chloro- 3H- imidazos [4,5-b] the Nicotinicum Acidum tert-butyl esters of 7-

In dry reaction bulb, it is separately added into 10 mL dichloromethane protective embankments, the chloro- 3H- imidazos [4 of 1.34 g (8.73 mmol) 7-, 5-b] pyridine, 2.85 g (13.1 mmol) di-tert-butyl dicarbonate, 10 mg DMAP are stirred at room temperature 1 hour, solution is become by muddiness to be clarified, and is terminated through TLC monitoring reactions.It is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=10:1) g of white solid 1.80, the % of yield 81.3 are obtained.

(2) (5) -2- [l- (3H- imidazos [4,5-b] pyridin-7-yl amino) propyl group] the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) _ W

The preparation of 62 ketone

In dry microwave reaction pipe, chloro- 3H- imidazos [4,5-b] the Nicotinicum Acidum tert-butyl esters of 1.80 g (7.10 mmol) 7- are separately added into,（5) g (4.04 mmol) of the chloro- 3- of -2- (1- aminopropyls) -5- (4- fluoroanilinos) quinazoline -4 (3H) -one 1.40,10 mL n-butanols, 1.4 mL (8.04 mmol) DIEA, microwave is heated to 180 °C of 20 min of reaction.It is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=1:1-1 :3) crude separation, prepares liquid phase separation and obtains the mg of faint yellow solid 40, the % of yield 2.1.

Mass spectrum (M+H): 464.0

1H-NMR(i/₆-DMSO, 400 MHz):6 12.60 (IH, br s), 9.32-8.93 (1H, m), 8.14-7.59 (5H, m), 7.18-6.91 (2H, m), 6.90-6.60 (4H, m), 5.46 (1H, m), 2.23-2.05 (1H, m), 2.05-1.80 (IH, m), 1.16 (3H, m)

Embodiment 10 (S) -4-f2-iW9ff- purine -6- bases amino) propyl group 1-5- fluorin-4-oxygens for quinazoline -3 (the benzonitrile f compounds 12 of 4 n- bases amino 1) preparation

(1) preparation of 4- cyanophenylhydrazines hydrochloride

By p-aminophenyl nitrile (25 g, 211 mmol) it is dissolved in 200 mL concentrated hydrochloric acids, 100 mL natrium nitrosums (15.8 g, the 229 mmol) aqueous solution is added dropwise under -15 °C, drop finishes, reaction solution is added drop-wise to two hydrated stannous chlorides (238 g under -10 °C, 1.05 mol) and the reaction system of 185 mL concentrated hydrochloric acids in, drop finish, 15 min are stirred under -0 °C, suction filtration solid Ether washs solid, dries, obtains 28 g white solids, yield 78.2%.

(2) preparation of the fluoro- 6- nitrobenzoyls hydrazides of N'- (4- cyano-phenyls) -2-

2- fluoride-6-nitrobenzoic acids (5.55 g, 30.0 mmol) are dissolved in 50 mL C Cl₂With 0.3 mL DMF, oxalyl chloride (5.71 g are slowly added dropwise thereto, 45.0 mmol), it is stirred at room temperature after 2 h, concentration removes solvent, 6 mL dioxane are then dissolved in, 4- cyanophenylhydrazines hydrochloride (5.09 g, 30.0 mmol), NaHC0 are added dropwise under cooling₃(7.56 g, 90.0 in the mL of dioxane 15 and the mL solution of water 15 mmol), completion of dropping, which is raised to, is stirred at room temperature half an hour, subtract the dense Shrink of pressure to after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, concentrate organic phase, silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) g of white solid 6.53, yield 72.6% are obtained.

(3) preparation of 2- amino-N'- (4- cyano-phenyls) -6- fluorobenzoyl hydrazines

By fluoro- 6- nitrobenzoyls hydrazides (4.2 g of N'- (4- cyano-phenyls) -2-, 14.0 mmol) it is dissolved in 30 mL methanol, 0.6 g l0% Pd/C is added thereto, logical hydrogen, 18 h are reacted at room temperature, reaction terminates, and filters out Pd/C, and organic phase concentration gained solid is directly used in next step reaction.

(4) in the dry reaction bulb of the preparation of (5) -1- [2- [2- (4- cyano group benzene) hydrazine formoxyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates, 2- amino-N'- (4- cyano-phenyls) -6- fluorobenzoyl hydrazine crude products that upper step is obtained（About 14.0 mmol)>(5) -2- (t-butoxycarbonyl amino) butyric acid (4.26 g, 21.0 mmol), DIEA (3.17 mL, 18.2 mmol) and HATU (6.38 g, 16.8!1^101) it is added in 40 ^^ dichloromethane protective embankments, 64 h is stirred at room temperature, adds water and dichloromethane, dichloromethane protective embankment is extracted, and merges organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=3:1) g of white solid 2.65, two step total recoverys 41.6%, are obtained.

(5) 0S) -4- [2- (l- aminopropyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-base amino] benzonitrile hydrochloride preparation

By (5) -1- [2- [2- (4- cyano group benzene) hydrazine formoxyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates (1.37 g; 3.0 mmol) it is dissolved in 30 mL ethanol; 3 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into oil bath and reacts 24 h under 85 °C; concentrated after cooling, obtain white solid and be directly used in next step.

(6) preparation of (5) -4- [2- [l- (9H- purine -6- bases amino) propyl group] -5- fluorin-4-oxygens are for quinazoline -3 (4H)-base amino] benzonitrile added into the 20 mL tert-butyl alcohols (5) -4- that step obtains [2- (1- aminopropyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-base amino) benzonitrile hydrochloride (about 3.0 mmol) and DIEA (1.56 mL, 9.0 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (556 mg of 6- are added thereto, 3.6 mmol), 36 h are reacted in reaction under 85 °C, cooling, concentration, silica gel column chromatography (ethyl acetate), obtain the mg of white solid 153, two step yields 11.2%.

Mass spectrum (Μ+Η): 456.2

'H-NMR^-DMSO, 400 MHz):δ 12.94 (1H, s), 9.67 (1 Η, s), 8.28-8.03 (2H, m), 7.95-7.24 (6H, m), 7.08-6.28 (2H, m), 5.38 (1H, m), 2.20-1.79 (2H, m), 1.01 (3H, m) The tf of embodiment 11)-2- " l- (9-purine-6- bases amino) propyl group " fluoro- 3-f3- fluoroanilinos of-5-)-quinazoline-4ag) -one（Compound 13) preparation

(1) the fluoro- NH3- fluorophenyls of 2-) -6- nitrobenzoyl hydrazides preparation

3- fluorophenyl hydrazine hydrochlorides (4.8 g, 29.73 mmol) are added in 15 mL dioxane and 15 mL water, then add NaHC0₃(5 g, 59.5 mmol), then fluoro- 6 nitrobenzoyl chlorides of ready-made 2- (mmol of 6.05＆ 29.73) 10 mL dioxane solutions are added dropwise into system, completion of dropping, which is raised to, is stirred at room temperature 3 h, is concentrated under reduced pressure into after 1/3rd volumes, there is solid precipitation, suction filtration obtains crude product, is washed with ether and a small amount of ethyl acetate, suction filtration, it is dried to obtain the g of white solid 5.67, yield 64.9%.

(2) preparation of the fluoro- N'- of 2- amino -6- (3- fluorophenyls) benzoyl hydrazine

By the fluoro- N- of 2- (3- fluorophenyls) -6- nitrobenzoyls hydrazides (5.67 g, 19.3 mmol) it is dissolved in 100 mL methanol, 600 mg l0% Pd/C is added thereto, logical hydrogen, 24 h are reacted at room temperature, and reaction terminates, and filters out Pd/C, 4.8 g, yield 94.3% are obtained after organic phase concentration.

(3) in the dry reaction bulb of the preparation of (5) -1- [the fluoro- 2- of 3- [2- (3- fluorophenyls) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates, by (5) -2- (t-butoxycarbonyl amino) butyric acid (5.8 g, 28.5 mmd), 2- amino -6- is fluoro- '-(3- fluorophenyls) benzoyl hydrazine (3.8 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) it is added in 80 mL DMF, 48 h are stirred at room temperature, it is spin-dried for DMF, add water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, preparation liquid phase is crossed after being concentrated under reduced pressure and obtains the g of white solid 3.6, yield 55.6%.

(4) preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (3- fluoroanilinos) quinazoline -4 (3H) -one hydrochloride

By (5) -1- [the fluoro- 2- of 3- [2- (3- fluorophenyls) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates (3.6 g; 8 mmol) it is dissolved in 40 mL ethanol; 5 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into oil bath and reacted 4 days under 85 °C; concentrated after cooling, cross preparation liquid phase and obtain the mg of white solid 650, receive Rate 22.1%.

(5) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- (3- fluoroanilinos)-quinazoline -4 (3H) -one

Obtained (5) -2- (1- aminopropyls) -5- fluoro- 3- (3- fluoroanilinos) (3H) the -one hydrochloride of quinazoline -4 (650 mg are walked on being added into the 40 mL tert-butyl alcohols, 1.77 mmol) and DIEA (0.92 mL, 5.28 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (819 mg of 6- are added thereto, 5.30 Inmol), 24 h are reacted in reaction under 85 °C, cooling, concentration, silica gel column chromatography (ethyl acetate), obtains the mg of white solid 207, yield 26.1%.

Mass spectrum (Μ+Η): 449.2

¹H-NMR (^-DMSO, 400 MHz):δ 12.99 (1 Η, br s), 9.23 (1H, s), 8.22-8.11 (1H, m), 8.05 (1H, s), 7.95-7.70 (2H, m), 7.39 (1H, d), 7.31-7.19 (2H, m), 6.92-6.74 (2H, m), 6.70-6.61 (1H, m), 5.40 (1H, m), 2.17-2.05 (1H, m), 2.04-1.85 (1H, m), 1.02 (3H, t)

The iS of embodiment 12)-2- " M9-fast cry of certain animals-6- bases amino) and the fluoro- 3- of propyl group 1-5- (3- methoxybenzenes amino " (the preparation of 3H -one (compound 14) of quinazoline-4

(1) preparation of the fluoro- N'- of 2- (3- methoxyphenyls) -6- nitrobenzoyl hydrazides

2- fluoride-6-nitrobenzoic acids (5.55 g, 30.0 mmol) are dissolved in 50 mL CH₂Cl₂With 0.3 mL DMF, oxalyl chloride (5.71 g are slowly added dropwise thereto, 45.0 mmol), 2 h are stirred at room temperature, concentration removes solvent, 6 mL dioxane are then dissolved in, 3- methoxyphenyl hydrazine hydrochlorides (5.23 g, 30.0 mmol), NaHC0 are added dropwise under cooling₃(7.56 g, 90.0 in the mL of dioxane 15 and the mL solution of water 15 mmol), completion of dropping, which is raised to, is stirred at room temperature half an hour, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, concentrate organic phase, silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) g of white solid 4.23, yield 46.2% are obtained.

(2) preparation of the fluoro- N'- of 2- amino -6- (3- methoxyphenyls) benzoyl hydrazine

The fluoro- N'- of 2- (3- methoxyphenyls) -6- nitrobenzoyls hydrazides (3.05 g, 10.0 mmol) is dissolved in 30 mL methanol, 0.5 g lO% Pd/C is added thereto, logical hydrogen, reacts 18 h, reaction terminates at room temperature, Pd/C is filtered out, is had Machine obtains 2.7 g, yield 98.1% after mutually concentrating.

(3) in the dry reaction bulb of the preparation of (5) -1- [the fluoro- 2- of 3- [2- (3- methoxybenzenes) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates, by (5) -2- (t-butoxycarbonyl amino) butyric acid (3.0 g, 14.76 mmol), the fluoro- N'- of 2- amino -6- (3- methoxyphenyls) benzoyl hydrazines (2.7 g, 9.81 mmol), DIEA (2.3 mL, 13.3 mmol) and HATU (4.0 g, 10.5 mmol) it is added in 20 mL dichloromethane protective embankments, 64 h are stirred at room temperature, add water and dichloromethane, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt washing paint, organic layer anhydrous sodium sulfate drying, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=3:1) g of white solid 1.4, yield 31.0%, are obtained.

(4) preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (3- methoxybenzenes amino) quinazoline -4 (3H) -one hydrochloride

By () -1- [the fluoro- 2- of 3- [2- (3- methoxybenzenes) hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates (600 mg; 1.31 mmol) it is dissolved in 20 mL ethanol; 2 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into oil bath and reacts 24 h under 85 °C; concentrated after cooling, obtain white solid and be directly used in next step.

(5) preparation of (5) -2- [l- (the fast cry of certain animals -6- bases amino of 9H-) propyl group] the fluoro- 3- of -5- (3- methoxybenzenes amino) quinazoline -4 (3H) -one

Obtained (5) -2- (1- aminopropyls) -5- fluoro- 3- (3- methoxybenzenes amino) (3H) -one of quinazoline -4 hydrochlorides (about 1.31 mmol) and DIEA (0.68 mL is walked on being added into the 20 mL tert-butyl alcohols, 3.91 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (242 mg of 6- are added thereto, 1.57 mmol), 36 h are reacted in reaction under 85 °C, cooling, concentration, silica gel column chromatography (ethyl acetate), obtain the mg of white solid 146, two step yields 24.2%.

Mass spectrum (M+H): 461.2

'H-NMR^-DMSO, 400 MHz, 80°C):δ 12.97 (IH, s), 9.00 (IH, s), 8.22-8.05 (2H, m), 7.85-7.69 (2H, m), 7.40 (IH, d), 7.32-7.21 (1H, m), 7.17-7.05 (IH, m), 6.60-6.41 (3H, m), 5.47 (IH, s), 3.68 (3H, s), 2.20-2.08 (IH, m), 2.02-1.92 (1H, m), 0.998 (3H, t)

The i5 of embodiment 13) -2-fl- (9H- purine -6- bases amino) fluoro- 3- 3- (trifluoromethyl) phenylamino quinazolines of propyl group 1-5-

- 4 (3 Η)-Μ (compound 15) preparation

(1) preparation of the fluoro- 6- nitros-N- of 2- [3- (trifluoromethyl) phenyl] benzoyl hydrazine

3- (trifluoromethyl) hydrazinobenzene hydrochloride salt (6.32 g, 29.73 mmol) is added in 15 mL dioxane and 15 mL 7, then adds NaHC0₃(5 g, 59.5 mmol), the dioxane solution (10 mL, 29.73 mmol) of fluoro- 6 nitrobenzoyl chlorides of ready-made 2- is then added dropwise into system, completion of dropping, which is raised to, is stirred at room temperature 3 h, it is concentrated under reduced pressure into after 1/3rd volumes, there is solid precipitation, suction filtration obtains crude product, washed with ether and a small amount of ethyl acetate, suction filtration, is dried to obtain the g of white solid 5.3, yield 51.8%.

(2) preparation of the fluoro- N'- of 2- amino -6- [3- (trifluoromethyl) phenyl] benzoyl hydrazine

By fluoro- 6- nitros-N43- (trifluoromethyl) phenyl of 2-] benzoyl hydrazine (5.3 g, 15.4 mmol) it is dissolved in 100 mL methanol, 600 mg l0% Pd/C is added thereto, logical hydrogen, 24 h are reacted at room temperature, and reaction terminates, and filters out Pd/C, 4.76 g, yield 98.7% are obtained after organic phase concentration.

(3) preparation of (5) -1- [the fluoro- 2- of 3- [2- [3- (trifluoromethyl) phenyl] hydrazine formoxyl] phenylamino] -1- oxo butyl- 2- carbamates

In dry reaction bulb, by (5) -2- (t-butoxycarbonyl amino) butyric acid (5.8 g, 28.5 mmol), 2- amino -6- fluoro- N'- [3- (trifluoromethyls）Phenyl] benzoyl hydrazine (4.51 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) enter 711 (6.0 § with 11,15.8 11^101) it is added to 8011^ 0] in ^^, 48 h are stirred at room temperature, DMF is spin-dried for, water and dichloromethane, dichloromethane extraction is added, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, preparation liquid phase is crossed after being concentrated under reduced pressure and obtains the g of white solid 1.29, yield 18.0%.

(4) (the preparation of the fluoro- 3- of -2- (1- aminopropyls) -5- [3- (trifluoromethyl) phenylamino] quinazoline -4 (3H) -one hydrochloride

By (5) small [the fluoro- 2- of 3- [2- [3- (trifluoromethyl) phenyl] hydrazine formoxyl] phenylamino] small oxo butyl- 2- carbamates (1.29 g; 2.59 mmol) it is dissolved in 40 mL ethanol; 5 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into oil bath and reacted 4 days under 85 °C; concentrated after cooling, cross preparation liquid phase and obtain the mg of white solid 220, yield 20.4%.

(5) CS) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- [3- (trifluoromethyl) phenylamino]-quinazoline -4 (3 /) -one preparation

Into the 40 mL tert-butyl alcohols add on step obtain (<S) the fluoro- 3- of -2- (l- aminopropyls) -5- [3- (trifluoromethyl) phenylamino] quinazoline -4 (3/) -one hydrochloride (220 mg, 0.528 mmol) and DIEA (0.28 mL, 1.61 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (243 mg of 6- are added thereto, 1.57 mmol), 24 h are reacted in reaction under 85 °C, cooling, concentration, column chromatography (ethyl acetate), obtains the mg of white solid 71, yield 27.0%.

Mass spectrum (M+H): 499.2

1H-NMR( _tf-DMS0, 400 MHz):δ 12.96 (1H, br s), 9.38 (1H, s), 8.19-7.96 (2H, m), 7.92-7.64 (2H, m), 7.56-7.35 (2H, m), 7.31-7.13 (4H, m), 5.43 (1H, m), 2.21-2.06 (IH, m), 2.04-1.98 (IH, m), 1.02 (3H, t)

Embodiment 14 (S) -3-【2- " l- (9ff- -6 ~ bases of purine amino) propyl group " -5- fluorin-4-oxygens are for quinazoline -3i4ff) 1 benzene first of-base amino（Compound 16) preparation

(1) preparation of the fluoro- 6- nitrobenzoyls hydrazides of N'- (3- cyano-phenyls) -2-

2- fluoride-6-nitrobenzoic acids (5.55 g, 30.0 mmol) are dissolved in 50 mL CH₂Cl₂With 0.3 mL DMF, oxalyl chloride (5.71 g are slowly added dropwise thereto, 45.0 mmol), it is stirred at room temperature after two hours, concentration removes solvent, 6 mL dioxane are then dissolved in, 3- cyanophenylhydrazines hydrochloride (5.09 g, 30.0 mmol) NaHC0 is added dropwise under cooling₃The dioxane of (7.56 g, 90.0 mmol)（15 mL) and water（15 mL) in solution, completion of dropping is warmed to room temperature stirring half an hour, is concentrated under reduced pressure into after 1/3rd volumes, and ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration concentrates organic phase, silica gel column chromatography（Petroleum ether:Ethyl acetate=2:1) g of white solid 7.2, the % of yield 80.0 are obtained.

(2) preparation of 2- amino-N'- (3- cyano-phenyls) -6- fluorobenzoyl hydrazines

By fluoro- 6- nitrobenzoyls hydrazides (4.2 g of N'- (3- cyano-phenyls) -2-, 14.0 mmol) it is dissolved in 30 mL methanol, 0.6 g l0 % Pd/C is added thereto, logical hydrogen, 18 h are reacted at room temperature, reaction terminates, and filters out Pd/C, and organic phase concentration gained solid is directly used in next step reaction.

(3) in the dry reaction bulb of the preparation of (5) -1- [2- [2- (3- cyano-phenyls) hydrazine carbonyl] the fluoro- phenylaminos of -3-] -1- oxo butyl- 2- carbamates, 2- amino-N'- (3- cyano-phenyls) -6- fluorobenzoyl hydrazines crude product (about 14.0 mmol) that upper step is obtained,（5) -2- (t-butoxycarbonyl amino) butyric acid (4.26 g, 21.0 mmol), DIEA (3.3 mL, 19 mmol) and HATU (6.38 g, 16.8 mmol) it is added in 40 mL dichloromethane, it is stirred at room temperature three days, adds water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography after being concentrated under reduced pressure（Petroleum ether:Ethyl acetate=3:1) g of white solid 2.9, the % of two step total recovery 45.5, are obtained.

(4) CS) -3- [2- (l- aminopropyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-base amino] benzonitrile hydrochloride preparation By (5)-l- [2- [2- (3- cyano-phenyls) hydrazine carbonyl] the fluoro- phenylaminos of -3-] small oxo butyl- 2- carbamates (1.37 g, 3.0 mmol) it is dissolved in 30 mL ethanol, 3 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath, stir after half an hour, reaction is moved into 85 °C of 24 h of reaction in oil bath, concentrated after cooling, obtain white solid and be directly used in next step.

(5) preparation of (5) -3- [2- [l- (9H- Piao Ling -6- bases amino) propyl group] -5- fluorin-4-oxygens for quinazoline -3 (4H bases amino] benzonitrile

Obtained (S) -3- [2- (l- aminopropyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-base amino] benzonitrile hydrochloride (about 3.0 mmol) and DIEA (1.56 mL is walked on being added into the 20 mL tert-butyl alcohols, 9.0 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (556 mg of 6- are added thereto, 3.6 mmol), 36 h are reacted in reaction under 85 °C, cooling, concentration, column chromatography（The volume of ethyl acetate 100%）, obtain the mg of white solid 168, the % of two step yield 12.3.

Mass spectrum（Μ+Η): 456.2

^-NMRC^-DMSO, 400 ΜΗζ):δ 12.95 (1 Η, s), 9.37 (1H, s), 8.20-8.07 (2H, m), 7.96-7.72 (2H, m), 7.47-7.20 (6H, m), 5.38 (1H, m), 2.18-1.85 (2H, m), 1.02 (3H, t)

Embodiment 15 (S) -2- " l- (9H- purine -6- bases amino) propyl group 1-3- 3,5- difluoroanilinos) quinazoline -4i3H) -one（Compound 17) preparation

(l) preparation of N "-(3,5- difluorophenyls) -2- nitrobenzoyl hydrazides

In dry reaction bulb, o-nitrobenzoic acid (5 g, 30 mmol) is dissolved in 50 mL CH₂Cl₂With 1 mL DMF, oxalyl chloride (5.71 g are slowly added dropwise under ice-water bath thereto, 45 mmol), 2 h are stirred at room temperature after completion of dropping, rotation removes solvent, is dissolved with 5 mL dioxane, is added dropwise to condition of ice bath and contains 3,5- difluorophenyl hydrazines hydrochloride (5.42 g, 30 mmol) NaHC0₃In the mL of dioxane 20 and the mL solution of water 20 of (10.08 g, 120 mmol), completion of dropping is warmed to room temperature 30 min of stirring, and partial solvent is evaporated off, water is added, there is white solid precipitation, is filtered, dry, obtain the g of white solid 7.3, the % of yield 83.

(2) preparation of 2- amino-N- (3,5- difluorophenyl) benzoyl hydrazine In dry reactor, add N- (3,5- difluorophenyl) -2- nitrobenzoyls hydrazides (7.3 g, 24.9 mmol), 60 mL methanol make solvent, the 10 % g of Pd/C 0.8, are passed through dry hydrogen, reaction is stayed overnight, TLC display reactions are completed, filtering, rotation thousand obtains the g of white solid 6.4, the % of yield 97.6.

(3) (<5) -1- [2- [2- (3, 5- difluorophenyls) diazanyl formoxyl] phenylamino] and -1- oxo butyl- 2- carbamates the dry single port bottle of preparation in, add (5) -2- (t-butoxycarbonyl amino) butyric acid (3.09 g, 15.2 mmol), DIEA (7.86 mL, 45.1 mmol), HATU (6.34 g, 16.7 mmol), 80 mL dichloromethanes protective embankments and 2 mL DMF dissolvings, 30 min are stirred at room temperature, add 2- amino-N- (3, 5- difluorophenyls) benzoyl hydrazine (4 g, 15.2 mmol), 72 h are stirred at room temperature, rotation removes dichloromethane protective embankment, add water, ethyl acetate is extracted, sample is mixed in concentration, column chromatography obtains the g of white solid 1.2, yield is 17.6 %.

(4) preparation of (5) -2- (1- aminopropyls) -3- (3,5- difluoroanilino) quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb; weigh (5) -1- [2- [2- (3; 5- difluorophenyls) diazanyl formoxyl] phenylamino] -1- oxo butyl- 2- carbamates (1.2 g, 2.68 mmol), add the dissolving of 50 mL ethanol; 5 mL concentrated hydrochloric acids are added dropwise under ice-water bath stirring; 30 min are stirred, 85 °C of stirring 16 h, LC-MS display reactions is warming up to and completes; concentrated after cooling, obtain white solid and be directly used in next step.

(5) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (3,5- difluoroanilinos) quinazoline -4 (3H) -one

Previous step product (5-2- (1- aminopropyls)-3- (3; 5- difluoroanilinos) quinazoline-4 (3H) -one hydrochloride; add the dissolving of the 20 mL tert-butyl alcohols; add DIEA (0.8 mL; 4.6 mmol); half an hour is stirred under ice bath; then add thereto under the chloro- 9H- purine of 6- (185 mg, 1.2 mmol), 85 Γ; nitrogen is protected; lucifuge reacts 5 h, cools down, concentration; it is anti-phase to be prepared into the mg of white solid 98, the % of two step yield 8.2.

Mass spectrum (Μ+Η): 449.2

1H-NMR( ₆-DMSO, 400 ΜΗζ):δ 12.95 (1 Η, br s), 9.50 (1H, s), 8.21-8.11 (1H, m), 8.07 (1H, d), 8.01 (1H, s), 7.98-7.85 (1H, m), 7.80 (1H, t), 7.59 (1H, d), 7.51 (1H, t), 6.75-6.55 (3H, m), 5.40 (1H, m), 2.17-2.07 (1H, m), 2.02-1.90 (1H, m), 1.03 (3H, t)

The preparation of (3^) -one (compound 18) of embodiment 16 (S) -2- " l-i9H- purine -6- bases amino) propyl group " -3- (3,5- difluoroanilinos) -5- Fluquinconazoles quinoline -4

(l) preparation of the fluoro- 6- nitrobenzoyls hydrazides of N- (3,5- difluorophenyls) -2-

2- fluoride-6-nitrobenzoic acids (16.51 g, 89.2 mmol) are dissolved in 100 mL CH₂Cl₂In, oxalyl chloride (17 is slowly added dropwise thereto_&13411^01), 2 h are stirred at room temperature, concentration removes solvent, then add dioxane into 30 mL solution for standby.3,5- difluorophenyl hydrazines hydrochloride (5.37 g, 29.73 mmol) is added to 30 mL dioxane and water (1:1) in, then NaHC0 is added₃(5 g, 59.5 mmol), then the dioxane solution of the standby fluoro- 6- nitrobenzoyl chlorides of 10 mL (about 29.73 mmol) 2- is added dropwise into system, completion of dropping, which is raised to, is stirred at room temperature 3 h, is concentrated under reduced pressure into after 1/3rd volumes, there is solid precipitation, suction filtration obtains crude product, is washed with ether and a small amount of ethyl acetate, suction filtration, it is dried to obtain the g of white solid 5.8, yield 62.6%.

(2) preparation of 2- amino-N'- (3,5- difluorophenyls) -6- fluorobenzoyl hydrazines

By N- (3,5- difluorophenyls) fluoro- 6- nitrobenzoyls hydrazides (5.8 g of -2-, 18.6 mmol) it is dissolved in 100 mL methanol, 600 mg 10% Pd/C is added thereto, leads to hydrogen, 24 h are reacted at room temperature, reaction terminates, Pd/C is filtered out, 5.1 g, yield 97.3% are obtained after organic phase concentration.

(3) preparation of (S)-l- [2- [2- (3,5- difluorophenyl) hydrazine formoxyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates

In dry reaction bulb, by (5) -2- (t-butoxycarbonyl amino) butyric acid (5.8 g, 28.5 mmol), 2- amino-N'- (3, 5- difluorophenyls) -6- fluorobenzoyls hydrazine (4.06 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) it is added in 80 mL DMF, 48 h are stirred at room temperature, most of DMF is removed in rotation, add water, dichloromethane is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, preparation liquid phase is crossed after being concentrated under reduced pressure and obtains the g of white solid 1.5, yield 22.4%.

(4) preparation of (3H) the -one hydrochloride of (5) -2- (1- aminopropyls) -3- (3,5- difluoroanilino) -5- Fluquinconazoles quinoline -4

By (5) -1- [2- [2- (3,5- difluorophenyl) hydrazine formoxyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates (1.5 g, 3.22 mmol) are dissolved in 40 mL ethanol, and 5 mL concentrated hydrochloric acids are added dropwise thereto under ice bath, stir after half an hour, reaction is moved into oil bath and reacted 4 days under 85 °C, is concentrated after cooling, cross preparation liquid phase and obtain the mg of white solid 440, yield 35.4%.

(5) preparation of (the 3H) _ ketone of (5) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (3,5- difluoroanilino) -5- Fluquinconazoles quinoline -4

Obtained CS is walked on being added into the 40 mL tert-butyl alcohols) -2- (l- aminopropyls) -3- (3,5- difluoroanilinos) -4 (3H) -one hydrochloride (440 mg of -5- Fluquinconazoles quinoline, 1.14 mmol) and DIEA (0.6 mL, 3.4 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (529 mg of 6- are added thereto, 3.42 mmol), it is warming up to 85 °C of 24 h of reaction, cooling, concentration, silica gel column chromatography (ethyl acetate), obtain the mg of white solid 197, yield 37.0%.

Mass spectrum (Μ+Η): 467.2

^-NMR^-DMSO, 400 ΜΗζ):δ 12.97 (IH, br s), 9.41 (IH, s), 8.30-7.90 (3H, m), 7.84-7.71 (IH, m), 7.39 (IH, d), 7.32-7.22 (IH, m), 6.80-6.67 (2H, m), 6.65-6.55 (IH, m), 5.36 (IH, m), 2.16-2.00 (IH, m), 1.96-1.82 (IH, m), 1.02 (3H, t)

Embodiment 17 (S) -2- " l- (9#- purine -6- bases amino) the chloro- 3-f3,5- difluoroanilinos of propyl group 1-5-) quinazoline -4 (3H) -one (compound 19) preparation

(1) preparation of (5) -1- [the chloro- 2- of 3- [2- (3,5- difluorophenyl) hydrazine carbonyl] phenylamino] -1- oxo butyl- 2- carbamates

7.48 g (21.0 mmol) (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chlorobenzoic acids are separately added into dry reaction bulb, 50 mL DCM and 50 mL DMF, 9.1 mL (52.3 mmol) DIEA, 5.60 g (31.0 mmol) 3,5- difluorophenyl hydrazine hydrochlorides, 10.37 g (27.3 mmol) HATU, is stirred overnight at room temperature.Rotary evaporation removes partial solvent, adds water, ethyl acetate extraction, washing, column chromatography（Petroleum ether:Ethyl acetate=3:1) g of light yellow solid 7.23, the % of yield 71.3 are obtained. (2) the chloro- 3- of (S) -2- (l- aminopropyls) -5- (3,5- the difluoroanilinos) (3H of quinazoline -4>The preparation of keto hydrochloride adds 900 mg (1.86 mmol) (5) -1- [the chloro- 2- of 3- [2- (3 in reaction bulb, 5- difluorophenyls) hydrazine carbonyl] phenylamino] -1- oxo butyl- 2- carbamates, lO mL ethanol, 3 mL concentrated hydrochloric acids, heating reflux reaction is stayed overnight.Room temperature is cooled to, white solid, suction filtration, ice ethanol and ether washing filter cake is separated out.Obtain the mg of white solid 300, the % of yield 40.2.

(3) 300 mg (0.748 mmol) (5 are separately added into the dry reaction bulb of the preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] the chloro- 3- of -5- (3,5- difluoroanilinos) quinazoline -4 (3H) -one>The chloro- 3- (3 of 2- (1- aminopropyls) -5-, 5- difluoroanilinos) quinazoline -4 (3H) -one hydrochloride, the 15 mL tert-butyl alcohols, 2 mL DIEA, the chloro- 9H- purine of 155 mg (1.00 mmol) 6-, heating reflux reaction 3 days.Rotary evaporation removes solvent, column chromatography（Petroleum ether:Ethyl acetate 1:1-1 :3) mg of white solid 272, the % of yield 75.3 are obtained.

Mass spectrum (M+H): 483.1

1H-NMR(i ₆-DMS0, 400 MHz):δ 12.96 (1 Η, br s), 9.39 (1H, s), 8.20-8.09 (1H, m), 8.02 (1H, s), 7.77-7.60 (2H, m), 7.57-7.48 (2H, m), 6.81-6.69 (2H, m), 6.67-6.56 (1H, m), 5.35 (1H, m), 2.15-1.92 (2H, m), 1.02 (3H, t)

The iS of embodiment 18) and-2- " 9-purine-6- bases amino) propyl group l-3- (2,6- difluoroanilinos)-5- Fluquinconazole quinoline-4i3ff -one

(1) preparation of the fluoro- 6- nitrobenzoyls hydrazides of W- (2,6- difluorophenyls) -2-

2- fluoride-6-nitrobenzoic acids (5.5 g, 29.7 mmol) are dissolved in 50 mL CH₂Cl₂With 0.4 mL DMF, oxalyl chloride (5.66 g are slowly added dropwise thereto, 44.6 mmol), it is stirred at room temperature after two hours, concentration removes solvent, is then dissolved in 8 mL dioxane, cooling, it is added dropwise to 2,6- difluorophenyl hydrazines hydrochloride (5.0 g, 27.7 mmol), NaHC0₃The dioxane of (6.72 g, 80.0 mmol)（20 mL) and water（20 mL) in solution, completion of dropping is warmed to room temperature stirring half an hour, is concentrated under reduced pressure into after 1/3rd volumes, and ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration concentrates organic phase, Diethyl ether recrystallization obtains the g of light yellow product 4.8, the % of yield 55.7.

(2) 2- amino-NH2,6- difluorophenyls) -6- fluorobenzoyl hydrazines preparation

By the fluoro- 6- nitrobenzoyls hydrazides of N- (2,6- difluorophenyls) -2-（4.8 g, 15.4 mmol) it is dissolved in 60 mL methanol, 0.5 g l0 % Pd/C is added thereto, leads to hydrogen, 36 h is reacted at room temperature, reaction terminates, and filters out Pd/C, 4.2 g, the % of yield 97.0 are obtained after organic phase concentration.

(3) preparation of (5) -1- [2- [2- (2,6- difluorophenyl) hydrazine carbonyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates

In dry reaction bulb, by (5) -2- (t-butoxycarbonyl amino) butyric acid (6.06 g, 29.8 mmol), 2- amino-iV- (2,6- difluorophenyls) -6- fluorobenzoyls hydrazine (4.2 g, 14.93 mmol), DIEA (2.9 mL, 16.7 mmol) and HATU (6.25 g

16.4 mmol) it is added in 200 mL dichloromethane, 48 h are stirred at room temperature, add water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, and merges organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, obtains the g of white solid 3.0, the % of yield 43.1 with preparation chromatographic isolation after being concentrated under reduced pressure.

(4) preparation of (3H) the -one hydrochloride of (5) -2- (1- aminopropyls) -3- (2,6- difluoroanilino) -5- Fluquinconazoles quinoline -4

By (5) -1- [2- [2- (2,6- difluorophenyls) hydrazine carbonyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates (3.0 g, 6.43 mmol) it is dissolved in 60 mL ethanol, 10 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath, stir after half an hour, reaction is moved into 85 °C of 16 h of reaction in oil bath, concentration prepares chromatographic isolation and obtains 1.3 g white solids, yield after cooling

52.5 %。

( 5 ) (<S) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (2, 6- difluoroanilinos) preparation of -5- Fluquinconazoles quinoline -4 (3H) -one adds (5) -2- (1- aminopropyls) -3- (2 into the 20 mL tert-butyl alcohols, 6- difluoroanilinos) -4 (3H) -one hydrochloride (1.3 g of -5- Fluquinconazoles quinoline, 3.38 mmol) and DIEA (1.75 mL, 10 mmol), stirred under ice bath and dissolve half an hour, then chloro- 9H- purine (1.6 g of 6- are added thereto, 10.4 mmol), 24 h are reacted in reaction under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the g of white solid 1.01, the % of yield 64.1.

Mass spectrum（Μ+Η): 447.2

1H-NMR (^-DMS0,400 Μ Η ζ):δ 13.00 (1 Η, br s), 9.09 (1H, s), 8.25-8.05 (2H, m), 7.89-7.80 (1H, m), 7.57 (1H, d), 7.39-7.27 (2H, m), 7.06-6.85 (3H, m), 6.05 (1H, m), 2.26-2.12 (1H, m), 2.01-1.88 (lH, m), 0.92 (3H, t)

Embodiment 19 (S) -5- fluorine fluoroanilino) -2-【l-【Methyl (the fast cry of certain animals -6- bases of 9ff- " amino " propyl group " (the 3ffl- ketone of quinazoline -4（Compound 21) preparation O.

-OH

BocHN-

(1) preparation of the fluoro- N- of 2- (4- fluorophenyls) -6- nitrobenzoyl hydrazides

2- fluoride-6-nitrobenzoic acids (5.5 g, 29.7 mmol) are dissolved in 50 mL CH₂C1₂With 0.4 mL DMF, oxalyl chloride (5.66 g are slowly added dropwise thereto, 44.6 mrnol), it is stirred at room temperature after two hours, concentration removes solvent, 8 mL dioxane are then dissolved in, are added dropwise under cooling to fluorophenyl hydrazine hydrochloride (4.829 g, 29.7 mmol), NaHC0₃The dioxane of (6.72 g, 80 mmol)（20 mL) and water（20 mL) in solution, completion of dropping, which is raised to, is stirred at room temperature half an hour, is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, organic phase is concentrated, Diethyl ether recrystallization obtains the g of light yellow product 4.4, the % of yield 50.5.

(2) preparation of the fluoro- N'- of 2- amino -6- (4- fluorophenyls) benzoyl hydrazine

By the fluoro- N- of 2- (4- fluorophenyls) -6- nitrobenzoyl hydrazides（4.4 g, 15.0 mmol) it is dissolved in 60 mL methanol, 0.5 g l0 % Pd/C is added thereto, leads to hydrogen, 36 h is reacted at room temperature, reaction terminates, and filters out Pd/C, 3.8 g, the % of yield 96.2 are obtained after organic phase concentration.

(3) preparation of (5) -2- (tertbutyloxycarbonyl (methyl) amino) butyric acid

By (5) -2- (t-butoxycarbonyl amino) butyric acid under ice bath（15.0 g, 73.8 mmol) anhydrous THF (600 mL) is dissolved in, add 60 %NaH kerosene dispersion（29.6 g, 740 mmol) it is stirred at room temperature 30 minutes, CH is added dropwise₃I (104.92 g, 739 mmol) reacts after finishing to be stayed overnight, and is spun off and is dissolved in after organic solvent in 200 mL water, is adjusted pH 7 with 1 N HC1, is rotated after EA extractions, obtain ll.O g products, the % of yield 68.6.

(4) (the preparation of -1- [the fluoro- 2- of 3- [2- (4- fluorophenyls) hydrazine carbonyl] phenylamino] -1- oxos butyl- 2- bases (methyl) t-butyl carbamate In dry reaction bulb, by (5) -2- (tertbutyloxycarbonyl (methyl) amino) butyric acid (5.2_&23.9 11 ∞ 101), 2- amino -6- it is fluoro--(4- fluorophenyls) benzoyl hydrazine (3.2 g, 12.2 mmol), DIEA (2.3 mL, 13.2 mmol) and HATU (5.02 g, 13.2 mmol) it is added in 200 mL DMF, it is stirred at room temperature 7 days, add water and dichloromethane, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, the g of white solid 2.6, the % of yield 46.1 are obtained after being concentrated under reduced pressure with preparation chromatographic isolation.

(5) preparation of the fluoro- 3- of (5) -5- (4- fluoroanilinos) -2- [1- (methylamino) propyl group] quinazoline -4 (3H) -one hydrochloride

By (5) small [the fluoro- 2- of 3- [2- (4- fluorophenyls) hydrazine carbonyl] phenylamino] -1- oxos butyl- 2- bases (methyl) t-butyl carbamate (2.6 g, 5.62 mmol) it is dissolved in 60 mL ethanol, 10 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath, stir after half an hour, reaction is moved into oil bath and reacts 64 h under 85 °C, concentration prepares chromatographic isolation and obtains 0.40 g white solids, the % of yield 18.7 after cooling.

(6) preparation of the fluoro- 3- of (5) -5- (4- fluoroanilinos) -2- [1- [methyl (9H- purine -6- bases) amino] propyl group] quinazoline -4 (3H) -one adds (5) -5- fluoro- 3- (4- fluoroanilinos) -2- [1- (methylamino) propyl group] (3H) -one hydrochlorides of quinazoline -4 (300 mg into the 10 mL tert-butyl alcohols, 0.788 mmol) and DIEA (0.45 mL, 2.58 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (241 mg of 6- are added thereto, 1.56 mmol), 72 h are reacted in reaction under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of yellow solid 140, the % of yield 38.4.

Mass spectrum（M+H): 463.1

1H-NMR(i/₆-DMS0, 400 MHz):5 12.82 (1H, s), 8.85-8.47 (2H, m), 8.15-7.46 (4H, m), 7.39-7.26 (1H, m), 7.10-6.86 (1H, m), 6.77-6.66 (1H, m), 6.62-6.51 (1H, m), 6.46-5.94 (1H, m), 3.66-2.94 (3H, d), 2.27-1.98 (2H, m), 0.93 (3H, t)

Embodiment 20 (S) -2- " l-i9H- purine -6- bases amino) propyl group " chloro- 3- of -5- [aminomethyl phenyl) 1 quinazoline -4f3H of amino) -one (compound 22) preparation

1

W 201

77

(1) (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chlorobenzoic acids are separately added into the dry reaction bulb of the preparation of (5)-l- [the chloro- 2- of 3- (2- methyl -2- phenylhydrazinos formoxyl) phenylamino] -1- oxo butyl- 2- carbamates（1.50 g, 4.20 mmol), 20 mL DCM and 10 mL DMF, 1.47 mL (8.44 mmol) DIEA, 770 mg (6.3 mmol) 1- methyl isophthalic acids-phenylhydrazine, 2.08 g (5.47 mmol) HATU, are stirred overnight at room temperature.Rotary evaporation removes partial solvent, adds water, and ethyl acetate extraction, washing, column chromatography obtains the mg of light yellow solid 750, yield 38.8%.

(2) preparation of the chloro- 3- of (5) -2- (1- aminopropyls) -5- [methyl (phenyl) amino] quinazoline -4 (3H) -one hydrochloride

Added in reaction bulb（5) -1- [the chloro- 2- of 3- (2- methyl -2- phenylhydrazinos formoxyl) phenylamino] -1- oxo butyl- 2- carbamates (750 mg; 1.63 mmol); 10 mL ethanol, 3 mL concentrated hydrochloric acids, heating reflux reaction is stayed overnight.Room temperature is cooled to, white solid, suction filtration, ice ethanol and ether washing filter cake is separated out.Obtain the mg of white solid 450, yield 73.0%.

(3) (the preparation of -2- [1- (9 purine -6- bases amino) propyl group] the chloro- 3- of -5- [methyl (phenyl) amino] quinazoline -4 (3H) -one

The chloro- 3- of (5) -2- (1- aminopropyls) -5- [methyl (phenyl) amino] quinazoline -4 (3H)-keto hydrochloride (450 mg is separately added into dry reaction bulb, 1.19 mmol), the 15 mL tert-butyl alcohols, 2 mL DIEA, chloro- 9H- purine (308 mg of 6-, 1.99 mmol), heating reflux reaction 2 days.Solvent is spin-dried for, column chromatography obtains the mg of white solid 260, further anti-phase to prepare the less mg of isomers 100 of the retention time on HPLC, the larger isomers 120mg of retention time, total recovery 40.1% on HPLC.Two isomers are placed in the in the mixed solvent of acetonitrile water can mutual inversion of phases.

Mass spectrum (M+H): 461.2

The less isomers of retention time on HPLC：

1H-NMR( ₆-DMS0, 400 MHz):δ 12.90 (1 Η, br s), 8.20-7.99 (2H, m), 7.77-7.65 (2H, m), 7.62-7.48 (2H, m), 7.25-7.10 (2H, m), 6.92-6.70 (3H, m), 5.44 (1H, m), 3.45 (3H, s), 2.20-2.07 (1H, m), 2.07-1.90 (1H, m), 1.01 (3H, t)

The larger isomers of retention time on HPLC：

1H-NMR(i/₆-DMS0, 400 MHz):δ 12.97 (1H, br s), 8.22-8.09 (2H, m), 7.94 (1H, m), 7.74 (1H, t), 7.61 (1H, d), 7.54 (1H, d), 7.24 (2H, t), 6.87 (1H, t), 6.66 (2H, d), 5.50 (1H, m), 3.39 (3H, s), 2.02-1.87 (2H, m), 0.886 (3H, t)

The preparation of the ffl-2-il- of embodiment 21 (9iy- purine -6- bases amino) propyl group " the fluoro- 3- of -5- " methyl (phenyl) amino " quinazoline -4 (3^) -one (compound 23)

(1) the fluoro- N of 2-¹- methyl -6- nitros-N¹The preparation of-phenylbenzohydrazide

2- fluoride-6-nitrobenzoic acids (3.7 g, 20.0 mmol) are dissolved in 20 mL CH₂C1₂With 0.2 mL DMF, oxalyl chloride (3.87 g are slowly added dropwise thereto, 30.5 mmol), it is stirred at room temperature after 2 h, concentration removes solvent, 4 mL dioxane are then dissolved in, 1- methyl isophthalic acids-phenyl hydrazine (2.4 g, 19.6 mmol) NaHC0 is added dropwise under cooling₃(3.36 g, 40.0 mmol) the mL of dioxane 10 and the mL solution of water 10 in, completion of dropping, which is raised to, is stirred at room temperature half an hour, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, concentrate organic phase, silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) g of white solid 4.9, yield 84.7% are obtained.

(2) preparation of 2- amino -6- methyl fluorides-N phenylbenzohydrazides

By 2- methyl fluoride -6- nitrobenzophenones benzoyl hydrazines (4.9 g, 16.94 mmol) it is dissolved in 30 mL methanol, 0.5 g 10% Pd/C is added thereto, logical hydrogen, 36 h are reacted at room temperature, and reaction terminates, and filters out Pd/C, 4.31 g, yield 98.1% are obtained after organic phase concentration.

(3) in the dry reaction bulb of the preparation of (5) -1- [the fluoro- 2- of 3- (2- methyl -2- phenylhydrazinos formoxyl) phenylamino] -1- oxo butyl- 2- carbamates, by (5) -2- (t-butoxycarbonyl amino) butyric acid (6.08 g, 29.92 mmol), 2- amino -6- methyl fluoride-N phenylbenzohydrazides (4.31 g, 16.62 mmol), DIEA (4.5 mL, 25.8 mmol) and HATU (8.36 g, 21.99 mmol) it is added to N, in N_ dimethylformamides (30 mL), 48 h are stirred at room temperature, add water and dichloromethane, dichloromethane is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=3:1) g of white solid 3.2, yield 43.3%, are obtained.

(4) preparation of (5) -1- [5- fluorin-4-oxygens generation -3- (methyl (phenyl) amino) -3,4- dihydroquinazoline -2- bases] propylcarbamate

In dry reaction bulb; by (5)-1-[the fluoro- 2- of 3- (2- methyl-2- phenylhydrazinos formoxyl) phenylamino]-1-oxo butyl- 2- carbamates (1.31 g; 2.95 mmol) and DMAP (0.38 g; 3.11 mmol) it is added in the tert-butyl alcohol (30 mL); 64 h are stirred at room temperature; cooling, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=1:1) g of white solid 0.58, is obtained, Yield 46.1%.

(5) preparation of the fluoro- 3- of (S) -2- (l- aminopropyls) -5- (methyl (phenyl) amino) quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb, by (5) -1- [5- fluorin-4-oxygens generation -3- (methyl (phenyl) amino) -3,4- dihydroquinazoline -2- bases] propylcarbamate (0.58 g, 1.36 mmol) it is dissolved in the mL of the dichloromethane protective embankment 10 and mL of ethanol 10 mixed solution, 4 mL concentrated hydrochloric acids are instilled thereto, 2 h are stirred at room temperature, and gained solid is directly used in next step after being concentrated under reduced pressure.

(6) preparation of (S) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- [methyl (phenyl) amino] quinazoline -4 (3H) -one adds the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (methyl (phenyl) amino) (3H) -one of quinazoline -4 hydrochlorides (about 1.36 mmol^D DIEA (0.3 mL into the 20 mL tert-butyl alcohols, 1.72 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (210 mg of 6- are added thereto, 1.36 mmol), it is warming up under 85 °C and reacts 36 h, cooling, concentration, silica gel column chromatography (ethyl acetate), obtain white solid, it is further anti-phase to prepare the less isomers of 30 mg retention times on HPLC, the larger isomers of 95 mg retention times on HPLC, total recovery 20.7%.Two isomers are placed in the in the mixed solvent of acetonitrile water can mutual inversion of phases.

Mass spectrum (M+H): 445.2

On HPLC the less isomers of retention time-

'H-NMRC^-DMSO, 400 MHz):δ 12.90 (1 Η, br s), 8.20-7.90 (2H, m), 7.86-7.65 (2H, m), 7.47 (1H, m), 7.35-7.05 (3H, m), 6.95-6.60 (3H, m), 5.43 (1H, m), 3.45 (3H, s), 2.20-1.80 (2H, m), 1.02 (3H, t)

The larger isomers of retention time on HPLC：

'H-NMR^-DMSO, 400 MHz) :δ 12.98 (1H, br s), 8.22-8.10 (2H, m), 7.94 (1H, m), 7.86-7.77 (1H, m), 7.49 (1H, d), 7.32-7.20 (3H, m), 6.87 (1H, t), 6.75-6.62 (2H, m), 5.51 (1H, m), 3.40 (3H, s), 2.05-1.83 (2H, m), 0.882 (3H, t)

The iS of embodiment 22) and -2- " l- (9ff- purine -6- bases amino) the chloro- 3-K4- fluorophenyls of propyl group 1-5-) methyl) 1 quinazoline of amino

Ketone（Compound 24) preparation

(1) 0S)-l- [the chloro- 3- of 5- (4- fluoroanilinos) -4- oxos -3,4- dihydroquinazoline -2- bases] propylcarbamate the dry reaction bulb of preparation in, (5) -2- (1- aminopropyls) -5- chloro- 3- (4- fluoroanilinos) quinazolines -4 (3H keto hydrochlorides (840 mg, 2.19 mmol) it is dissolved in 20 mL dichloromethane protective embankments, it is separately added into (0.92 mL, 6.60 mmol) triethylamine, Boc₂0 (720 mg, 3.30 mmol), DMAP (20 mg, 0.16mmol), room temperature reaction is stayed overnight.Solvent is spin-dried for, column chromatography obtains the mg of white solid 800, yield 81.7%.

(2) preparation of (5) -1- [the chloro- 3- of 5- [(4- fluorophenyls) (methyl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate

By CS)-l- [the chloro- 3- of 5- (4- fluoroanilinos) -4- oxos -3,4- dihydroquinazoline -2- bases] propylcarbamate (800 mg, 1.79 mmol) it is dissolved in lO mL DMF, add potassium carbonate (371 mg, 2.68 mmol), iodine first protective embankment (381 mg, 2.68 mmol), be stirred overnight at room temperature reaction.Solvent is spin-dried for, column chromatography obtains 580 mg white solids, yield 70.4%.

(3) preparation of the chloro- 3- of (5) -2- (1- aminopropyls) -5- [(4- fluorophenyls) (methyl) amino] quinazoline -4 (3H) -one hydrochloride

By (5) -1- [the chloro- 3- of 5- [(4- fluorophenyls) (methyl) amino] -4- oxos -3,4- dihydroquinazoline -2- bases] propylcarbamate (580 mg, 1.26 mmol) it is dissolved in 15 mL dichloromethane protective embankments, lead to the dry h of HC1 gases 1 under condition of ice bath, terminate through TLC monitoring reactions.Directly solvent is spin-dried for, the mg white solids of crude product 530 are obtained.

(4) preparation of (5) -2- [l- (the fast cry of certain animals -6- bases amino of 9H-) propyl group] the chloro- 3- of -5- [(4- fluorophenyls) (methyl) amino] quinazoline -4 (3 /) -one

In dry reaction bulb, be separately added into (<S) the mg of the chloro- 3- of -2- (l- aminopropyls) -5- [(4- fluorophenyls) (methyl) amino] (3H) -one of quinazoline -4 hydrochloride, crude 530, the 15 mL tert-butyl alcohols, 3 mL DIEA, chloro- 9H- Piao Ling (300 mg of 6-, 1.94 mmol), heating reflux reaction 2 days.Solvent is spin-dried for, column chromatography obtains the mg of white solid 370, the step yield 61.3% of the above two.Mass spectrum (Μ+Η): 479.2 O-NMRC^-DMSO, 400 MHz):δ 12.94 (1H, d), 8.18-7.93 (2H, m), 7.85-7.66 (2H, m), 7.64-7.50 (2H, m), 7.11-6.95 (2H, m), 6.94-6.65 (2H, m), 5.55-5.35 (1H, m), 3.43-3.38 (3H, d)_; 2.20-1.85 (2H, m), 1.01-0.897 (3H, m).

Fast cry of certain animals -6- bases the amino of the f5 2-il-fflg- of embodiment 23) the fluoro- 3-K4- fluorophenyls of propyl group 1-5-) 1 quinazoline of (methyl) amino

- 4 (3H) -one（Compound 25) preparation

(1) preparation of the fluoro- N- of 2- (4- fluorophenyls) -6- nitrobenzoyl hydrazides

2- fluoride-6-nitrobenzoic acids (5.5 g, 29.7 mmol) are dissolved in 50 mL CH₂C1₂With 0.4 mL DMF, oxalyl chloride (5.66 g are slowly added dropwise thereto, 44.6 mmol), it is stirred at room temperature after two hours, concentration removes solvent, is then dissolved in 8 mL dioxane, is added dropwise under cooling to fluorophenyl hydrazine hydrochloride (4.829 g, 29.7 mmol), NaHC0₃The dioxane of (6.72 g, 80 mmol)（20 mL) and water（20 mL) in solution, completion of dropping, which is raised to, is stirred at room temperature half an hour, subtracts the dense Shrink of pressure to after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, organic phase is concentrated, Diethyl ether recrystallization obtains the g of light yellow product 4.4, the % of yield 50.5.

(2) preparation of the fluoro- N'- of 2- amino -6- (4- fluorophenyls) benzoyl hydrazine

By the fluoro- Λ of 2- (4- fluorophenyls) -6- nitrobenzoyl hydrazides（4.4 g, 15.0 mmol) it is dissolved in 60 mL methanol, 0.5 g l0 % Pd/C is added thereto, leads to hydrogen, 36 h is reacted at room temperature, reaction terminates, and filters out Pd/C, 3.8 g, the % of yield 96.2 are obtained after organic phase concentration.

(3) preparation of (5) -1- [the fluoro- 2- of 3- [2- (4- fluorophenyls) hydrazine carbonyl] phenylamino] -1- oxo butyl- 2- carbamates In dry reaction bulb, by (S) -2- (t-butoxycarbonyl amino) butyric acid (5.8 g, 28.6 mmol), 2- amino -6- fluorine _ ' _ (4- fluorophenyls) benzoyl hydrazine (3.8 g, 14.4 mmol), DIEA (3.7 mL, 21.2 mmol) and HATU (6.0 g, 15.8 mmol) it is added in 200 mL dichloromethane protective embankments, 48 h are stirred at room temperature, add water and dichloromethane, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, the g of white solid 3.4 is obtained after being concentrated under reduced pressure with preparation chromatographic isolation, the % of yield 52.6.

(4) (5) -1- [the fluoro- 3- of 5- (4- fluoroanilinos) -4- oxos -3,4- dihydroquinazoline -2- bases] propylcarbamate preparation by (5) -1- [the fluoro- 2- of 3- [2- (4- fluorophenyls) hydrazine carbonyl] phenylamino] -1- oxo butyl- 2- carbamates (1.8 g

4.01 mmol) it is dissolved in the 60 mL tert-butyl alcohols, DMAP (0.54 g, 4.42 mmol) is added into reaction bulb, backflow is stayed overnight, and 1.1 g white solids, the % of yield 63.7 are concentrated under reduced pressure to give after cooling.

(5) preparation of (5) -1- [the fluoro- 3- of 5- [(4- fluorophenyls) (methyl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate

In dry reaction bulb,（5>1- [the fluoro- 3- of 5- (4- fluoroanilinos) -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate（1.1 g, 2.56 mmol) 20 mL dry DMFs are dissolved in, add CH₃I (U6 g, 8.17 mmol), K₂CO₃(0.70 g, 5.06 mmol), are stirred at room temperature 72 h.Reaction solution is poured into 100 mL frozen water, ethyl acetate is extracted three times, merge and dried after organic phase, saturated common salt water washing three times, 980 mg white solids, the % of yield 86.1 are obtained after vacuum distillation.

(6) in the dry reaction bulb of the preparation of the fluoro- 3- of (- G- aminopropyls) -5- [(4- fluorophenyls) (methyl) amino] quinazoline -4 (3H) -one hydrochloride, by (5) -1- [the fluoro- 3- of 5- [(4- fluorophenyls) (methyl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate（980 mg, 2.20 mmol) it is dissolved in absolute ethyl alcohol（30 mL) in, hydrogen chloride gas is led into system until reaction is complete, 800 mg solids are obtained after revolving（Hydrochloride）, the % of yield 95.5.

(7) preparation of (S) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- [(4- fluorophenyls) (methyl) amino] quinazoline -4 (3 /) -one

In dry reaction bulb, (5) -2- (1- aminopropyls) -5- fluoro- 3- [(4- fluorophenyls) (methyl) amino] (3H) -one hydrochlorides of quinazoline -4 (623 mg are added into the 30 mL tert-butyl alcohols, 1.64 mmol) and DIEA (0.71 mL, 4.07 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (378 mg of 6- are added thereto, 2.45 mmol), reaction reacts 24 under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of white solid 209, the % of yield 27.6.

Mass spectrum（Μ+Η): 463.2

1H-NMR(i/(j-DMS0, 400 ΜΗζ):δ 12.88 (1 Η, br s), 8.19-8.03 (2H, m), 7.85-7.73 (2H, m), 7.51-7.40 (1H, m), 7.32-7.23 (1H, m), 7.11-6.94 (2H, m), 6.92-6.67 (2H, m), 5.45 (1H, m), 3.43 (3H, s), 2.18-1.84 (2H, m), 1.04 (3H, t) (S-2- " l- (9-fast cry of certain animals-6- bases amino) propyl group "-3- " cyclopropyl (4- fluorophenyls) the amino "-S- Fluquinconazole quinolines of embodiment 24

(1) preparation of N- (l- ethoxies cyclopropyl) -4- fluoroanilines

In dry reaction bulb, para-fluoroaniline（11.1 g, 100 mmol) it is dissolved in 250 mL methanol, and it is some to add dry 4A molecular sieves, then adds 50 mL glacial acetic acids and the silyloxy cyclopropane of 1- ethyoxyls -1- three（22.6 g, 130 mmol), it is stirred at room temperature until raw material disappears.

(2) preparation of N- cyclopropyl -4- fluoroanilines

Sodium borohydride is added in batches in step reaction solution upwards（28 g, 740 mmol), in N after finishing₂Night is flowed through in protection next time, cools down, and filtering adds 200 mL frozen water after vacuum distillation, adjusts pH to EA after neutrality to extract three times, is washed after merging organic phase with 2NNaOH solution, dries, be concentrated under reduced pressure to give 6.8 g products, the % of two step yield 45.0.

(3) preparation of N- cyclopropyl -4- fluorine nitrosoanilines

In dry reaction bulb, under ice bath, by N- cyclopropyl -4- fluoroanilines（6.4 g, 42.3 mmol) 35 mL glacial acetic acids are dissolved in, then it is added dropwise into solution dissolved with natrium nitrosum（3.8 g, 55.1 mmol) the 40 mL aqueous solution, and keeping temperature be no more than 20 V, react 2 h.Ice bath is lowered pH to EA after neutrality and extracted three times, is concentrated under reduced pressure after merging organic phase, column chromatography（PE:EA=5:1) g of white solid 4.2, the % of yield 55.1 are obtained.

(4) preparation of 1- cyclopropyl -1- (4- fluorophenyls) hydrazine

In dry reaction bulb, to Lithium Aluminium Hydride under ice bath（L M, 22.5 mL) in be added dropwise dissolved with N- cyclopropyl -4- fluorine Nitrosoaniline (4.0 g, 22.2 mmol) 20 mL THF solutions, and be stirred vigorously, 30 mL ethyl acetate are added dropwise after reaction completely and are quenched, after half an hour, 40 % NaOH solutions stirring half an hour is added dropwise again, organic phase is separated, aqueous phase is washed twice with ethyl acetate again, merge and dried after organic phase, it is concentrated under reduced pressure to give the g of solid 2.6, the % of yield 70.5.

(5) preparation of the fluoro- N- of N- cyclopropyl -2- (4- fluorophenyls) -6- nitrobenzoyl hydrazides

2- fluoride-6-nitrobenzoic acids (2.8 g, 15.1 mmol) are dissolved in 30 mL CH₂Cl₂With 0.4 mL DMF, oxalyl chloride (2.8 g are slowly added dropwise thereto, 22.1 mmol), it is stirred at room temperature after two hours, concentration removes solvent, it is then dissolved in 8 mL dioxane, 1- cyclopropyl -1- (4- fluorophenyls) hydrazines (2.5 g are added dropwise under cooling, 15.0 mmol) 15 mL dioxane solutions in, completion of dropping, which is raised to, is stirred at room temperature half an hour, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate is extracted, anhydrous sodium sulfate drying, suction filtration, concentration organic phase obtains the g of light yellow product 2.4, the % of yield 48.0.

(6) the fluoro- Λ 4- fluorophenyls of 2- amino cyclopropyl -6-) benzoyl hydrazine preparation

By N- cyclopropyl -2- fluoro- N- (4- fluorophenyls) -6- nitrobenzoyl hydrazides（2.4 g, 7.2 mmol) it is dissolved in 50 mL methanol, the % of 0.3 g 10 Pd/C is added thereto, leads to hydrogen, 12 h is reacted at room temperature, reaction terminates, and filters out Pd C, 2.0 g, the % of yield 91.6 are obtained after organic phase concentration.

(7) preparation of (5) -1- [2- [2- cyclopropyl -2- (4- fluorophenyls) hydrazine carbonyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates

In dry reaction bulb, by (5) -2- (t-butoxycarbonyl amino) butyric acid (1.48_& 7.3 11^₀1), the fluoro- iV- of 2- amino cyclopropyl -6- (4- fluorophenyls) benzoyl hydrazine (2.0 g, 6.6 mmol), DIEA (1.3 mL, 7.5 mmol) and HATU (2.77_&7.3 11^101) it is added in 50 11^ 01^^, 48 h are stirred at room temperature, add water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, and merges organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, obtains the g of white solid 1.8, the % of yield 55.8 with preparation chromatographic isolation after being concentrated under reduced pressure.

(8) preparation of (5)-1-[3- [cyclopropyl (4- fluorophenyls) amino]-5- fluorin-4-oxygens generation-3,4- dihydroquinazoline-2- bases] propylcarbamates

By (5) small [2- [2- cyclopropyl -2- (4- fluorophenyls) hydrazine carbonyl] -3- fluoroanilinos] -1- oxo butyl- 2- carbamates (1.8 g, 3.68 mmol) it is dissolved in the 60 mL tert-butyl alcohols, DMAP (0.54 g are added into reaction bulb, 4.42 mmol), backflow is stayed overnight, vacuum distillation obtains 1.1 g white solids, the % of yield 63.5 after cooling.

(9) in the dry reaction bulb of the preparation of (5) -2- (1- aminopropyls) -3- [cyclopropyl (4- fluorophenyls) amino] -5- Fluquinconazoles quinoline -4 (3H) -one hydrochloride,（5)-1-[3- [cyclopropyl (4- fluorophenyls) amino]-5- fluorin-4-oxygens generation-3,4- dihydroquinazoline-2- bases] propylcarbamate (1.1 g, 2.34 mmol) it is dissolved in 30 mL absolute ethyl alcohols, lead to hydrogen chloride gas into system until reaction is complete, 700 mg solids are obtained after revolving（Hydrochloride）, the % of yield 73.5.

(10) (5) -2- [l- (9H- purine -6- bases amino) propyl group] -3- [cyclopropyl (4- fluorophenyls) amino] -5- Fluquinconazoles quinoline -4 (3H) -one Prepare

In dry reaction bulb, (3H) -one hydrochloride (665 mg of (5) -2- (1- aminopropyls) -3- [cyclopropyl (4- fluorophenyls) amino] -5- Fluquinconazoles quinoline -4 are added into the 30 mL tert-butyl alcohols, 1.63 mmol) with DIEA (0.71 mL, 4.08 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (378 mg of 6- are added thereto, 2.45 mmol), 24 h are reacted in reaction under 85 ' C, cooling, concentration, prepares chromatographic isolation and obtains the mg of white solid 135, the % of yield 17.0.

Mass spectrum（M+H): 489.2

1H-NMR( ₆-DMS0, 400 MHz):δ 12.66 (1 Η, s), 8.07-7.83 (3H, m), 7.63 (2H, t), 7.34 (1H, dd), 6.70-6.45 (4H, m), 5.67-5.56 (1H, m), 3.29-3.22 (1H, m), 2.26-2.12 (1H, m), 2.01-1.83 (1H, m), 1.46-1.35 (1H, s), 1.13-1.01 (1H, s), 0.97 (3H, t), 0.80-0.57 (2H, m)

Embodiment 25 (S) -2- " l-f9#- purine -6- bases amino) -4 (3^ -one of propyl group 1-3- (diphenyl amino) -5- Fluquinconazoles quinoline（Compound 27) preparation

(1) (S)-l- (5- fluorin-4-oxygens generation -4H- benzos [rf] [l, 3] oxazine -2- bases) propylcarbamate preparation

2- amino -6- fluobenzoic acids (1.00 g are added in 100 dry mL reaction bulbs, 6.45 mmol), (5) -2- (t-butoxycarbonyl amino) butyric acid (1.571 g, 7.73 mmol), then 8.0 mL pyridines are added, triphenyl phosphite (2.00 g, 6.45 mmol) is eventually adding, is stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(2) CS-l- [3- (diphenyl amino) -5- fluorin-4-oxygens generations -3,4- dihydroquinazoline -2- bases] propylcarbamate preparation prepare (S)-l- (5- fluorin-4-oxygens generation -4H- benzos [d] [l, 3] oxazine -2- bases) propylcarbamate reaction solution in be directly added into hydrazo-benzene（1.305 g, 7.08 mmol), return stirring reacts 8 hours in 100 °C of oil bath, then cools down, is concentrated under reduced pressure, passes through column chromatography（PE:EA=6:1) purifying obtains the g of faint yellow solid 2.00, and two step yields are 63.5 %. (3) preparation of (the 3H) _ ketone trifluoroacetate of (S) -2- (l- aminopropyls) -3- (diphenyl amino) -5- Fluquinconazoles quinoline -4 adds (5) -1- [3- (diphenyl amino) -5- fluorin-4-oxygens generations -3 in dry lOO mL reaction bulbs, 4- dihydroquinazoline -2- bases] propylcarbamate (1.00 g, 2.05 mmol), dissolved with 20 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 10 is added dropwise under conditions of ice bath, completion of dropping, then take and continue to stir in room temperature, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(4) preparation of (3/) -one of (5) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (diphenyl amino) -5- Fluquinconazoles quinoline -4

The product obtained by previous step is dissolved with the 40 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, adjusts pH to alkalescence system with DIEA, then adds the chloro- 9H- purine of 6-（0.380 g, 2.46 mmol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares liquid phase purifying and obtains the g of white solid 0.300, the % of two step yield 28.9.

Mass spectrum（M+H): 507.2

'H-NMRC^-DMSO, 400 MHz):δ 12.95 (1 Η, s), 8.17-8.04 (2H, m), 7.92-7.77 (2H, m), 7.53-7.42 (1H, m), 7.41-7.10 (11H, m), 5.65 (1H, m), 2.02-1.40 (2H, m), 0.74 (3H, t)

The Cy of embodiment 26) -4 (3H) -one of -2- " l- (9 y- purine -6- bases amino) propyl group " -3- (Cyclohexylamino) -5- Fluquinconazoles quinoline（Change

(1) preparation of 2- fluoride-6-nitrobenzoic acids methyl esters

2- fluoride-6-nitrobenzoic acids (12.03 g, 65.0 mmol) are dissolved in 50 mL CH₂C1₂With 0.3 mL DMF, oxalyl chloride (12.35 g are slowly added dropwise thereto, 97.3 mmol), , Nong Shrink after two hours are stirred at room temperature and remove solvent, it is then dissolved in 8 mL dioxane, slowly it is added drop-wise in the lOO mL absolute methanols under ice bath, reaction is gone to after completion of dropping and reacted two hours at room temperature, is concentrated under reduced pressure, obtain the g of white solid 12.70, the % of yield 98.1. (2) preparation of 2- amino -6- fluorophenyl carbamates

2- fluoride-6-nitrobenzoic acids methyl esters (12.70 g, 63.8 mmol) is dissolved in 30 mL methanol, 10 % Pd/C (65 mg) is added, react 8 hours under an atmosphere of hydrogen, Pd/C is filtered out, 10.60 g white solids, yield 98.2 are concentrated to give

%。

(3) preparation of (5) -2- [2- (t-butoxycarbonyl amino) amide-based small] -6- fluorophenyl carbamates

In dry reaction bulb, by the 2- amino -6- fluorophenyl carbamates (wares 11 of 8.46 ＆ 50₀1)、 （5) -2- (t-butoxycarbonyl amino) butyric acid (12.19 g, 60 mmol), DIEA (10.2 mL, 58.6 mmol) and HATU (24.72 g, 65 mmol) be added in lOO mLNN- dimethylformamides, 64 h are stirred at room temperature, water and dichloromethane protective embankment are added, the extraction of dichloromethane protective embankment merges organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography after being concentrated under reduced pressure（Petroleum ether:Ethyl acetate=3:1) g of white solid 12.14, the % of yield 68.5, are obtained.

(4) (5) -2-t2- (t-butoxycarbonyl amino) butyrylamino] -6- fluobenzoic acids preparation

By (5) -2- [2- (t-butoxycarbonyl amino) amide-based small] -6- fluorophenyl carbamates (12.14 g, 34.3 mmol) it is dissolved in 100 mL tetrahydrofurans, the 50 mL aqueous solution dissolved with a hydronium(ion) lithia (4.31 g, 103 mmol) are added under ice bath.4 h are reacted at room temperature, are completed through TLC monitoring reactions.Added water into system, watery hydrochloric acid regulation pH-3-4 separates out solid, filtered, dries, obtain the g of white solid 10.22, the % of yield 87.5.

(5) preparation of (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) propylcarbamate

By (5) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- fluobenzoic acids (3.4 g, 10 mmol) and acetic anhydride (4.1 g, 40.2 mmol) it is dissolved in the 100 mL tert-butyl alcohols, reacted 8 hours under 100 °C, cooling, it is concentrated under reduced pressure to give the g of white solid 2.94, the % of yield 91.2.

(6) CS)-l- [3- (Cyclohexylamino) -5- fluorin-4-oxygens generations -3,4- dihydroquinazoline -2- bases] propylcarbamate preparation by (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [] [l, 3] oxazine -2- bases) propylcarbamate (806 mg, 2.50 mmol) and cyclohexyl hydrazine hydrochloride (452 mg, 3.0 mmol) it is dissolved in 30 mL pyridines, stirred 8 hours at 100 °C, cooling, it is concentrated under reduced pressure, gained residue is through column chromatography（PE:EA=1:1) mg of faint yellow solid 609, the % of yield 58.2 are obtained.

(7) preparation of (3H) the -one trifluoroacetate of (5) -2- (1- aminopropyls) -3- (Cyclohexylamino) -5- Fluquinconazoles quinoline -4

By (5) -1- [3- (Cyclohexylamino) -5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases] propylcarbamate（609 mg, 1.46 mmol) it is dissolved in dichloromethane protective embankment（20 mL) trifluoroacetic acid is slowly added dropwise under ice bath（6 mL), drop finishes, and reaction is transferred to and stirred two hours at room temperature, and TLC monitoring reactions are finished, and the gained crude solid that is concentrated under reduced pressure is directly used in next step.

(8) CS) -4 (3H of -2- [l- (the fast cry of certain animals -6- bases amino of 9H-) propyl group] -3- (Cyclohexylamino) -5- Fluquinconazoles quinoline>The preparation of ketone is by (3H) -one trifluoroacetate of solid (5) -2- (1- aminopropyls) -3- (Cyclohexylamino) -5- Fluquinconazoles quinoline -4 obtained by upper step (about 1.46 mmol) is dissolved in the 20 mL tert-butyl alcohols, add DIEA (0.76 mL, 4.36 mmol), stirred half an hour under ice bath, the chloro- 9H- purine of 6- (271 mg, 1.75 mmol) is then added thereto, 36 h are reacted in reaction under 85 °C, cooling, concentration, silica gel column chromatography（The % volumes of ethyl acetate 100）, obtain the mg of white solid 135, the % of two step yield 21.2.Mass spectrum（M+H): 437.2

lH-NMR(flf₆-DMSO, 400 MHz):δ 12.85 (IH, br s), 8.22-8.13 (2H, m), 7.82-7.69 (IH, m), 7.52-7.35 (2H, m), 7.26 (IH, t), 6.26 (IH, s), 5.98 (IH, m), 2.15-1.98 (1H, m), 1.92-1.48 (6H, m), 1.35-1.05 (6H, m), 0.945 (3H, m)

Embodiment 27 (S)-2- " l-i9ff- purine-6- bases amino) ethyl 1-3- (phenylamino) (3 -one of quinazoline-4（Compound 29)

(1) preparation of 2- aminobenzoic acids

2- benzocaines are added in dry reaction bulb（1.652 g, lO mmol), lithium hydroxide monohydrate（1.68 g, 40 mmol), 30 mL methanol are added, at room temperature the h of stirring reaction 3, TLC shows that reaction is finished, stop reaction, be spin-dried for, add water, ethyl acetate extraction, anhydrous sodium sulfate drying, is concentrated to dryness, and obtains the g of white powdery solids 1.31, and yield is 95.6 %.

(2) preparation of (5) small (4- oxo -4H- benzos [1,3] oxazine -2- bases) ethylcarbamate

In dry stand up reaction bottle, 2- aminobenzoic acids are added（1.00 g, 7.29 mmol), (<S) -2- t-butoxycarbonyl aminos propionic acid（1.52 g, 8.03 mmol) and triphenyl phosphite（2.492 g, 8.03 mmol), add 10 mL pyridines and do and react 12 h under solvent, 55 °C, without processing, directly carry out next step reaction.

(3) CS)-l- [4- oxos -3- (phenylamino) -3,4- dihydroquinazoline -2- bases] ethylcarbamate preparation

In the reaction system of previous step, phenylhydrazine is directly added into（0.868 g, 8.03 mmol), 100 °C of 10 h of reaction are warming up to, silica gel mixed sample, column chromatography are directly added into after cooling（Petroleum ether:Ethyl acetate=6:1) g of white solid 1.256 is obtained, two step yields are 45.3 %. (4) preparation of (S) -2- (l- amino-ethyls) -3- (phenylamino) quinazoline -4 (3H) -one trifluoroacetate

In dry reaction bulb, (5) small [4- oxos -3- (phenylamino) -3,4- dihydroquinazoline -2- bases] ethylcarbamate is added（0.761 g, 2.0 mmol), dichloromethane protective embankment 5 mL, the mL of trifluoracetic acid 5 are added, 3 h are stirred at room temperature, stops rotation after reaction and removes solvent, the g of white solid 0.758 is obtained, yield is 96.1 %.

(5) preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] -3- (phenylamino) quinazoline -4 (3H) _ ketone

(5) -2- (1- amino-ethyls) -3- (phenylamino) (3H) -one of quinazoline -4 trifluoroacetates (0.758 g, 1.92 mmol), the chloro- 9H- purine of 6- are added in dry reaction bulb（0.326 g, 2.11 mmol), the 10 mL tert-butyl alcohols are added, DIEA (1.82 mL, 10.5 mmol) reacts 12 h under 90 °C, is directly spin-dried for mixing sample, prepare liquid phase and purify to obtain the g of white solid 0.258, yield is 33.7 %.

Mass spectrum（M+H): 399.2

1H-NMR( ₆-DMS0, 400 MHz):δ 12.99 (IH, s), 9.12 (IH, s), 8.22-8.03 (3H, m), 7.91-7.74 (2H, m), 7.61 (1H, d), 7.50 (1H, t), 7.30-7.15 (2H, m), 6.98 (2H, d), 6.85 (1H, t), 5.52 (1H, m), 1.66 (3H, d)

The iS of embodiment 28)-2- " l- (9-purine-6- bases amino) ethyl 1-5- chloro- 3- (phenylamino) (3H) -one of quinazoline-4 compound 30) preparation

(1) preparation of (5) -1- (the chloro- 4- oxos -4H- benzos of 5- [[1,3] oxazine -2- bases) ethylcarbamate

In dry reaction bulb, it is separately added into 2- amino -6- chlorobenzoic acids (857 mg, 4.99 mmol), (5) -2- (t-butoxycarbonyl amino) propionic acid (1.13 g, 5.97 mmol), 5 mL pyridines, triphenyl phosphite (1.86 g, 5.99 mmol), 55 reactions are stayed overnight.Terminate through LC-MS monitoring reactions, be directly used in the next step.

(2) CS)-l- [the chloro- 4- oxos -3- (phenylamino) of 5- -3,4- dihydroquinazoline -2- bases] ethylcarbamate preparation

Hydrazinobenzene hydrochloride salt (867 mg, 6.0 mmol) is added in step reaction system upwards, it is small that temperature is risen into 100 °C of reactions 8 When.Solvent is spin-dried for, column chromatography（Petroleum ether:Ethyl acetate=5:1) g of white solid 2.0, the step yield 96.6% of the above two are obtained

(3) preparation of (5) -2- (1- amino-ethyls) -5- chloro- 3- (phenylamino) quinazoline -4 (3H) -one trifluoroacetate

In dry reaction bulb, by 0-1- [the chloro- 4- oxos-3- (phenylamino)-3 of 5-, 4- dihydroquinazoline-2- bases] ethylcarbamate (880 mg, 2.12 mmol) it is dissolved in the mixed solution of 6 mL dichloromethanes protective embankments and 3 mL trifluoroacetic acids, l h are stirred under ice bath, are terminated through TLC monitoring reactions.Solvent is spin-dried for, products therefrom is directly used in the next step.

(4) (>S) the preparation of -2- [l- (9H- purine -6- bases amino) ethyl] -5- chloro- 3- (phenylamino) quinazoline -4 (3H) _ ketone

(S) -2- (l- amino-ethyls) -5- chloro- 3- (phenylamino) quinazoline -4 (3) -one trifluoroacetates (about 2.12 mmol) that upper step is obtained are dissolved in the 15 mL tert-butyl alcohols, add DIEA (2 mL, 11.5 mmol), chloro- 9H- purine (395 mg of 6-, 2.55 mmol), heating reflux reaction two days.It is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=1:2-1 :4) mg of white solid 356, the step yield 38.8% of the above two are obtained.

Mass spectrum (M+H): 433.2

1H-NMR( ₆-DMS0, 400 MHz):(the 1H of δ 12.98, s), 9.01 (1 Η, s), 8.25-8.07 (2 Η, m), 7.90-7.60 (2H, m), 7.57-7.48 (2H, m), 7.25 (2H, t), 7.03 (2H, d), 6.86 (1H, t), 5.48 (1H, 1.65 m), (3H, d) embodiments 29 (S) -2- " l-i9 purine -6- bases amino) ethyl 1-5- fluoro- 3- (phenylamino) quinazoline -4 (3H) -one（Compound

(1) preparation of the fluoro- N- phenylbenzohydrazides of 2- amino -6-

By the fluoro- 6- nitrobenzophenones benzoyl hydrazines of 2-（1.38 g, 5.01 mmol) it is dissolved in 20 mL methanol, 0.3 g lO % Pd/C is added thereto, leads to hydrogen, 24 h is reacted at room temperature, reaction terminates, and filters out Pd/C, 1.20 g, the % of yield 97.7 are obtained after organic phase concentration.

(2) preparation of (5) -1- [the fluoro- 2- of 3- (2- phenylhydrazines carbonyl) phenylamino] -1- oxo propyl- 2- carbamates In dry reaction bulb, by (5) -2- (t-butoxycarbonyl amino) propionic acid (1.11 g, 5.87 mmol), fluoro- N- phenylbenzohydrazides (1.20 g of 2- amino -6-, 4.89 mmol), DIEA (1.3 mL, 7.47 mmol) and HATU (2.23 g, 5.86 mmol) it is added in 40 mL dichloromethane, 48 h are stirred at room temperature, water and dichloromethane protective embankment is added, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography after being concentrated under reduced pressure（Petroleum ether：Ethyl acetate=3:1) g of white solid 1.55, the % of yield 76.1, are obtained.

(3) preparation of (5) -2- (1- amino-ethyls) -5- fluoro- 3- (phenylamino) quinazoline -4 (3H) -one hydrochloride

By (5) -1- [the fluoro- 2- of 3- (2- phenylhydrazines carbonyl) phenylamino] -1- oxo propyl- 2- carbamates (1.55 g, 3.72 mmol) it is dissolved in 30 mL ethanol, 3 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath, stir after half an hour, reaction is moved into oil bath and reacts 16 h under 85 ' C, concentrated after cooling, obtain white solid and be directly used in next step.

(4) (5>The preparation of 2- [l- (9H- purine -6- bases amino) ethyl] -5- fluoro- 3- (phenylamino) quinazoline -4 (3H) -one

Obtained (5) -2- (1- amino-ethyls) -5- fluoro- 3- (phenylamino) quinazoline -4 (3H)-keto hydrochloride (about 3.72 01) and 01 ￡ eight (1.95 ^^, 11.2 is walked on being added into the 20 mL tert-butyl alcohols!1111101), stirred half an hour under ice bath, the chloro- 9H- of 6- crash purines (575 mg, 3.72 mmol) are then added thereto, 24 h are reacted in reaction under 85 °C, cool down, concentration, column chromatography

(ethyl acetate）, obtain the mg of white solid 612, the % of two step yield 39.5.

Mass spectrum（Μ+Η): 417.2

1H-NMR ( ₆-DMSO, 400 ΜΗζ):δ 12.98 (1H, s), 9.03 (1 Η, s), 8.25-8.06 (2 Η, m), 7.91-7.69 (2H, m), 7.54-7.15 (4H, m), 7.07-6.68 (3H, m), 5.51 (1H, m), 1.65 (3H, d)

Embodiment 30 (S) -2- " l- (9H ~ purine -6- bases amino) ethyl 1-3- (phenylamino) -5- (trifluoromethyl) quinazolinones

(1) (5) -1- [4- oxos -5- (trifluoromethyl) -4H- benzos [[1,3] oxazine -2- bases] ethylcarbamate the dry reaction bulb of preparation in, by 2- amino -6- (trifluoromethyl) benzoic acid (1.5 g, 7.31 mmol) it is dissolved in 50 mL pyridines, successively add (5) -2- (t-butoxycarbonyl amino) propionic acid (1.6 g, 8.46 mmol), triphenyl phosphite (2.3 g⁷. Mmol) after reacting 24 h under 60 °C, until raw material disappears.

(2) preparation of (5) -1- [4- oxos -3- (phenylamino) -5- (trifluoromethyl) -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Phenylhydrazine (0.95 g, 8.78 mmol) is added into above-mentioned reaction solution, and is warming up to 100 °C of 8 h of reaction, until raw material disappears.Organic solvent and column chromatography are spun off after cooling（PE:EA=6:1) g of faint yellow solid 1.5, the % of yield 45.8 are obtained.

(3) preparation of (5) -2- (1- amino-ethyls) -3- (phenylamino) -5- (trifluoromethyl) quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb, by (5) -1- [4- oxos -3- (phenylamino) -5- (trifluoromethyl) -3,4- dihydroquinazoline -2- bases] ethylcarbamate（1.5 g, 3.34 mmol) it is dissolved in 30 mL absolute ethyl alcohols, hydrogen chloride gas is led into system until reaction is complete, 1.2 g solids are obtained after revolving（Hydrochloride）, the % of yield 93.4.

(4) (5) -2-n- (9H- purine -6- bases amino) ethyl] -3- (phenylamino) -5- (trifluoromethyl) quinazoline -4 (3H) -one the dry reaction bulb of preparation in, (3H) -one hydrochloride (1.0 g of (5) -2- (1- amino-ethyls) -3- (phenylamino) -5- (trifluoromethyl) quinazoline 4 are added into the 30 mL tert-butyl alcohols, 2.60 mmol) and DffiA (2.0 mL, 11.5 mmol), chloro- 9H- purine (700 mg of 6-, 4.53 mmol), 24 h are reacted in reaction under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of white solid 610, the % of yield 50.3.

Mass spectrum（M+H): 467.2

1H-NMR( ₆-DMS0, 400 MHz):δ 12.99 (IH, s), 9.16 (IH, s), 8.16 (IH, d), 8.13 (1H, s), 8.01-7.84 (4H, m), 7.26 (2H, t), 7.03 (2H, d), 6.87 (IH, t), 5.49 (IH, m), 1.67 (3H, d)

Embodiment 31 (S) -2-【W9#- purine -6- bases amino) 3/ Π -one of the chloro- 3- of ethyl 1-5- (4- fluoroanilinos) quinazoline -4（Change

(1) preparation of (5) -1- (the chloro- 4- oxos -4H- benzos of 5- [[1,3] oxazine -2- bases) ethylcarbamate In dry reaction bulb, it is separately added into 2- amino -6- chlorobenzoic acids (857 mg, 4.99 mmol), (S) -2- (t-butoxycarbonyl amino) propionic acid (1.13 g, 5.97 mmol), 5 mL Jie are than pyridine, triphenyl phosphite (1.86 g, 5.99 mmol), 55 °C of reactions are stayed overnight.Terminate through LC-MS monitoring reactions, be directly used in the next step.

(2) (5) small [the chloro- 3- of 5- (4- fluoroanilinos) -4- oxos -3,4- dihydroquinazoline -2- bases] preparation of ethylcarbamate adds in upper step reaction system to fluorophenyl hydrazine hydrochloride (975 mg, 6.0 mmol), temperature is risen into 100 °C of 8 h of reaction.Solvent is spin-dried for, column chromatography（Petroleum ether：Ethyl acetate=5:1) g of white solid 1.92, the % of two step yield of the above 89.0 are obtained.

(3) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (4- fluoroanilinos) quinazoline -4 (3H) -one trifluoroacetate

In dry reaction bulb, by (5) -1- [the chloro- 3- of 5- (4- fluoroanilinos) -4- oxos -3,4- dihydroquinazoline -2- bases] ethylcarbamate (800 mg, 1.85 mmol) it is dissolved in the mixed solution of 6 mL dichloromethane and 3 mL trifluoroacetic acids, l h are stirred under ice bath, are terminated through TLC monitoring reactions.Solvent is spin-dried for, products therefrom is directly used in the next step.

(4) preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one

Upper step product (5) -2- (1- amino-ethyls) -5- chloro- 3- (4- fluoroanilinos) (3H) -one of quinazoline -4 trifluoroacetates (about 1.85 mmol) are dissolved in the 15 mL tert-butyl alcohols, add DIEA (2 mL, 11.5 mmol), chloro- 9H- purine (344 mg of 6-, 2.23 mmol), heating reflux reaction two days.Solvent is spin-dried for, column chromatography for separation obtains the mg of white solid 390, the step yield 46.8% of the above two.

Positive HPLC, Daicel chiral analysis post（OD-H, 5.0 μ ι η, 150X4.6 mm), mobile phase：N-hexane:Ethanol=90:(ethanol dissolves by 10, the mL/min of flow velocity 1.0, the V of column temperature 35, the ran of Detection wavelength 270, the mg/mL of sample introduction concentration 0.5）, sampling volume：Ι Ο μ, it is 73.9 to determine chiral purity:26.1 ( S:R).

Mass spectrum (M+H): 451.2

1H-NMR( ₆-DMSO, 400 MHz):(the 1H of δ 12.97, s), 8.99 (1 Η, s), 8.30-8.09 (2H, m), 8.00-7.89 (1H, m), 7.77-7.60 (2H, m), 7.57-7.46 (2H, m), 7.16-7.00 (3H, m), 5.48 (1H, 1.65 m), (3H, d) embodiments 32 (S)-2- " l-i9-purine-6- bases amino) ethyl " the fluoro- 3- of-5- (4- fluoroanilinos) quinazoline-4f3ff) -one（Compound 34) preparation

(1) preparation of the fluoro- N'- of 2- (4- fluorophenyls) -6- nitrobenzoyl hydrazides

2- fluoride-6-nitrobenzoic acids (19.9 g, 107 mmol) are dissolved in 150 mL CH₂Cl₂With 2 mL D F, oxalyl chloride (14.1 mL are slowly added dropwise thereto, 161 mrnol), it is stirred at room temperature after 2 h, concentration removes solvent, 15 mL dioxane are then dissolved in, are added dropwise under cooling to fluorophenyl hydrazine hydrochloride (17.5 g, 107 mmol) NaHC0₃(6.72 g, 80.0 mmol) the mL of dioxane 20 and the mL solution of water 20 in, completion of dropping, which is raised to, is stirred at room temperature 0.5 h, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, organic phase is concentrated, Diethyl ether recrystallization obtains the g of light yellow product 16.6, the % of yield 52.6.

(2) preparation of the fluoro- N'- of 2- amino -6- (4- fluorophenyls) benzoyl hydrazine

By the fluoro- N'- of 2- (4- fluorophenyls) -6- nitrobenzoyls hydrazides (4.4 g, 15.0 mmol) it is dissolved in 60 mL methanol, 0.5 g 10% Pd/C is added thereto, logical hydrogen, 36 h are reacted at room temperature, reaction terminates, and filters out Pd/C, and organic phase concentration gained solid is directly used in next step reaction.

(3) CS)-l- [the fluoro- 2- of 3- [2- (4- fluorobenzene) hydrazine formoxyl] phenylamino] -1- oxo propyl- 2- carbamates preparation

In dry reaction bulb, the 2- amino fluoro- N of -6- that upper step is obtained,-(4- fluorophenyls) benzoyl hydrazine crude product（About 15.0 mmol) (5) -2- (t-butoxycarbonyl amino) propionic acid (4.25 g, 22.5 imnol), DIEA (3.39 mL, 19.5 mmol) and HATU (6.84 g, 18.0 mmol) it is added in 200 mL dichloromethane protective embankments, 48 h are stirred at room temperature, add water and dichloromethane protective embankment, dichloromethane institute extracts, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, organic layer anhydrous sodium sulfate drying after being concentrated under reduced pressure, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=2:1) g of white solid 3.9, two step total recoverys 59.8%, are obtained.

(4) preparation of the fluoro- 3- of (5) -2- (1- amino-ethyls) -5- (4- fluoroanilinos) quinazoline -4 (3H) -one hydrochloride

By 0-1- [the fluoro- 2- of 3- [2- (4- fluorobenzene) hydrazine formoxyl] phenylamino]-1- oxo butyl- 2- carbamates (3.4 g; 7.8 mmol) it is dissolved in 50 mL ethanol; 5 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath; stir after half an hour; reaction is moved into oil bath and reacts 24 h under 85 °C; concentrated after cooling, obtain the g of white solid 2.56, yield 93.6%. (⁵) preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] the fluoro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one adds (5) -2- (1- aminopropyls) -5- fluoro- 3- (4- fluoroanilinos) (3H) the -one hydrochloride of quinazoline -4 (1.05 g into the 40 mL tert-butyl alcohols, 3.0 mmol) and DIEA (1.56 mL, 9.0 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (556 mg of 6- are added thereto, 3.6 mmol), it is warming up under 85 °C and reacts 36 h, cooling, concentration, silica gel column chromatography (ethyl acetate), obtain the mg of white solid 282, yield 21.6%.

Mass spectrum (Μ+Η): 435.2

'H-NMR(i/₆-DMSO, 400 MHz):(the 1H of δ 12.99, s), 9.01 (1 Η, s), 8.16 (2H, m), 7.95 (1H, m 7.84-7.69 (1H, m), 7.37 (1H, d), 7.24 (1H, t), 7.15-7.00 (4H, m), 5.51 (1H, m), 1.65 (3H, d) tfV2-fl- of embodiments 33 (9H- purine -6- bases amino) ethyl fluoroanilino) quinazoline -4i3H) -one（Compound

(1) preparation of 2- aminobenzoic acids

2- nitrobenzoic acids (10 g are added in dry reaction bulb, 59.8 mmol), the dissolving of 200 mL methanol is slowly added to the 10 % g of palladium carbon 0.5, it is passed through hydrogen, displaced air three times, reacts 6 hours at room temperature, filtering, filter cake methanol is washed three times, concentration, obtains the g of light yellow solid 7.1, the % of yield 86.6.

(2) preparation of (5) -1- (4- oxo -4H- benzos [] [l, 3] oxazine -2- bases) ethylcarbamate

In dry stand up reaction bottle, 2- aminobenzoic acids (2 g, 14.6 mmol) are added,（5) -2- (t-butoxycarbonyl amino) propionic acid (3 g, 15.9 mmol) and triphenyl phosphite (5 g, 16.1 mmol), add 15 mL pyridines and make solvent, 12 h are reacted under 55 °C, without processing, next step reaction are directly carried out.

(3) preparation of (5) -1- [3- (4- fluoroanilinos) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

In reaction system one step up, it is directly added into fluorophenyl hydrazine hydrochloride (2.6 g, 16.0 mmol), is warming up to 100.C reacts 8 h, and silica gel mixed sample is directly added into after cooling, crosses post and obtains the g of white solid 5, two step yields are 85.9 %. (4) in the dry reaction bulb of the preparation of (S) -2- (l- amino-ethyls) -3- (4- fluoroanilinos) quinazoline -4 (3H) -one trifluoroacetate, add (5) -2- (1- t-butoxycarbonyl aminos ethyl) -3- (4- fluoroanilinos) quinazoline -4 (3H)-ketone (2 g, 5 mmol), add the mL of dichloromethane 10, the mL of trifluoracetic acid 11,3 h are stirred at room temperature, stop rotation after reaction and remove solvent, the g of white solid 1.9 is obtained, yield is 92.2 %.

(5) preparation of (5) -2- (l- (9H- purine -6- bases amino) ethyl) -3- (4- fluoroanilinos) quinazoline -4 (3H) -one

(5) -2- (1- amino-ethyls) -3- (4- fluoroanilinos) (3H) the -one trifluoroacetate of quinazoline -4 (1.5 g are added in dry reaction bulb, 3.64 mmol), chloro- 9H- purine (0.93 g of 6-, 6 mmol), add the mL of the tert-butyl alcohol 10, DIEA (4.7 mL, 27 mmol), 12 h are reacted under 90 °C, directly it is spin-dried for dissolving sample, prepare liquid phase and purify to obtain the g of white solid 0.5, yield is 33 %.Mass spectrum（Μ+Η)·· 417.2

¹H-NMR( ₆-DMSO, 400 MHz):(1 Η of δ 12.98, s), 9.08 (1H, s), 8.23-8.02 (2H, m), 8.05 (1H, d), 7.98-7.66 (3H, m), 7.58 (1H, d), 7.49 (1H, t), 7.15-7.00 (3H, m), 5.53 (1H, 1.66 m), (3H, d) embodiments 34 (S) -2- " l-i9H- purine -6- bases amino) ethyl " -3- 4- fluoroanilinos) -5- (trifluoromethyl) quinazoline

- -one（Compound 36) preparation

(1) (5) -1- [4- oxos -5- (trifluoromethyl) -4H- benzos [] [l, 3] oxazine -2- bases] ethylcarbamate the dry reaction bulb of preparation in, by 2- amino -6- (trifluoromethyl) benzoic acid (1.5 g, 7.31 mmol) it is dissolved in 50 mL pyridines, successively add (5) -2- (t-butoxycarbonyl amino) propionic acid (1.6 g, 8.46 mmol), triphenyl phosphite (2.3 g, 7.41 mmol) after reacting 24 h under 60 °C, until raw material disappears.

(2) preparation of (5) small [3- (4- fluoroanilinos) -4- oxos -5- (trifluoromethyl) -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Added into above-mentioned reaction solution to fluorophenyl hydrazine hydrochloride (1.5 g, 9.23 mmol), and be warming up to 100 °C of 8 h of reaction, until raw material disappears.Organic solvent and column chromatography are spun off after cooling（PE:EA=6:1) g of faint yellow solid 1.6 is obtained, two steps are received The % of rate 46.9.

(3) preparation of (5) -2- (l- amino-ethyls) -3- (4- fluoroanilinos) -5- (trifluoromethyl) quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb, by (- 1- [3- (4- fluoroanilinos) -4- oxos -5- (trifluoromethyl) -3,4- dihydroquinazoline -2- bases] ethylcarbamate (1.6 g, 3.43 mmol) it is dissolved in 30 mL absolute ethyl alcohols, lead to hydrogen chloride gas into system until reaction is complete, 1.3 g solids are obtained after revolving（Hydrochloride）, the % of yield 94.1.

(4) preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] -3- (4- fluoroanilinos) -5- (trifluoromethyl) quinazoline -4 (3H) -one

In dry reaction bulb, (- 2- (1- amino-ethyls) -3- (4- fluoroanilinos) -5- (trifluoromethyl) (3H) the -one hydrochloride of quinazoline -4 (1.0 g are added into the 30 mL tert-butyl alcohols, 2.48 mmol) and DIEA (2.0 mL, 11.5 mmol), chloro- 9H- purine (700 mg of 6-, 4.53 mmol), 24 h are reacted in reaction under 85 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of white solid 500, the % of yield 41.6.

Mass spectrum（M+H): 485.20

1H-NMR( rDMS0, 400 MHz):δ 12.99 (1 Η, s), 9.13 (1H, s), 8.24-8.12 (2H, m), 8.07-7.78 (4H, m), 7.20-7.01 (4H, m), 5.49 (1H, m), 1.66 (3H, d)

The iS 2-il-f ^- purine -6- bases amino of embodiment 35) the chloro- 4- fluoroanilinos of the chloro- 3-0- of ethyl 1-5-) quinazoline -40H) -one chemical combination 37) preparation

(1) preparation of the chloro- 4- fluorobenzene callosity hydrochlorides of 2-

The chloro- 4- fluoroanilines of 1.46 g (10 mmol) 2- are added to the mixing of 20 mL concentrated hydrochloric acids and 10 mL trifluoroacetic acids In solvent, 828 mg (12 mmol) natrium nitrosum is added（It is dissolved in 6 mL water）, react 1 hour under ice bath, the hydrochloric acid solution of 3.38 g (15 mmol) two hydrated stannous chlorides be slowly added dropwise（15 mL concentrated hydrochloric acids）, finish, move to room temperature reaction 12 hours.Suction filtration, ether washes paint filter cake, dries, obtains the g of white solid 1.10, yield 55.8%.

(2) (the preparation of -1- [the chloro- 3- of 5- (the chloro- 4- fluoroanilinos of 2-) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

In dry reaction bulb, it is separately added into 858 mg (5.00 mmol) 2- amino -6- chlorobenzoic acids, 1.04 g (5.50 mmol) (S) -2- (t-butoxycarbonyl amino) propionic acid, 10 mL pyridines, 1.71 g (5.52 mmol) triphenyl phosphite, 55 V react 10 hours.The chloro- g of 4- fluorophenyl hydrazine hydrochlorides 1.10 of 2- (5.58 mmol) are added, temperature is risen into 100 °C reacts 8 hours.Solvent is spin-dried for, column chromatography（Petroleum ether:Ethyl acetate=5:1) g of white solid 1.30, yield 55.6, are obtained

%。

(3) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (the chloro- 4- fluoroanilinos of 2-) quinazoline -4 (3H) -one

In dry reaction bulb, by 1.30 g (2.78 mmol) (5) -1- [the chloro- 3- of 5- (the chloro- 4- fluoroanilinos of 2-) -4- oxos -3,4- dihydroquinazoline -2- bases] ethylcarbamate is dissolved in the in the mixed solvents of 10 mL dichloromethanes protective embankments and 5 mL trifluoroacetic acids, stir 2 hours, terminate through TLC monitoring reactions under ice bath.Solvent is spin-dried for, products therefrom is directly used in the next step.

(4) the chloro- 3- of upper step product (5) -2- (1- amino-ethyls) -5- (the chloro- 4- fluoroanilinos of 2-) quinazoline -4 (3H) -one (about 2.78 mmol) is dissolved in the 15 mL tert-butyl alcohols by the preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- (the chloro- 4- fluoroanilinos of 2-) quinazoline -4 (3H) -one, add DIEA (2 mL, 11.5 mmol), the chloro- 9H- purine of 474 mg (3.07 mmol) 6-, heating reflux reaction two days.It is spin-dried for solvent, column chromatography（Ethyl acetate:Petroleum ether=2:1) mg of white solid 300, the step yield 22.3% of the above two, are obtained.

Mass spectrum (M+H): 485.1

1H-NMR(i/₆-DMS0, 400 MHz):δ 12.95 (1 Η, s), 8.60 (1H, s), 8.14 (2H, s), 8.05-7.94 (1H, m), 7.70 (1H, t), 7.59-7.47 (2H, m), 7.43-7.35 (1H, m), 7.30-7.10 (2H, m), 5.44 (1H, s), 1.67 (3H, d)

Embodiment 36 (S 2- " the fast cry of certain animals -6- bases amino of l-i9H-) chloro- 3-f4- fluoro-2-methylbenzenes amidos of ethyl 1-5-) quinazoline -40m- assimilations compound 38) preparation

(1) preparation of 4- fluoro-2-methylbenzenes hydrazine hydrochloride

1.00 g (8 mmol) 4- fluoro-2-methylbenzene amine is added in 20 mL concentrated hydrochloric acids, 1.10 g (15.9 mmol) natrium nitrosum is added（It is dissolved in 6 mL water）, react 1 hour under ice bath, the hydrochloric acid solution of 4.50 g (20 mmol) two hydrated stannous chlorides be slowly added dropwise（15 mL concentrated hydrochloric acids）, finish, move to room temperature reaction 12 hours.Suction filtration, ether washing filter cake, dries, obtains the mg of white solid 800, yield 56.6%.

(2) preparation of (5) small [the chloro- 3- of 5- (4- fluoro-2-methylbenzenes amido) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

In dry reaction bulb, it is separately added into 858 mg (5.00 mmol) 2- amino -6- chlorobenzoic acids, 1.04 g (5.50 mmol) (5) -2- (t-butoxycarbonyl amino) propionic acid, 10 mL pyridines, (5.52 mmol) Ya Pity triphenyl phosphate esters, 55 V react 10 hours 1.71 g.The mg (4.53 mmol) of 4- fluoro-2-methylbenzenes hydrazine hydrochloride 800 is added, temperature is risen into 100 V reacts 8 hours.Cooling, solvent is spin-dried for, column chromatography（Petroleum ether:Ethyl acetate=5:1) g of white solid 1.40, the % of yield 69.1, are obtained.

(3) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (4- fluoro-2-methylbenzenes amido) quinazoline -4 (3H) -one

In dry reaction bulb, by 1.40 g (3.13 mmol) (5) -1- [the chloro- 3- of 5- (4- fluoro-2-methylbenzenes amido) -4- oxos -3,4- dihydroquinazoline -2- bases] ethylcarbamate is dissolved in the in the mixed solvents of 10 mL dichloromethanes protective embankments and 5 mL trifluoroacetic acids, stir 2 hours, terminate through TLC monitoring reactions under ice bath.Solvent is spin-dried for, products therefrom is directly used in the next step.One (4) preparation of (5) -2- [l- (the fast cry of certain animals -6- bases amino of 9H-) ethyl] the chloro- 3- of -5- (4- fluoro-2-methylbenzenes amido) quinazoline -4 (3H) _ ketone

Upper step product (5) -2- (1- amino-ethyls) -5- chloro- 3- (4- fluoro-2-methylbenzenes amido) quinazoline -4 (3H) -one (about 3.13 mmol) is dissolved in the 20 mL tert-butyl alcohols, add DIEA (2 mL, 11.5 mmol), the chloro- 9H- purine of 534 mg (3.45 mmol) 6-, heating reflux reaction two days.Cooling, is spin-dried for solvent, column chromatography（100% ethyl acetate）, obtain the mg of white solid 700, the step yield 48.2% of the above two.

Mass spectrum (Μ+Η): 465.2

1H-NMR( -DMS0, 400 ΜΗζ):δ 12.95 (1 Η, s), 8.28 (1H, s), 8.13 (2H, s), 7.95-7.84 (1H, s), 7.70 (1H, t), 7.59-7.47 (2H, m), 7.07-6.85 (2H, m), 5.48 (1H, m), 2.36 (3H, s), 1.73-1.63 (3H, m)

Embodiment 37 (S) -2-【The preparation of l- (the chloro- 4- fluoroanilinos of the 9H- purine-6- bases amino chloro- 3-f2,6- bis- of the 1 ethyl 1-5-) Π of quinazoline-40 -one (compound 39)

(1) preparation of the chloro- 4- fluorophenyl hydrazine hydrochlorides of 2,6- bis-

The chloro- 4- fluoroanilines of 1.80 g (10 mmol) 2,6- bis- are added to the in the mixed solvent of 20 mL concentrated hydrochloric acids and 10 mL trifluoroacetic acids, 828 mg (12 mmol) natrium nitrosum is added（It is dissolved in 6 mL water）, react 1 hour under ice bath, the hydrochloric acid solution of 3.38 g (15 mmol) two hydrated stannous chlorides be slowly added dropwise（15 mL concentrated hydrochloric acids）, finish, move to Room temperature reaction 12 hours.Suction filtration, ether washing filter cake, dries, obtains the g of white solid 1.70, yield 73.4%.

(2) preparation of (5) -1- [the chloro- 3- of 5- (the chloro- 4- fluoroanilinos of 2,6- bis-) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

In dry reaction bulb, it is separately added into 858 mg (5.00 mmol) 2- amino -6- chlorobenzoic acids, 1.04 g (5.50 mmol) (5) -2- (t-butoxycarbonyl amino) propionic acid, lO mL B compare pyridine, 1.71 g (5.52 mmol) triphenyl phosphite, 55.C reacts 10 hours.The chloro- g of 4- fluorophenyl hydrazine hydrochlorides 1.27 of 2,6- bis- (5.49 mmol) are added, temperature is risen into 100 °C reacts 8 hours.Cooling, solvent is spin-dried for, column chromatography（Petroleum ether:Ethyl acetate=5:1) g of white solid 2.10, yield 83.7%, are obtained.

(3) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (2,6- bis- chloro- 4- fluoroanilinos) quinazoline -4 (3H) -one

In dry reaction bulb, by 2.10 g (4.19 mmol) (5) -1- [chloro- 3- (2 of 5-, the chloro- 4- fluoroanilinos of 6- bis-) -4- oxos -3,4- dihydroquinazoline -2- bases] ethylcarbamate is dissolved in the in the mixed solvents of 10 mL dichloromethanes protective embankments and 5 mL trifluoroacetic acids, stir 2 hours, terminate through TLC monitoring reactions under ice bath.Solvent is spin-dried for, products therefrom is directly used in the next step.

(4) preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- (2,6- bis- chloro- 4- fluoroanilinos) quinazoline -4 (3H) -one

By the chloro- 3- (2 of upper step product (5) -2- (1- amino-ethyls) -5-, the chloro- 4- fluoroanilinos of 6- bis-) quinazoline -4 (3H) -one (about 4.19 mmol) is dissolved in the 20 mL tert-butyl alcohols, add DIEA (2 tnL, 11.5 mmol), the chloro- 9H- purine of 714 mg (4.62 mmol) 6-, heating reflux reaction two days.Cooling, is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=1:1) mg of white solid 700, the step yield 32.2% of the above two, are obtained.

Mass spectrum (Μ+Η): 519.1

'H-NMR^-DMSO, 400 MHz):δ 13.04 (IH, s), 8.63 (IH, s), 8.17 (2H, d), 7.80 (IH, t), 7.77-7.71 (IH, m), 7.59 (1H, d), 7.57-7.49 (IH, m), 7.42-7.27 (2H, m), 6.18 (1H, m), 1.65 (3H, m)

The preparation of the tfV241- of embodiment 38 (9H- purine -6- bases amino) the chloro- 3- of ethyl 1-5- (the fluoro- 2,6- accelerine bases of 4-) quinazoline -4 (3H) -one (compound 40)

(1) preparation of fluoro- 2, the 6- dimethyl hydrazinobenzene hydrochloride salts of 4-

1.39 g (lO mmol) 2,6- dimethyl -4- fluoroanilines are added to the in the mixed solvent of 20 mL concentrated hydrochloric acids and 10 mL trifluoroacetic acids, 828 mg (12 mmol) natrium nitrosum is added（It is dissolved in 6 mL water）, react 1 hour under ice bath, the hydrochloric acid solution of 3.38 g (15 mmol) stannous chloride be slowly added dropwise（15 mL concentrated hydrochloric acids）, finish, move to room temperature reaction 15 hours.Suction filtration, ether washing filter cake, dries, obtains the g of white solid 1.14, yield 59.8%.

(2)-[the chloro- 3- of 5- (fluoro- 2, the 6- accelerine bases of 4-) -4- oxo -3, the 4- dihydroquinazoline -2- bases] preparation of ethylcarbamate

In dry reaction bulb, it is separately added into 858 mg (5.00 mmol) 2- amino -6- chlorobenzoic acids, 1.04 g (5.50 mmol) 0S) -2- (t-butoxycarbonyl amino) propionic acid, 10 mL pyridines, 1.71 g (5.52 mmol) triphenyl phosphite, 55 V react 10 hours.The g (5.98 mmol) of 2,6- dimethyl -4- fluorophenyl hydrazine hydrochlorides 1.14 is added, temperature is risen into 100 reaction 8 hours.Solvent is spin-dried for, column chromatography (petroleum ether:Ethyl acetate=5:1) g of white solid 1.6, yield 69.4%, are obtained.

(3) the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (4- fluoro- 2,6- accelerine bases) quinazoline -4 (3H) _ keto hydrochloride the dry reaction bulb of preparation in, by 580 mg (1.26 mmol) (5) -1- [chloro- 3- (2 of 5-, 6- dimethyl -4- fluoroanilinos) -4- oxos -3,4- dihydroquinazoline -2- bases] ethylcarbamate is dissolved in 10 mL dichloromethane protective embankments, HC1 gases are passed through under ice bath, are terminated after 15 minutes through TLC monitoring reactions.Solvent is spin-dried for, products therefrom is directly used in the next step.

(4) (<S) the preparation of -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- (the fluoro- 2,6- accelerine bases of 4-) quinazoline -4 (3H) -one By the chloro- 3- (2 of upper step product (5) -2- (l- amino-ethyls) -5-, 6- dimethyl -4- fluoroanilinos) (3H) -one of quinazoline -4 hydrochloride (about 1.26 mmol) is dissolved in the 20 mL tert-butyl alcohols, add DIEA (2 mL, 11.5 mmol), the chloro- purine of 232 mg (1.50 mmol) 6-, heating reflux reaction two days.Solvent is spin-dried for, liquid phase separation is prepared and obtains the mg of white solid 300, the step yield 49.7% of the above two.

Mass spectrum (M+H): 479.2

1H-NMR(i ₆-DMSO, 400 MHz):δ 13.05 (1 Η, s), 8.19-8.15 (2H, m), 7.86 (1H, s), 7.77 (1H, t), 7.68 (1H, d), 7.56 (1H, dd), 7.45-7.35 (1H, m), 6.94-6.85 (1H, m), 6.74-6.63 (1H, m), 6.31 (1H, m), 2.38 (3H, s), 1.84 (3H, s), 1.67 (3H, d)

The 5)-2- Κ 9-fast cry of certain animals-6- bases amino of embodiment 39) (cyclopropyl) methyl " the fluoro- 3- of-5- (4- fluoroanilinos) quinazoline-4i3H)-assimilation compound 41) preparation

(1) preparation of 2- amino -6- fluobenzoic acids

2- fluoride-6-nitrobenzoic acids (8.325 g are added in 250 dry mL reaction bulbs, 45.0 mmol), dissolved with methanol, then 0.900 g 10% Pd/C is added, it is stirred overnight at room temperature, then Pd/C is filtered out, is concentrated under reduced pressure to give the g of faint yellow solid 6.800, yield 97.3%.

(2) preparation of (5)-cyclopropyl (5- fluorin-4-oxygens generation -4H- benzos [1,3] oxazine -2- bases) methyl carbamic acid tert-butyl ester

2- amino -6- fluobenzoic acids (1.085 g, 7.0 mmol), (5) -2- (t-butoxycarbonyl amino) -2- cyclopropaneacetic acids are added in 50 dry mL reaction bulbs（1.505 g, 7.0 mmol), 6.0 mL pyridines are then added, triphenyl phosphite (2.170 g, 7.0 mmol) is stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(3) OS)-cyclopropyl [the fluoro- 3- of 5- (4- fluoroanilinos) -4- oxo -3,4- dihydroquinazoline -2- bases] methyl carbamic acid tert-butyl ester preparation Preparing (5)-cyclopropyl (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) the methyl carbamic acid tert-butyl ester reaction solution in be directly added into fluorophenyl hydrazine hydrochloride (1.138 g, 7.0 mmol), return stirring reacts 8 h in 100 °C of oil bath, then cool down, be concentrated under reduced pressure, pass through column chromatography (PE:EA=6:1) purifying obtains the g of faint yellow solid 2.130, and two step yields are 68.7%.

(4) preparation of (5) -2- [amino (cyclopropyl) methyl] the fluoro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) _ ketone trifluoroacetate

(- cyclopropyl [the fluoro- 3- of 5- (4- fluoroanilinos) -4- oxos -3 are added in 100 dry mL reaction bulbs, 4- dihydroquinazoline -2- bases] the methyl carbamic acid tert-butyl ester (0.630 g, 1.42 rnmol), dissolved with 12.0 mL dichloromethane, 6.0 mL trifluoroacetic acids are added dropwise under conditions of ice bath, completion of dropping, then take and continue to stir in room temperature, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(5) CS) preparation of -2- [(the fast cry of certain animals -6- bases amino of 9H-) (cyclopropyl) methyl] the fluoro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one dissolves (5) -2- [amino (cyclopropyl) methyl] the fluoro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) _ ketone obtained by previous step with the 20.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, system is adjusted into ρ Η to alkalescence with DIEA, then chloro- 9 Η of 6--purine (0.264 g is added, 1.71 mmol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.311, two step yields 47.5%.

Mass spectrum (Μ+Η): 461.2

1H-NMR(i/₆-DMSO, 400 ΜΗζ):δ 12.97 (1H, br s), 9.11 (1H, s), 8.22-8.00 (2H, m), 7.88-7.75 (1H, m), 7.60-7.45 (2H, m), 7.28 (1H, t), 7.06-6.84 (3H, m), 6.74-6.63 (1H, m), 5.49-5.27 (1H, m), 1.59-1.40 (1H, m), 0.75-0.30 (4H, m)

Embodiment 40 (S)-2- " (9-purine-6- bases amino) (cyclopropyl) methyl " the chloro- 3- of-5- (4- fluoroanilinos) quinazoline-4 (3-

(1) (5)-(chloro- 4- oxos -4H- benzos [rf] [l of 5-, 3] oxazine -2- bases) (cyclopropyl) methyl carbamic acid tert-butyl ester the dry reaction bulb of preparation in, it is separately added into 515 mg (3.0 mmol) 2- amino -6- chlorobenzoic acids, 710 mg (3.3 mmol)

(5) -2- (t-butoxycarbonyl amino) -2- cyclopropaneacetic acids, 5 mL pyridines, 1.02 g (3.3 mmol) triphenyl phosphite, 55 V reactions are stayed overnight.Terminate through LC-MS monitoring reactions.

(2) preparation of (5)-[the chloro- 3- of 5- (4- fluoroanilinos) -4- oxo -3,4- dihydroquinazoline -2- bases] (cyclopropyl) methyl carbamic acid tert-butyl ester

Added in upper step reaction system to the mg of fluorophenyl hydrazine hydrochloride 536 (3.3 mmol), temperature is risen into 100 °C reacts 8 hours.Solvent is spin-dried for, column chromatography（Petroleum ether:Ethyl acetate=5:1) g of white solid 1.2, the % of two step yield of the above 87 are obtained.

(3) in the dry reaction bulb of the preparation of (S) -2- [amino (cyclopropyl) methyl] the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one trifluoroacetate, by 1.2 g (2.61 mm₀L) (5-[the chloro- 3- of 5- (4- fluoroanilinos)-4- oxos-3,4- dihydroquinazoline-2- bases] (cyclopropyl) methyl carbamic acid tert-butyl ester is dissolved in the mixed solution of 10 mL dichloromethanes protective embankments and 5 mL trifluoroacetic acids, stir 1 hour, terminate through TLC monitoring reactions under ice bath.Solvent is spin-dried for, products therefrom is directly used in the next step.

(4) (5) -2- (amino (cyclopropyl) methyl) the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one trifluoroacetate that the preparation of (5) -2- [(9H- purine -6- bases amino) (cyclopropyl) methyl] the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one obtains upper step is dissolved in the 15 mL tert-butyl alcohols, add 2 mL DIEA, the chloro- 9H- purine of 445 mg (2.88 mmol) 6-, heating reflux reaction two days.It is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=1:2) obtain crude product and washed with ethyl acetate to obtain the mg of white solid 200, the % of two step yield of the above 16.1.

Mass spectrum (M+H): 477.2

^-NMRC^-DMSO, 400 MHz):δ 12.98 (1H, s), 9.10 (1 Η, s), 8.29-8.02 (2H, m), 7.82-7.47 (4H, m), 7.06-6.84 (4H, m), 5.40 (1H, m), 1.59-1.41 (1H, m), 0.76-0.32 (4H, m)

The preparation of the ffl-2- of embodiment 41 " W9H- purine-6- bases amino) propyl group " the chloro- 3- of-5- (pyridin-3-yl amino) quinazoline-4 (3 -one f compounds 43)

(l) preparation of (5)-l- (the chloro- 4- oxos -4H- benzos of 5- [[1,3] oxazine -2- bases) propylcarbamate

In dry reaction bulb, it is separately added into 2.2 g (6.17 mmol) 0S) -2- [2- (t-butoxycarbonyl amino) butyrylamino] -6- chlorobenzoic acids, the 25 mL tert-butyl alcohols, 3.15 g (30.8 mmol) acetic anhydride, heating reflux reaction is stayed overnight.Solvent is spin-dried for, next step is directly used in.

(2) CS)-l- [the chloro- 4- oxos -3- of 5- (pyridin-3-yl amino) -3,4- dihydroquinazoline -2- bases] propylcarbamate preparation

Take the half (about 3.09 mmol) of step product to be dissolved in 5 mL pyridines, add 3- hydrazino pyridines hydrochloride (524 mg, 3.60 mmol), be heated to 100 °C of 8 h of reaction.It is spin-dried for solvent, column chromatography（Petroleum ether:Ethyl acetate=1:1) mg of light yellow solid 630 is obtained, in summary two step yields 47.6%.

(3) preparation of the chloro- 3- of (S) -2- (l- aminopropyls) -5- (pyridin-3-yl amino) quinazoline -4 (3H) -one trifluoroacetate

By (5) -1- [chloro- 4- oxos -3- of 5- (pyridin-3-yl amino) -3,4- dihydroquinazoline -2- bases] propylcarbamate (630 mg, 1.47 mmol) it is dissolved in the mixed solution of 10 mL dichloromethanes protective embankments and 5 mL trifluoroacetic acids, 1 h is reacted under ice bath, is terminated through TLC monitoring reactions.Solvent is spin-dried for, yellow solid is obtained, the next step is directly used in.

(4) (<S) the preparation of -2- [l- (9H- purine -6- bases amino) propyl group] the chloro- 3- of -5- (pyridin-3-yl amino) quinazoline -4 (3H) -one

By (5) -2- (1- aminopropyls) -5- chloro- 3- (pyridin-3-yl amino) quinazoline -4, (3H ketone trifluoroacetate (about 1.47 mmol) is dissolved in the 20 mL tert-butyl alcohols, add DIE A (2 mL, 11.5 mmol), the chloro- 9H- purine of 340 mg (2.20 mmol) 6-, heating reflux reaction 1 day.Solvent is spin-dried for, column chromatography（Ethyl acetate）Obtain the mg of white solid 150, the step yield 22.8% of the above two.

Mass spectrum (M+H): 448.2

'H-NMR(c?₆-DMSO, 400 MHz):δ 12.96 (1H, s), 9.27 (1 Η, s), 8.35 (1H, s), 8.21-8.01 (3H, m), 7.97-7.86 (1H, m), 7.79-7.60 (1H, m), 7.59-7.48 (2H, m), 7.45-7.34 (1H, m), 7.31-7.05 (1H, m), 5.45 (1H, m), 2.20-1.78 (2H, m), 1.02 (3H, t) Embodiment 42 (S) -2- " M9 purine -6- bases amino) the fluoro- 3- of propyl group 1-5- (pyridin-3-yl the amino) -3^ of quinazoline -4) -one compound 44) and preparation

(1) preparation of fluoro- 6- nitros-N- (pyridin-3-yl) benzoyl hydrazines of 2-

2- fluoride-6-nitrobenzoic acids (12.03 g, 65.0 mmol) are dissolved in 50 mL CH₂Cl₂With 0.3 mL DMF, oxalyl chloride (12.347 g are slowly added dropwise thereto, 97.3 mrnol), 2 h are stirred at room temperature, concentration removes solvent, 12 mL dioxane are then dissolved in, 3- hydrazino pyridines (7.09 g, 65.0 mmol), NaHC0 are added dropwise under cooling₃(10.92 g, 130.0 mmol) the mL of dioxane 30 and the mL solution of water 30 in, completion of dropping, which is raised to, is stirred at room temperature half an hour, it is concentrated under reduced pressure into after 1/3rd volumes, ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, organic phase is concentrated, the g of brown solid 14.65, yield 81.5% is obtained.

(2) preparation of 2- amino -6- fluorine (pyridin-3-yl) benzoyl hydrazine

By the fluoro- 6- nitros-N- of 2- (P is than pyridine -3- bases) benzoyl hydrazine (14.65 g, 53.0 mmol) it is dissolved in 130 mL methanol, 1.5 g 10% Pd/C is added thereto, logical hydrogen, 42 h are reacted at room temperature, reaction terminates, and filters out Pd/C, and organic phase concentration gained solid is directly used in next step reaction.

(3) preparation of (5) -1- [the fluoro- 2- of 3- [2- (pyridin-3-yl) diazanyls formoxyl] phenylamino] -1- oxo butyl- 2- carbamates

In dry reaction bulb, 2- amino -6- fluorine (pyridin-3-yl) benzoyl hydrazine crude product that upper step is obtained（About 53.0 mmol),（5) -2- (t-butoxycarbonyl amino) butyric acid (12.93 g, 63.6 mmol), DIEA (10.2 mL, 58.5 mmol) and HATU (24.2 g, 63.7 mmol) it is added in i.e.-mL of dimethylformamide 100,64 h are stirred at room temperature, add water and dichloromethane protective embankment, dichloromethane protective embankment is extracted, merge organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography (petroleum ether after being concentrated under reduced pressure:Ethyl acetate=3:1) g of white solid 6.52, two step total recoverys 28.5%, are obtained. (4) (5) -1- [the fluoro- 2- of 3- [2- (pyridin-3-yl) diazanyls formoxyl] phenylamino] small oxo butyl- 2- carbamates (11^01 of 6.52 ＆ 15.11) are dissolved in 50 11^ ethanol by the preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (pyridin-3-yl amino) quinazoline -4 (3H) -one hydrochloride, 5 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath, stir after half an hour, reaction is moved into oil bath and reacts 24 h under 85 °C, pH 8 is adjusted after cooling, concentration, it is anti-phase to prepare, obtain the g of white solid 0.95, yield 18.0%.

(5) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- (pyridin-3-yl amino) quinazoline -4 (3H) -one

(5) -2- (1- aminopropyls) -5- fluoro- 3- (pyridin-3-yl amino) (3H) the -one hydrochloride of quinazoline -4 (0.95 g is added into the 20 mL tert-butyl alcohols, 2.72 mmol) and DIEA (0.6 mL, 3.44 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (562 mg of 6- are added thereto, 3.64 mmol), 36 h are reacted in reaction under 85 °C, cooling, concentration, silica gel column chromatography (ethyl acetate), obtains the mg of white solid 93, yield 7.9%.

Mass spectrum (M+H): 432.2

1H-NMR( _d-DMSO, 400 MHz):δ 12.96 (IH, s), 9.28 (1H, s), 8.37-8.30 (1H, m), 8.20-8.11 (IH, m), 8.11-8.02 (2H, m), 7.95-7.72 (2H, m), 7.45-7.34 (2H, m), 7.31-7.18 (2H, m), 5.46 (1R m), 2.20-1.82 (2H, m), 1.02 (3H, t).

The tfV2-il- of embodiment 43 (9 purine -6- bases amino) fluoro- 34 methyl of propyl group 1-5-（Pyridin-3-yl)-4 3 -one of 1 quinazoline of amino（Compound 45) preparation

(1) preparation of 4- methyl (pyridin-3-yl) benzsulfamide

3- aminopyridines（14.1 g, 0.15 mol) and p-methyl benzenesulfonic acid chlorine（30 g, 0.157 mol) it is dissolved in 20 mL pyridines In, reacted 2 hours under 100 °C, cooling pours into reaction solution in frozen water, separate out solid, suction filtration, absolute ethyl alcohol recrystallization obtains the g of white solid 36, yield 96.7%.

(2) preparation of NA- dimethyl (pyridin-3-yl) benzsulfamide

By 4- methyl (pyridin-3-yl) benzsulfamide (4.96 g, 20 mmol) and potassium carbonate（5.52 g, 40 mmol) it is heated to reflux in 40 mL acetone, iodomethane (5.67 g, 40 mol) is added drop-wise in reaction solution in half an hour, continues back flow reaction 2 hours, cooling, suction filtration, acetone washing solid, concentrates filtrate, obtain the g of brown oil 4.7, yield 89.5%.

(3) preparation of N- picolines -3- amine

By N, 4- dimethyl (pyridin-3-yl) benzsulfamide (4.96 g, 18.9 mmol) is dissolved in 80% concentrated sulfuric acid（20 mL) in, reacted 4 hours under 100 °C, cooling, adjust pH value to 9 with ammoniacal liquor reaction solution, be extracted with ethyl acetate, anhydrous sodium sulfate drying is concentrated under reduced pressure, obtain the g of brown oil 1.86, yield 91.0%.

(4) preparation of N- methyl-N-nitrosos pyridine -3- amine

By N- picoline -3- amine (1.86 g, 17.2 mmol) it is dissolved in 25 mL concentrated hydrochloric acids, the 25 mL aqueous solution of natrium nitrosum (1.43 g, 20.7 mmol) are added dropwise at -15 times, drop finishes, reaction is transferred to and reacted one hour at room temperature, adjusts pH value to 9 with ammoniacal liquor, is extracted with ethyl acetate, Anhydrous potassium carbonate is dried, it is concentrated under reduced pressure, obtains the g of brown oil 2.15, yield 91.3%.

(5) preparation of 3- (1- methyl diazanyl) pyridine

Under ice-water bath, by N- methyl-N-nitroso pyridine -3- amine（2.15 g, 15.7 mmol) anhydrous tetrahydro furan（20 mL) solution is slowly added drop-wise to I N Lithium Aluminium Hydride tetrahydrofuran solution（17 mL) in, continue to stir under ice bath and dissolve one hour, add 10 mL 40% sodium hydroxide solution, be extracted with ethyl acetate, Anhydrous potassium carbonate is dried, and is concentrated under reduced pressure, is obtained the g of brown oil 1.73, yield 89.2%.

(6) (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [d] [l, 3] oxazine -2- bases) propylcarbamate preparation

By 2- amino -6- fluobenzoic acids (776 mg, 5.0 mmol), (5) -2- (t-butoxycarbonyl amino) butyric acid (1.22 g, 6.0 mmol) and triphenyl phosphite（1.55 g, 5.0 mmol) it is dissolved in 8 mL pyridines and is stirred 10 hours under 55 °C, cool down, reaction solution is directly used in next step reaction.

(7) preparation of (5) -1- [the fluoro- 3- of 5- [methyl (pyridin-3-yl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate

Upwards step obtained by (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [d] [l, 3] oxazine -2- bases) propylcarbamate（About 5.0 mmol) 3- (1- methyl diazanyl) pyridine is directly added into reaction solution（739 mg, 6.0 mmol), reaction is warming up to 100 °C and stirred 8 hours, cooling is concentrated under reduced pressure, gained residue is through silica gel column chromatography（PE:EA=1:1) mg of yellow-brown solid 603 is obtained, two step yields are 28.2%. (8) preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- [methyl (pyridin-3-yl) amino] quinazoline -4 (3H) -one trifluoroacetate is by (5) small [the fluoro- 3- of 5- [methyl (pyridin-3-yl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate（603 mg, 1.41 mmol) it is dissolved in dichloromethane（20 mL) trifluoroacetic acid is slowly added dropwise under ice bath（5 mL), drop finishes, and reaction is transferred to and stirred two hours at room temperature, and TLC monitoring reactions are finished, and the gained crude solid that is concentrated under reduced pressure is directly used in next step.

(9) (the preparation of 5-2- [l- (9H- purine-6- bases amino) propyl group] the fluoro- 3- of-5- [methyl (pyridin-3-yl) amino] quinazoline-4 (3H) -one

The fluoro- 3- of (5) -2- (1- aminopropyls) -5- [methyl (P is than pyridine -3- bases) amino] (3H) -one of quinazoline -4 trifluoroacetates (about 1.41 mmol) and DIEA (0.74 mL are added into the 20 mL tert-butyl alcohols, 4.24 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (240 mg of 6- are added thereto, 1.55 mmol), 36 h are reacted in reaction under 85 °C, cool down Nong Shrink, silica gel column chromatography（Ethyl acetate）, obtain the mg of white solid 127, two step yields 20.2%.

Mass spectrum（M+H): 446.2

1H-NMR (^-DMSO, 400 MHz):δ 12.97 (1 Η, s), 8.28-7.77 (6H, m), 7.49 (1H, d), 7.34-7.07 (3H, m), 5.49 (1H, m), 3.50-3.41 (3H, m), 2.18-1.80 (2H, m), 1.30-0.82 (3H, m)

The propyl group l-3- pyridin-3-yls amino of fluoro- 2414 methyl of embodiment 44 (the fast cry of certain animals -6- bases of 9ff-) amino 1) quinazoline

--m (compound 46) preparation

(1) CS) -2- [tertbutyloxycarbonyl (methyl) amino] butyric acid preparation

By CS under ice bath) -2- (t-butoxycarbonyl amino) butyric acid（20.32 g, 100 mmol) 600 mL anhydrous tetrahydro furans are dissolved in, the sodium hydride (40 g, 1 mol) for adding 60 % is stirred at room temperature 30 minutes, and CH is added dropwise₃I (141.9 g, 1 mol) reacts after finishing to be stayed overnight, and is removed under reduced pressure after most of organic solvent and is poured into 200 mL water, adjusts pH 7, ethyl acetate extraction, nothing Aqueous sodium persulfate is dried, and suction filtration is concentrated under reduced pressure, and crude product is recrystallized in petroleum ether, obtains the yellowish coloured particles of 12.79 g, the % of yield 58.9.

(2) preparation of 3- hydrazino pyridines hydrochloride

3- aminopyridines (19.95 g, 212 mmol) are dissolved in concentrated hydrochloric acid (200 mL), -15！：Lower dropwise addition natrium nitrosum（15.80 g, 229 mmol) the aqueous solution（100 mL), drop finishes, and reaction solution is added drop-wise into two hydrated stannous chlorides under -10 °C（58.7 g, 260 mmol) and concentrated hydrochloric acid（185 mL) reaction system in, drop finish, at 0 °.15 min suction filtration solids of lower stirring, ether washing solid, dry, obtain 17.96 g white solids, the % of yield 58.0.

(3) (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) propyl group (methyl) t-butyl carbamate preparation by 2- amino -6- fluobenzoic acids (776 mg, 5.0 mmol), (5) -2- [tertbutyloxycarbonyl (methyl) amino] butyric acid (1.31 g, 6.0 mmol) and triphenyl phosphite (1.55 g, 5.0 mmol) it is dissolved in pyridine (12 mL) and is stirred 10 hours under 55 °C, cooling, reaction solution is directly used in next step reaction.

(4) preparation of (5) -1- [5- fluorine 4- oxos -3- (pyridin-3-yl amino) -3,4- dihydroquinazoline -2- bases] propyl group (methyl) t-butyl carbamate

Upwards step obtained by (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [] [l, 3] oxazine -2- bases) propyl group (methyl) t-butyl carbamate（About 5.0 mmol) 3- hydrazino pyridine hydrochlorides are directly added into reaction solution（874 mg, 6.0 mmol), reaction is warming up to 100 °C and stirred 8 hours, cooling is concentrated under reduced pressure, gained residue is through silica gel column chromatography（The % volumes of ethyl acetate 100）The mg of yellow-brown solid 624 is obtained, two step yields are 29.2 %.

(5) preparation of the fluoro- 2- of (5)-5- [1- (methylamino) propyl group]-3- (pyridin-3-yl amino) quinazoline-4 (3H) -one trifluoroacetate will (5-1- [5- fluorin-4-oxygens generation-3- (pyridin-3-yl amino)-3,4- dihydroquinazoline-2- bases] propyl group (methyl) t-butyl carbamate（624 mg, 1.46 mmol) it is dissolved in dichloromethane protective embankment（20 mL) 6 mL trifluoroacetic acids are slowly added dropwise under ice bath, reaction is transferred to and stirred two hours at room temperature, TLC monitoring reactions are finished, the gained crude solid that is concentrated under reduced pressure is directly used in next step.

(6) CS) the fluoro- 2- of -5- [1- [methyl (9H- purine -6- bases) amino] propyl group] -3- (pyridin-3-yl amino) quinazoline -4 (3H) -one preparation

Solid (5) fluoro- 2- of -5- [1- (methylamino) propyl group] -3- (pyridin-3-yl amino) (3H) -one of quinazoline -4 trifluoroacetates (about 1.46 mmol) obtained by upper step are dissolved in the 20 mL tert-butyl alcohols, add DIEA (0.76 mL, 4.36 mmol), half an hour is stirred under ice bath, then chloro- 9H- purine (271 mg of 6- are added thereto, 1.75 mmol), 36 h are reacted under 85 °C, cooling, concentration, column chromatography（Ethyl acetate）, obtain the mg of white solid 118, the % of two step yield 18.1.

Mass spectrum（Μ+Η): 446.2

^-NMRC^-DMSO, 400 ΜΗζ):δ 12.82 (1 Η, s), 9.07,8.81 (1H, two singlets), 8.11-7.78 (4H, M), 7.76-7.48 (2H, m), 7.40-7.05 (2H, m), 6.92-6.60 (1H, m), 5.31 (1H, m), 3.65,2.94 (3H, two singlets), 2.25-1.92 (2H, m), 1.22 (3H, m)

Embodiment 45 (S) -2- " the fast cry of certain animals -6- bases amino of M9 T-) the fluoro- 3- of propyl group 1-5- (pyridin-4-yl amino) quinazoline -40m- ketone

(1) preparation of 4- hydrazino pyridines

Will be to chloropyridine hydrochloric acid salt（25.3 g, 168.7 mmol) and 85 % hydrazine hydrate（47 mL, 824 mmol) mix and stirred one hour under reflux state, cooling separates out solid, and suction filtration washs solid with isopropanol, obtains the g of 4- hydrazino pyridines 16.1, the % of yield 87.5.

(2) preparation of the fluoro- N- of 2- (the fluoro- 6- nitro benzoyls of 2-) -6- nitros-N- (pyridin-4-yl) benzoyl hydrazine

By 2- fluoride-6-nitrobenzoic acids（12.03 g, 65.0 mmol) it is dissolved in 50 mL CH₂C1₂With 0.3 mL DMF, oxalyl chloride (12.347 g are slowly added dropwise thereto, 97.3 mmol), it is stirred at room temperature after two hours, concentration removes solvent, 12 mL dioxane are then dissolved in, 4- hydrazino pyridines (7.09 g, 65.0 mmol), NaHC0 are added dropwise under cooling₃The dioxane of (10.92 g, 130 mmol)（30 mL) and water（30 mL) in solution, completion of dropping is warmed to room temperature stirring half an hour, is concentrated under reduced pressure into after 1/3rd volumes, and ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration concentrates organic phase, obtains the g of brown solid 14.66, the % of yield 50.9.

(3) preparation of fluoro- 6- nitros-N'- (pyridin-4-yl) benzoyl hydrazines of 2-

By the fluoro- N- of 2- (the fluoro- 6- nitro benzoyls of 2-) -6- nitros-N- (pyridin-4-yl) benzoyl hydrazine（14.66 g, 33.1 mmol) it is dissolved in 20 mL absolute ethyl alcohols, 85 % hydrazine hydrate is added into solution（15 mL), stir 2 hours at room temperature, separate out solid after most of solvent that is concentrated under reduced pressure, suction filtration, petroleum ether solid obtains the g of brown solid 8.45, the % of yield 92.4.

(4) preparation of the fluoro- N'- of 2- amino -6- (pyridin-4-yl) benzoyl hydrazine

By fluoro- 6- nitros-N'- (pyridin-4-yl) benzoyl hydrazines of 2-（8.45 g, 30.6 mmol) it is dissolved in 130 mL methanol, 1.5 g l0 % Pd/C is added thereto, leads to hydrogen, 42 h is reacted at room temperature, reaction terminates, Pd/C is filtered out, and organic phase concentration gained solid is directly used in next step reaction.

(5) preparation of (S)-l- [the fluoro- 2- of 3- [2- (pyridin-4-yl) hydrazines carbonyl] aniline] -1- oxo butyl- 2- carbamates

In dry reaction bulb, 2- amino -6- fluoro- N'- (pyridin-4-yl) the benzoyl hydrazines crude product (about 30.6 mmol) that upper step is obtained, (5) -2- (t-butoxycarbonyl amino) butyric acid (9.33 g, 45.9 mmol), DIEA (6.4 mL, 36.75 mmol) it is added to NN- dimethylformamides with HATU (13.96 g, 36.71 mmol)（80 mL) in, 64 h are stirred at room temperature, water and dichloromethane is added, the extraction of dichloromethane protective embankment merges organic phase, washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography after being concentrated under reduced pressure（Petroleum ether:Ethyl acetate=3:1) g of white solid 3.76, the % of two step total recovery 28.5, are obtained.

(6) preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (pyridin-4-yl amino) quinazoline -4 (3H) -one hydrochloride

By (5) -1- [the fluoro- 2- of 3- [2- (pyridin-4-yl) hydrazines carbonyl] aniline] small oxo butyl- 2- carbamates (3.76 g, 8.71 mmol) it is dissolved in 50 mL ethanol, 5 mL concentrated hydrochloric acids are added dropwise into reaction bulb under ice bath, stir after half an hour, reaction is moved into oil bath and reacts 24 h under 85 °C, pH-8 is adjusted after cooling, concentration, prepare liquid phase purifying, obtain the g of white solid 0.95, the % of yield 31.2.

(7) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- (pyridin-4-yl amino) quinazoline -4 (3H) -one adds (5) -2- (1- aminopropyls) -5- fluoro- 3- (pyridin-4-yl amino) quinazoline that step is obtained into the 20 mL tert-butyl alcohols

- 4 (3H) -one hydrochloride (0.65 g, 1.86 mmol) and DIEA (0.6 mL, 3.44 mmol), stirred half an hour under ice bath, the chloro- 9H- purine of 6- (480 mg, 3.1 mmol) is then added thereto, reaction reacts 36 h at 85 °C, cooling, concentration, column chromatography（Ethyl acetate）, obtain the mg of white solid 101, the % of yield 12.6.

Mass spectrum（M+H): 432.2

1H-NMR( ₆-DMSO, 400 MHz):δ 9.78 (1H, d), 9.81-9.74 (1 Η, m), 9.72 (1 Η, d), 8.62 (1 Η, s), 8.31 (1H, s), 7.76 (1H, dd), 7.42 (1H, d), 7.36 (1H, d), 7.29 (1H, t), 7.15 (1H, d), 5.48 (1H, m), 2.27-2.14 (1H, m), 2.03-1.87 (1H, m), 1.06 (3H, t)

The iS of embodiment 46) and -2- " l- (9H- purine -6- bases amino) the chloro- 3-f5- fluorine pyridine -2- bases amino of ethyl 1-5-) quinazoline -4i3m- ketone（Compound 53) preparation

CF.COOH

(1) the fluoro- 2- hydrazino pyridines of 5-

2,5- difluoro pyridines (1.50 g, 13.0 mmol), 80% hydrazine hydrate (0.90 mL, 13.7 mmol) are added in microwave tube, microwave is heated to 120 V, reacts 1 hour.Room temperature is cooled to, is filtered, filter cake petroleum ether dries to obtain the mg of white solid 525, yield 31.8%.

(2) preparation of (5) -1- (the chloro- 4- oxos -4H- benzos of 5- [[1,3] oxazine -2- bases) ethylcarbamate

2- amino -6- chlorobenzoic acids (515 mg are added in 100 dry mL reaction bulbs, 3.0 mmol), (5) -2- (t-butoxycarbonyl amino) propionic acid (624 mg, 3.3 mmol), then the mL of pyridine 5.0 is added, triphenyl phosphite is eventually adding（1.10 g, 3.55 mmol), stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(3 ) (>S) the preparation of-l- [the chloro- 3- of 5- (5- fluorine pyridine -2- bases amino) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Preparing (5) -1- (chloro- 4- oxos -4H- benzos [[1 of 5-, 3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into fluoro- 2- hydrazino pyridines (420 mg of 5-, 3.3 mmol), return stirring reacts 8 hours in 100 °C of oil bath, then cool down, be concentrated under reduced pressure, column chromatography（PE:EA=10:1) purifying obtains the mg of weak yellow liquid 700, and two step yields are 53.7%.

(4) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (5- fluorine pyridine -2- bases amino) quinazoline -4 (3H) -one trifluoroacetate adds (5) -1- [the chloro- 3- of 5- (5- fluorine pyridine -2- bases amino) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate in 100 dry mL reaction bulbs（700 mg, 1.61 mmol) dissolved with 20.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 10.0 is added dropwise under ice cooling, 4, completion of dropping, then continue to stir at room temperature, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction. (5) prepared by (S) -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- (5- fluorine pyridine -2- bases amino) quinazoline -4 (3H) _ ketone dissolves previous step products therefrom with the 40.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, adjust pH to alkalescence system with DIEA, then add the chloro- 9H- purine of 6-（308 mg, 1.99 mmol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.190, two step yields 26.1%.Mass spectrum（Μ+Η): 451.7

'H-NMR^-DMSO, 400 MHz):δ 12.97 (IH, br s), 9.79,9.64 (IH, two singlets), and 8.19-8.07 (2H, m), 8.02-7.93 (IH, m), 7.81-7.58 (4H, m), 7.57-7.51 (IH, m), 7.06-6.95 (1H, m), 5.78,5.56 (IH, two multiplets), 1.61,1.44 (3H, two doublets)

The 2- of embodiment 47 " the fast cry of certain animals -6- bases amino of M9#-) -2,2,2- trifluoroethyls " the chloro- 3- 4- fluoroanilinos of -5-) quinazoline -40m-

(1) (5) -3, the preparation of 3,3- tri- fluoro- 2- (1- phenethyls imines) ethyl propionates

Glacial acetic acid (4.2 g, 70 mmol) is dissolved in 20 mL chloroform, (S)-l- phenyl ethylamines are added at room temperature（8.47 g, 70 mmol), 5 min of stirring are finished, 20 mL chloroformic solutions of the fluoro- ethyl 2-oxopropanoates of 3,3,3- tri- (10.88 g, 64 mmol) are added, the ho of back flow reaction 24 is spin-dried for solvent, column chromatography（PE:EA=100:1) g of product 8.2, yield 46.7% are obtained.

The preparation of (2) 3,3,3- tri- fluoro- 2- (1- phenyl-ethylenes amino) ethyl propionates

Will (<S) -3,3,3- tri- fluoro- 2- (1- phenethyls imines) ethyl propionates (8.2 g, 30 mmol) are dissolved in 20 mL triethylamine, and 16 h are stirred at room temperature.System is spin-dried for obtaining 8 g crude products to be directly used in next step.

(3) preparation of 2- amino -3,3,3- trifluoroacetic acid carbethoxy hydrochlorides

The upper g of step crude product 8 is dissolved in 20 mL ether, 8 mL 1 N HC1 is added, 16 h is stirred at room temperature. System is spin-dried for obtain 4 g crude products.

(4) 2- amino -3,3, the preparation of 3- trifluoroacetic acid hydrochlorides

The upper g of step crude product 4 is dissolved under 10 mL dense HC1,90 °C and reacts 8 h.Directly being spin-dried for system obtains 2.9 g crude products.

(5) preparation of 2- (t-butoxycarbonyl amino) -3,3,3- trifluoroacetic acids

The upper g of step crude product 2.9 is dissolved in the in the mixed solvent of 25 mL THF and 25 mL water in 100 mL reaction bulbs, sodium carbonate is added（2.8 g, 26.4 mmol), then add di-tert-butyl dicarbonate（2.88 g, 13.2 mmol), react at room temperature 16 h.The THF in system is spin-dried for, watery hydrochloric acid is neutralized to pH=2-3, and ethyl acetate extraction is dried, is spin-dried for obtaining the g of product 1.95.

(6) 1- (the chloro- 4- oxos -4H- benzos [[1 of 5-, 3] oxazine -2- bases) -2, the preparation of 2,2- trifluoroethyl t-butyl carbamates adds 2- amino -6- chlorobenzoic acids (987 mg, 5.75 mmol) in 100 dry mL reaction bulbs, 2- (t-butoxycarbonyl amino) -3,3,3- trifluoroacetic acids (1.95 g, 8.0 mmol), then the mL of pyridine 6 is added, triphenyl phosphite is eventually adding（L84 g, 5.9 mmol), 15 h are stirred in 55 °C of oil bath.System is directly used in next step reaction.

(7) preparation of 1- [the chloro- 3- of 5- (4- fluoroanilinos) -4- oxo -3,4- dihydroquinazoline -2- bases] -2,2,2- trifluoroethyl t-butyl carbamates

It is directly added into the reaction solution of upper step to fluorophenyl hydrazine hydrochloride（1.07 g, 6.58 mmol), return stirring reacts 8 hours in 100 °C of oil bath, then cools down, is concentrated under reduced pressure, passes through column chromatography（PE:EA=10:1-4:1) purifying obtains the mg of solid 330, and two step yields are 11.8%.

(8) preparation of 2- (1- amino -2,2,2- trifluoroethyls) the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one hydrochloride

1- [the chloro- 3- of 5- (4- fluoroanilinos) -4- oxo -3,4- dihydroquinazoline -2- bases] -2,2,2- trifluoroethyl t-butyl carbamates are added in 100 dry mL reaction bulbs（330 mg, 0.68 mmol), dissolved with 20.0 mL dichloromethanes protective embankments, HC1 gas is led under conditions of ice bath, reacted 2 h, after TLC detection raw material reactions completely, stop reaction, be then concentrated under reduced pressure, obtain the mg of crude product 300.

(9) preparation of 2- [l- (9H- purine -6- bases amino) -2,2,2- trifluoroethyls] the chloro- 3- of -5- (4- fluoroanilinos) quinazoline -4 (3H) -one

The mg of previous step products therefrom 300 is dissolved with 20.0 mL tert-pentyl alcohols in the reaction bulb that 100 mL are dried, the chloro- 9H- purine of 6- is then added（195 mg, 1.26 mmol), 5 drop glacial acetic acid are added, then 24 h are reacted in 90 °C of oil bath.Then cool down, neutrality is neutralized to saturated sodium bicarbonate aqueous solution, be concentrated under reduced pressure, column chromatography

(PE:EA=10:1-1 :3) mg of white solid 110, two step yields 32.0% are obtained.

Mass spectrum（M+H): 505.2 ¹H-NMR( -DMS0, 400 MHz):δ 12.96 (1H, s), 8.92 (1H, s), 8.50-8.20 (1H, m), 8.18-8.05 (2H, m), 7.85 (1H, t), 7.78 (1H, d), 7.66 (1H, t), 7.25-6.95 (1H, m), 6.80-6.45 (4H, m)

The SV2- of embodiment 48 " l-i9-purine-6- bases amino) the chloro- 3- dimethylaminos of ethyl 1-5-) 3 -one of quinazoline-4（Compound 57) preparation

(1) preparation of N- methyl-N-nitrosos methylamine

Dimethylamine hydrochloride is added in 250 dry mL reaction bulbs（4.89 g, 60.0 mmol), 50 mL glacial acetic acids are then slowly added into, natrium nitrosum is added dropwise under conditions of ice bath（5.38 g, 78.0 mmol) the 40 mL aqueous solution, completion of dropping is stirred overnight at room temperature.Detected under LC-MS after no raw material, stop reaction, gained reaction solution is directly used in next step reaction.

The preparation of (2) 1,1- dimethylhydrazine

In the reaction solution for preparing N- methyl-N-nitroso methylamines zinc powder is slowly added under conditions of ice bath（15.60 g, 239 mmol), add and be stirred at room temperature, until stop reaction without raw material under TLC detections, filter zinc powder, gained filtrate is directly used in the（4) step is reacted.

(3) preparation of (5) -1- (the chloro- 4- oxos -4H- benzos [d] of 5- [l, 3] oxazine -2- bases) ethylcarbamate

2- amino -6- chlorobenzoic acids (1.72 g, 10.0 mmol) are added in 100 dry mL reaction bulbs, (<S) -2- (t-butoxycarbonyl amino) propionic acid (2.08 g, 11.0 mmol), then add the mL of pyridine 10.0, are eventually adding triphenyl phosphite（3.10 g, 10.0 mmol), stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(4) (5) small [5- chloro- 3- (dimethylamino) -4- oxos -3,4- dihydroquinazoline -2- bases] ethylcarbamate preparation prepare (5) -1- (chloro- 4- oxos -4H- benzos [d] [l of 5-, 3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into 1,1- dimethylhydrazines, return stirring reacts 8 hours in 100 °C of oil bath, then cool down, be concentrated under reduced pressure Pass through column chromatography（PE:EA=10:1) purifying obtains the g of weak yellow liquid 1.42, and two step yields are 38.7%

(5) preparation of (5) -2- (1- amino-ethyls) -5- chloro- 3- (dimethylamino) quinazoline -4 (3H) -one trifluoroacetate

(5) -1- [the 4- dihydroquinazoline -2- bases of 5- chloro- 3- (dimethylamino) -4- oxos -3] ethylcarbamate is added in 100 dry mL reaction bulbs（The mmol of 0.710 g 1.94) dissolved with 20.0 mL dichloromethane, the mL of trifluoroacetic acid 10.0 is added dropwise under conditions of ice bath, completion of dropping, then continue to stir at room temperature, under TLC detections after raw material reaction completely, stop reaction, be then concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(6) prepared by (S) -2- [l-(9H- purine -6- bases amino) ethyl] -5- chloro- 3- (dimethylamino) quinazoline -4 (3H) _ ketone

The product of previous step institute is dissolved with the 40.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, with DIEA by system tune ρ Η to alkalescence, the then addition chloro- 9H- purine of 6-（The mmol of 0.330 g 2.13), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.270, the mass spectrum of two step yield 36.2%（Μ+Η): 384.80

'H-NMR^-DMSO, 400 MHz):δ 12.96 (1 Η, s), 8.15 (2H, s), 7.86-7.77 (1H m), 7.66 (1H t),

7.52-7.45 (2H, m), 5.83 (1H, m), 3.09, 3.07 (6H, two singlets), 1.57 (3H, d).

The quinazolinone of embodiment 49 (S -2- " l- (9H- purine -6- bases amino) ethyl " chloro- 3- of -5- " methyl f ethyls) amino 1

The preparation of (compound 59)

(1) preparation of N- methyl-N-nitrosos ethamine

N- Methylethyls amine (5.9 g lOO mmol) is dissolved in glacial acetic acid (50 mL), is placed under ice bath and stirs 10 minutes.It is slowly dropped to after natrium nitrosum (9.0 g, nOmmol) is dissolved in water (40 mL) in system, room temperature reaction 2 hours is moved to after completion of dropping.LC-MS monitoring reactions terminate, and system is directly used in next step.

(2) preparation of N- Methylethyls hydrazine

The reaction solution for preparing N- methyl nitroso ethamine is moved under ice bath and stirred, and addition zinc powder (mmol of 26 g 400) slowly, feeding after finishing, stirring half an hour then moves to room temperature reaction 12 hours under ice bath.TLC monitoring reaction knots Beam.Suction filtration, filter cake is washed with ethyl acetate, and filtrate is spin-dried for, and obtains the g of colorless oil 5.8, yield 78.3%.

(3) preparation of (5) -1- (the chloro- 4- oxos -4H- benzos of 5- [[1,3] oxazine -2- bases) ethylcarbamate

2- amino -6- chlorobenzoic acids (1.72 g are added in 100 dry mL reaction bulbs, 10.0 mmol), (S) -2- (t-butoxycarbonyl amino) propionic acid (2.37 g, 12.5 mmol), then the mL of pyridine 25 is added, triphenyl phosphite is eventually adding（3.40 g, 11.0 mmol), stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(4) preparation of (5) -1- [the chloro- 3- of 5- [methyl (ethyl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Preparing (5) -1- (chloro- 4- oxos -4H- benzos [[1 of 5-, 3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into N- Methylethyls hydrazine (1.11 g, 15.0 mmol), return stirring reacts 12 hours in 100 ° of 〇 oil bath, then cool down, be concentrated under reduced pressure, column chromatography（PE:EA=1 :1) purifying obtains the g of white solid 1.48, and two step yields are 38.9%.

(5) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- [methyl (ethyl) amino] quinazoline -4 (3H) -one

(5) small [the chloro- 3- of 5- [methyl (ethyl) amino] -4- oxos -3 are added in 100 dry mL reaction bulbs, 4- dihydroquinazoline -2- bases] ethylcarbamate (0.148 g, 0.389 mmol) dissolved with 10.0 mL dichloromethane, the mL of trifluoroacetic acid 5.0 is added dropwise under conditions of ice bath, completion of dropping, room temperature continues to stir, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(6) prepared by (5) -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- [methyl (ethyl) amino] quinazoline -4 (3H) -one dissolves the chloro- 3- of (5) -2- (1- amino-ethyls) -5- [methyl (ethyl) amino] (3H) -one of quinazoline -4 obtained by previous step with the 20.0 mL tert-butyl alcohols in the reaction bulb that lOO mL are dried, adjust pH to alkalescence system with DIEA, then add the chloro- 9H- purine of 6-（60 mg, 0.39 mmol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the mg of white solid 73, two step yields 47%.

Mass spectrum（Μ+Η): 399.2

1H-NMR( ₆-DMSO, 400 ΜΗζ):δ 12.95 (1 Η, br s), 8.19-8.10 (2H, m), 7.89-7.80 (0.5H, m), 7.73-7.62 (1.5H, m), 7.55-7.45 (2H, m), 6.10-5.81 (1H, m), 3.60-3.37 (1.5H, m), 3.26-3.14 (0.5H, m), 3.04,3.01 (3H, two singlets), and 1.60-1.53 (3H, m), 1.06 (3H, q)

The iS 2- of embodiment 50【L-f9-purine-6- bases amino) ethyl l- 3- dimethylaminos)-5- Fluquinconazoles quinoline-4 (3^) -one（Compound 60) preparation

(1) preparation of N- methyl-N-nitrosos methylamine

Dimethylamine hydrochloride is added in 250 dry mL reaction bulbs（4.89 g, 60.0 mrnol), 50 mL glacial acetic acids are then slowly added into, natrium nitrosum is added dropwise under conditions of ice bath（5.38 g, 78.0 mmol) the 40 mL aqueous solution, completion of dropping is stirred overnight at room temperature.Detected under LC-MS after no raw material, stop reaction, gained reaction solution is directly used in next step reaction.

(2) preparation of 1,1- dimethylhydrazines

In the reaction solution for preparing N- methyl-N-nitroso methylamines zinc powder is slowly added under conditions of ice bath（15.60 g, 239 mmol), add and be stirred at room temperature, until stopping reaction without raw material under TLC detections, filter zinc powder, concentrate filtrate, be directly used in four-step reaction.

(3) preparation of (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate

2- amino -6- fluobenzoic acids (1.55 g are added in 100 dry mL reaction bulbs, 10.0 mmol), (5) -2- (t-butoxycarbonyl amino) propionic acid (2.08 g, 11.0 mmol), then the mL of pyridine 10.0 is added, triphenyl phosphite is eventually adding（3.10 g, 10.0 mmol) stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(4) preparation of (5) -1- [3- (dimethylamino) -5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Preparing (- 1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into 1, the pyridine solution of 1- dimethylhydrazines, return stirring reacts 8 hours in 100 °C of oil bath, then cool down, be concentrated under reduced pressure, pass through column chromatography（PE:EA=10:1) purifying obtains the g of weak yellow liquid 2.42, and two step yields are 69.1%.

(5) (5) -2- (1- amino-ethyls) -3- (dimethylaminos）The preparation of -5- Fluquinconazoles quinoline -4 (3H) -one

(S)-l- [3- (dimethylamino) -5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases] ethylcarbamate is added in 100 dry mL reaction bulbs（2.42 g, 6.91 mmol) dissolved with 20.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 10.0 is added dropwise under conditions of ice bath, completion of dropping, continue to stir at room temperature, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction. (6) prepared by (3H) -one of (5) -2- [l- (9H- purine -6- bases amino) ethyl] -3- (dimethylamino) -5- Fluquinconazoles quinoline -4 dissolves previous step products therefrom with the 40.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, adjust pH to alkalescence system with DIEA, then add the chloro- 9H- purine of 6-（0.80 g, 5.18 mmol), back flow reaction 48 hours in 90 oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.260, two step yields 10.2%.Mass spectrum（M+H): 369.2

1H-NMR(J₍₅-DMSO, 400 MHz):(the 1H of δ 12.96, s), 8.15 (2 Η, s), 7.84-7.77 (1H, m), 7.72 (1H, dd), 7.36 (1H, d), 7.22 (1H, dd), 5.84 (1H, m), 3.09,3.07 (6H, two singlets), 1.58 (3H, d) embodiments 51 (S) -2- " l-i9#- purine -6- bases amino) ethyl 1-3- (methyl f ethyls) amino) (the preparation of 3^- ketone (compound 61) of -5- Fluquinconazoles quinoline -4

(1) preparation of N- methyl nitroso ethamine

N- Methylethyls amine (5.9 g, lOO mmol) is dissolved in glacial acetic acid (50 mL), is placed under ice bath and stirs 10 minutes.It is slowly dropped to after natrium nitrosum (9.0 g, 130mmol) is dissolved in water (40 mL) in system, room temperature reaction 2 hours is moved to after completion of dropping.LC-MS monitoring reactions terminate, and system is directly used in next step.

(2) preparation of N- Methylethyls hydrazine

The reaction solution for preparing N- methyl-N-nitroso ethamine is moved under ice bath and stirred, and addition zinc powder (26 g, 400 mmol) slowly, feeding after finishing, stirring half an hour then moves to room temperature reaction 12 hours under ice bath.TLC monitoring reactions terminate.Suction filtration, filter cake is washed with ethyl acetate, and filtrate is spin-dried for, and obtains the g of colorless oil 5.8, the yield 78.3% of above two-step reaction.

(3) preparation of (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate

2- amino -6- fluobenzoic acids (4.2 g are added in 100 dry mL reaction bulbs, 27.1 mmol), (5) -2- (t-butoxycarbonyl amino) propionic acid (6.4 g, 33.8 mmol), then the mL of pyridine 42 is added, triphenyl phosphite is eventually adding（9.2 g, 29.7 mmol), stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction. (⁴) (5) it is small [³- (methyl (ethyl) amino) -5- is fluoro-⁴- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate preparation

Preparing (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into N- Methylethyls hydrazine (2.2 g, 29.7 mmol), return stirring reacts 8 hours in 100 °C of oil bath, then cool down, be concentrated under reduced pressure, column chromatography (PE:EA=1 :1) purifying obtains the g of weak yellow liquid 3.5, and two step yields are 35.4%.

(5) preparation of (5) -2- (1- amino-ethyls) -3- (methyl (ethyl) amino) -5- Fluquinconazoles quinoline -4 (3H) -one

(5) small [3- (methyl (ethyl) amino) -5- fluorin-4-oxygens generation -3 is added in 100 dry mL reaction bulbs, 4- dihydroquinazoline -2- bases] ethylcarbamate (1.0 g, 2.74 mmol) dissolved with 15.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 5.0 is added dropwise under conditions of ice bath, completion of dropping, room temperature continues to stir, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(6) prepared by (5) -2- [l- (9H- purine -6- bases amino) ethyl] -3- (methyl (ethyl) amino) -5- Fluquinconazoles quinoline -4 (3H) -one

(3H) -one of (5) -2- (1- amino-ethyls) -3- (methyl (ethyl) amino) -5- Fluquinconazoles quinoline -4 obtained by previous step is dissolved with the 15.0 mL tert-butyl alcohols in the reaction bulb that lOO mL are dried, adjust ρ Η to alkalescence system with DIEA, add chloro- 9 Η of 6--purine（424 mg, 2.74 minol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the mg of white solid 80, two step yields 7.7%.

Mass spectrum（Μ+Η): 383.2

'H-NMR(^-DMSO, 400 MHz):δ 12.96 (1H, s), 8.25-8.06 (2 Η, m), 7.90-7.58 (2 Η, m), 7.43-7.34 (1H, m), 7.27-7.17 (1H, m), 6.09-5.82 (1H, m), 3.61-3.37 (1.5H, m), 3.27-3.15 (0.5 H, m), 3.05,3.01 (3H, two singlets), and 1.61-1.52 (3H, m), 1.06 (3H, q)

The fS of embodiment 52) -2-【W9 purine -6- bases amino) propyl group 1-3- (lignocaine) -5- Fluquinconazole quinoline ketone（Compound 62) preparation

(1) preparation of N- ethyls-N- nitroso ethamine

Diethylamine is added in 500 dry mL reaction bulbs（10.95 g, 150.0 mmol), 120 mL glacial acetic acids are then slowly added into, the 120 mL aqueous solution of natrium nitrosum (13.46 g, 195.0 mmol) are added dropwise under conditions of ice bath, completion of dropping is stirred overnight at room temperature.Then with dilute adjusting PH with base to neutrality, with dichloromethane protective embankment aqueous phase extracted, merge organic phase, with anhydrous sodium sulfate drying, be concentrated under reduced pressure, column chromatography（PE:EA=6:1) purifying obtains the g of weak yellow liquid 13.31, and yield is 87 %.

(2) preparation of 1,1- diethyl hydrazines

N- ethyl-N- nitroso ethamine is added in 50 dry mL reaction bulbs（1.02 g, 10.0 mmol), 3.0 mL glacial acetic acids are then added, zinc powder is slowly added under conditions of ice bath（2.60 g, 40.0 mmol), add and be stirred at room temperature, until stopping reaction without raw material under TLC detections, filter zinc powder, gained filtrate is directly used in four-step reaction.

(3) (5-1- (5- fluorin-4-oxygens generation-4H- benzos [] [l, 3] oxazine-2- bases) propylcarbamate preparation

The fluorine-based benzoic acid of 2- amino-6- (0.50 g is added in 100 dry mL reaction bulbs, 3.22 mmol), (5-2- (t-butoxycarbonyl amino) butyric acid (0.787 g, 3.87 mmol), then the mL of pyridine 8.0 is added, triphenyl phosphite (1.10 g, 3.55 mmol) is eventually adding, is stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(4) (5) -1- [3- (diethylamino) -5- fluorin-4-oxygens generations -3,4- dihydroquinazoline -2- bases] propylcarbamate preparation prepare (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [] [l, 3] oxazine -2- bases) propylcarbamate reaction solution in be directly added into 1,1- diethyl hydrazines, 100！Oil bath in return stirring react 8 hours, then cool down, be concentrated under reduced pressure, column chromatography（PE:EA=10:1) purifying obtains the g of weak yellow liquid 0.710, and two step yields are 56.2 %.

(5) preparation of (3H) -one of (5) -2- (1- aminopropyls) -3- (lignocaine) -5- Fluquinconazoles quinoline -4

(- 1- [3- (diethylamino) -5- fluorin-4-oxygens generation -3,4- dihydroquinazolines -2- are added in 100 dry mL reaction bulbs Base] propylcarbamate（0.710 g, 1.81 mmol) dissolved with 20.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 10.0 is added dropwise under conditions of ice bath, completion of dropping, then continue to stir under room temperature condition, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(6) prepared by (the 3H) _ ketone of (5) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (lignocaine) -5- Fluquinconazoles quinoline -4

The product of previous step institute is dissolved with the 40.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, with DIEA by system tune pH to alkalescence, the then addition chloro- 9H- purine of 6-（0.308 g, 1.99 mmol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.260, the % of two step yield 35.Mass spectrum（M+H): 411.20

1H-NMR( ₆-DMSO, 400 MHz):δ 12.99 (IH, s), 8.25-8.13 (2H, m), 7.81-7.73 (IH, m), 7.50-7.38 (2H, m), 7.32-7.15 (IH, m), 6.12 (IH, m), 3.71-3.20 (4H, m), 2.16-1.80 (2H, m), 1.22 (3H, m), 1.05-0.92 (6H, m)

The iS of embodiment 53) and-2- " W9 purine-6- bases amino) propyl group "-5- chloro- 3- (dimethylamino) (3 -one of quinazoline-4（Compound 63) preparation

(1) (the preparation of 5-1- (the chloro- 4- oxos-4H- benzos of 5- [[1,3] oxazine-2- bases) propylcarbamate

2- amino -6- chlorobenzoic acids (1.71 g, 10.0 mmol), (S) -2- (t-butoxycarbonyl amino) butyric acid are added in dry reaction bulb（2.23 g, 11.0 mmol) and triphenyl phosphite (3.10 g, 10.0 mmol), 10 mL pyridinium dissolutions are added,

55 ' C stirring reactions 8 hours, next step reaction is directly used in without processing.

(2) preparation of (5) -1- [5- chloro- 3- (dimethylamino) -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate

1,1- dimethylhydrazines (0.66 g, 11.0 mmol) are directly added into reaction system one step up, 100 °C of 8 h of reaction is warming up to, silica gel mixed sample, column chromatography (petroleum ether-petroleum ether is directly added into after cooling:Ethyl acetate=5:1) g of pale yellow oil 2.5 is obtained, two step yields are 65.6%.

(3) preparation of (5) -2- (1- aminopropyls) -5- chloro- 3- (dimethylamino) quinazoline -4 (3H) _ ketone

(5) small [5- chloro- 3- (dimethylamino) -4- oxos -3 are added in dry reaction bulb, 4- dihydroquinazoline -2- bases] propylcarbamate (2.5 g, 6.56 mmol), the dissolving of 20 mL dichloromethane is added, trifluoro is added dropwise under conditions of ice bath Room temperature reaction 2 hours is moved to after the mL of acetic acid 10, completion of dropping, stops rotation after reaction and removes solvent and trifluoracetic acid, products therefrom is directly used in next step reaction.

(4) preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] -5- chloro- 3- (dimethylamino) quinazoline -4 (3H) _ ketone

By previous step product dissolved with the 30 mL tert-butyl alcohols, add the chloro- 9H- purine of 6- (1.11 g, 7.18 mmol), DIEA (3.25 mL, 18.7 mmol), back flow reaction 48 hours in 90 °C of oil bath.Cooling, is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.230, two step yields 8.8%.

Mass spectrum (M+H): 399.2

'H-NMR(i/₆-DMSO, 400 MHz):δ 12.88 (1 Η, s), 8.15 (2H, s), 7.71-7.64 (1H, m), 7.64 (1H, t), 7.50-7.44 (2H, m), 5.78 (1H, m), 3.09,3.06 (6H, two singlets), 2.05-1.86 (2H, m), 1.03 (3H, t)

Embodiment 54 (S) -2- " l- (9H ~ purine -6- bases amino) propyl group " dimethylamino) -5- Fluquinconazole quinoline ketone（Chemical combination

(1) preparation of N- methyl nitroso methylamine

Dimethylamine hydrochloride is added in 250 dry mL reaction bulbs（4.89 g, 60.0 mmol), 50 mL glacial acetic acids are then slowly added into, natrium nitrosum is added dropwise under conditions of ice bath（5.38 g, 78.0 mmol) the 40 mL aqueous solution, completion of dropping is stirred overnight at room temperature.Detected under LC-MS after no raw material, stop reaction, gained reaction solution is directly used in next step reaction.

(2) preparation of 1,1- dimethylhydrazines

In the reaction solution for preparing N- methyl nitroso methylamines zinc powder is slowly added under conditions of ice bath（15.60 g, 239 mmol), add and be stirred at room temperature, until stopping reaction without raw material under TLC detections, filter zinc powder, concentrate filtrate, be directly used in the reaction of (4) step.

(3) preparation of (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) propylcarbamate 2- amino -6- fluobenzoic acids (1.55 g are added in 100 dry mL reaction bulbs, 10.0 mmol), (5) -2- (t-butoxycarbonyl amino) butyric acid (2.23 g, l l.O mmol), then the mL of pyridine 10.0 is added, triphenyl phosphite is eventually adding（3.10 g, 10.0 mmol), stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(4) preparation of (5) small [3- (dimethylamino) -5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases] propylcarbamate

Preparing (- 1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) propylcarbamate reaction solution in be directly added into 1, the pyridine solution of 1- dimethylhydrazines, return stirring reacts 8 hours in 100 ° 0 of oil bath, then cool down, be concentrated under reduced pressure, pass through column chromatography（PE:EA=10:1) purifying obtains the g of weak yellow liquid 2.12, and two step yields are 58.2%.

(5) preparation of (3H) -one of (5) -2- (1- aminopropyls) -3- (dimethylamino) -5- Fluquinconazoles quinoline -4

(5) -1- [3- (dimethylamino) -5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases] propylcarbamate is added in 100 dry mL reaction bulbs（2.12 g, 5.82 mmol) dissolved with 20.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 10.0 is added dropwise under conditions of ice bath, completion of dropping, then take and continue to stir in room temperature, under TLC detections after raw material reaction completely, stop reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(6) 0S) -2- [l- (9H- purine -6- bases amino) propyl group] -3- (dimethylamino) -5- Fluquinconazoles quinoline -4 (3H) -one prepare

The product of previous step institute is dissolved with the 40.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, with DIEA by system tune pH to alkalescence, the then addition chloro- 9H- purine of 6-（0.80 g, 5.18 mmol), back flow reaction 48 hours in 90 oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.230, two step yields 10.3%.Mass spectrum（M+H): 383.2

1H-NMR( ₆-DMSO, 400 MHz):δ 12.95 (1H, s), 8.15 (2 Η, s), 7.76-7.63 (2H, m), 7.35 (1H, d), 7.21 (1H, t), 5.80 (1H, m), 3.09,3.07 (6H, two singlets), 2.06-1.88 (2H, m), 1.03 (3H, t)

The iS V42- of embodiment 55 " l- (9 purine -6- bases amino) ethyl 1-5- fluorin-4-oxygens are for quinazoline -3f4g)-yl " acetamide hydrochloride（Compound 65) preparation

(1) preparation of (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate

2- amino -6- fluobenzoic acids (1.550 g, 10.0 mmol) are added in dry lOO mL reaction bulbs,（5) -2- (t-butoxycarbonyl amino) propionic acid (2.079 g, 11.0 mmol), the mL of pyridine 10.0 is then added, triphenyl phosphite (3.100 g are eventually adding, lO.O mmol), stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(2) preparation of (5) -1- (3- acetylaminohydroxyphenylarsonic acid 5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases) ethylcarbamate

Prepare (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [^] [1,3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into acethydrazide（0.814 g, 11.0 mmol), return stirring reacts 8 hours in 100 °C of oil bath, then cools down, is concentrated under reduced pressure, passes through column chromatography（PE:EA=2:1-100%EA) purifying obtains the g of faint yellow solid 0.53, and two step yields are 14.5%.

(3) CS)-N- [2- (l- amino-ethyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-yl] acetamide preparation

CS is added in 100 dry mL reaction bulbs)-l- (3- acetylaminohydroxyphenylarsonic acid 5- fluorin-4-oxygens generation -3,4- dihydroquinazoline -2- bases) ethylcarbamate（0.45 g, 1.23 mmol), dissolved with 20.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 5.0 is added dropwise under conditions of ice bath, then completion of dropping is taken and continue to stir in room temperature, under TLC detections after raw material reaction completely, stop reaction, be then concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(₄) ₆_ chlorine _₉_ (tetrahydrochysene _₂/ _ pyrans _₂_ yl) _ 9H- purine preparation

The chloro- 9H- purine of 6- is added in the reaction bulb of 100 dry mL（25.36 g, 164 mmol), one hydration p-methyl benzenesulfonic acid (0.565 g, 2.97 mmol) and dihydropyran (44.9 mL, 492 mmol) flowed back 2 hours in 90 °C of oil bath, room temperature is cooled to, with 2 N NaHC0₃(2X 100mL), the saline solution of saturation（50 mL) washing.Organic phase anhydrous sodium sulfate drying, is spin-dried for obtaining the g of white solid 36.1, yield： 92.1%.

(5) N- [5- fluorin-4-oxygens generation -2- [(15) -1- [9- (tetrahydrochysene -2H- pyrans -2- bases) -9H- purine -6- bases amino] ethyl] quinazolines - 3 (4H)-yls] acetamide preparation

The CS that obtains (3) step in the reaction bulb that 50 mL are dried)-N- [2- (l- amino-ethyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-yl] acetamides are with 5.0 mL n-Butanol solubles, adjust pH to alkalescence system with DIEA, then add 6- chloro- 9- (tetrahydrochysene -2H- pyrans -2- bases) -9H- purine（0.351 g, 1.47 mmol), back flow reaction 4 hours in 110 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares plate separation（Dichloromethane protective embankment:Methanol=13:1) g of faint yellow solid 0.135, two step yields 23.5% are obtained.

(6) preparation of (5)-N- [2- [l- (9H- purine -6- bases amino) ethyl] -5- fluorin-4-oxygens are for quinazoline -3 (4H)-yl] acetamide hydrochloride

By N- [5- fluorin-4-oxygens generation -2- [(15) -1- [9- (tetrahydrochysene -2H- pyrans -2- bases) -9H- purine -6- bases amino] ethyl] quinazoline -3 (4H)-yl] acetamide（0.13 g, 0.279 mmol) 5 mL methanol are dissolved in, adding 2 to system drips concentrated hydrochloric acid, after reaction is stirred 2 hours, is spin-dried for obtaining 0.13 g yellow solids.Yellow solid is dissolved with 3 mL methanol, the mL of ether 10 is then slowly added dropwise, solid is separated out, obtains talking the mg of yellow solid 57, yield 48.7% after filtering.

Mass spectrum（Μ+Η): 483.1

1H-NMR( ₆-DMS0, 400 ΜΗζ):δ 11.00 (1 Η, br s), 9.56-9.08 (1H, m), 8.65-8.51 (2H, m), 7.92-7.81 (1H, m), 7.62-7.51 (1H, m), 7.42-7.31 (1H, m), 5.77-5.55 (1H, m), 2.06,2.02 (3H, two singlets), 1.62,1.55 (3H, two doublets)

The iS V- of embodiment 56 " 2- " l- (9-purine-6- bases amino) ethyl 1-5- fluorin-4-oxygens are for quinazoline-3 (4g)-yl " Methanesulfomides

(l) CS)-l- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate preparation

2- amino -6- fluobenzoic acids (1.550 g are added in 100 dry mL reaction bulbs, 10.0 mmol), (5) -2- (t-butoxycarbonyl amino) propionic acid (2.079 g, 11.0 mmol), then the mL of pyridine 10.0 is added, triphenyl phosphite (3.100 g, 10.0 mmol) is eventually adding, is stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction. (2) (5) -1- [the fluoro- 3- of 5- (methylsulfonyl amido) -4- oxos -3,4- dihydroquinazoline -2- bases] preparation of ethylcarbamate is directly added into methylsulfonyl hydrazine in the reaction solution for preparing (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate（1.22 g, 11.1 mmol), at 100 °.Oil bath in return stirring react 8 hours, then cool down, be concentrated under reduced pressure, pass through column chromatography（PE:EA=4:1-2:1) purifying obtains the g of faint yellow solid 1.10, and two step yields are 27.50%.

(3) preparation of (5)-N- [2- (l- amino-ethyls) -5- fluorin-4-oxygens are for quinazoline -3 (4H)-yl] Methanesulfomide

(5) -1- [the fluoro- 3- of 5- (methylsulfonyl amido) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate is added in dry lOO mL reaction bulbs（0.52 g, 1.30 mmol), dissolved with 20.0 mL dichloromethanes protective embankments, the mL of trifluoroacetic acid 10.0 is added dropwise under conditions of ice bath, completion of dropping continues to stir at room temperature, under TLC detections after raw material reaction completely, stop reaction, be concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(4) CS) preparation of-N- [2- [l- (9H- purine -6- bases amino) ethyl] -5- fluorin-4-oxygens are for quinazoline -3 (4H)-yl] Methanesulfomide dissolves previous step products therefrom with the 10.0 mL tert-butyl alcohols in the reaction bulb that 50 mL are dried, adjust ρ Η to alkalescence system with DIEA, then add the chloro- 9H- purine of 6-（0.239 g, 1.55 mmol), back flow reaction 48 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.152, two step yields 27.9%.Mass spectrum（Μ+Η): 419.1

Beautiful-wake up SO, 400 Μ Η ζ):δ 13.01 (1H, s), 11.12 (1 Η, br s), and 8.24-8.10 (2H, m), 7.89-7.78 (2H, m), 7.48 (1H, d), 7.33 (1H, t), 5.83 (1H, m), 3.35 (3H, s), 1.59 (3H, m)

The ffl-2- of embodiment 57 " l-i9 purine -6- bases amino) the fluoro- 3- of propyl group 1-5- (isoindoline -2- bases) quinazoline -4am- ketone

(1) preparation of isoindoline -2- carbamates 1 is added in dry reaction bulb, 2- bis- (bromomethyl) benzene (5.28 g, 20 mmol) and tertbutyloxycarbonyl hydrazine (2.64 g, 20 mmol), the DMF dissolvings that 10 mL are dried, 50 °C are warming up to, triethylamine (5.6 mL, 40.2 mmol) is slowly added to, maintain thermotonus half an hour, room temperature is cooled to afterwards to continue to react 3 hours, is added water, ethyl acetate is extracted three times, organic phase is washed with water, dry, be concentrated to give crude product 4.0 g, the thick % of yield 85.4.

(2) preparation of isoindoline -2- amine hydrochlorates

In dry reaction bottle, isoindoline -2- carbamates (4.0 g, 17.1 mmol) and 10 mL absolute methanols are added, dry hydrogen chloride gas is passed through, is reacted 1 hour, filtering, obtain the g of white solid 2.7, the % of yield 92.5.

(3) preparation of (5) small (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) propylcarbamate

In dry stand up reaction bottle, add fluoro- 2- aminobenzoic acids (1.0 g of 6-, 6.45 mmol), (5) -2- t-butoxycarbonyl aminos butyric acid (1.44 g, 7.09 mmol) and triphenyl phosphite (2.36 g, 7.61 mmol), add 10 mL pyridines and make solvent, 12 h are reacted under 55 °C, without processing, next step reaction are directly carried out.

(4) preparation of (5) small [the fluoro- 3- of 5- (isoindoline -2- bases) -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate

In the reaction system of previous step, isoindoline -2- semicarbazide hydrochlorides (1.21 g, 7.09 mmol) are directly added into, 100 ' C is warming up to and reacts 10 h, silica gel mixed sample, column chromatography are directly added into after cooling（Petroleum ether:Ethyl acetate=3:1) g of white solid 1.4 is obtained, two step yields are 49.5 %.

(5) preparation of the fluoro- 3- of (5) -2- (1- aminopropyls) -5- (isoindoline -2- bases) quinazoline -4 (3) -one trifluoroacetate

In dry reaction bulb, (5) small [the fluoro- 3- of 5- (different 0 draws diindyl quinoline -2- bases) -4- oxo -3,4- dihydroquinazoline -2- bases] propylcarbamate is added（0.65 g, 1.48 mmol), dichloromethane protective embankment 5 mL, the mL of trifluoracetic acid 5 are added, 3 h are stirred at room temperature, stops rotation after reaction and removes solvent, the g of grease 0.64 is obtained, yield is 95.6 %.

(6) (5) -2- (1- aminopropyls) -3- (isoindoline -2- bases) -5- fluoro- quinazoline -4 (3H) -one trifluoroacetates (0.64 g is added in the dry reaction bulb of the preparation of (5) -2- [l- (9H- purine -6- bases amino) propyl group] the fluoro- 3- of -5- (isoindoline -2- bases) quinazoline -4 (3H) -one, 1.41 mmol), chloro- 9H- purine (0.26 g of 6-, 1.68 mmol), add the 10 mL tert-butyl alcohols, DIEA (1.45 mL, 8.33 mmol), 9 (react 12 h under TC, directly it is spin-dried for, prepare liquid phase and purify to obtain white solid 0.29_g, yield is 45.1 %.

Mass spectrum（Μ+Η): 457.2

1H-NMR(i/₆-DMSO, 400 ΜΗζ):δ 12.95 (IH, s), 8.15 (2H, s), 7.86-7.70 (2H, m), 7.42 (1H, d), 7.37-7.19 (5H, m), 5.95 (1H, m), 4.91 (IH, d), 4.82-4.69 (2H, m), 4.51 (IH, d), 2.13-1.92 (2H, m), 1.02 (3H, t)

(S-the 2- of embodiment 58【L-i9^T- purine-6- bases amino) ethyl " the chloro- 3-f5- fluoro indole quinolines-1- bases of-5-) (3 -one of quinazoline-4

(1) preparation of 5- fluoro indole quinolines

In 250 mL round-bottomed flask, the fluoro- 1H- indoles of the mL of glacial acetic acid 150 and 5- is added（12 g, 88.8 mmol), weigh sodium cyanoborohydride（11.2 g, 178 mmol) it is added portionwise in system, LC-MS monitoring reaction process, room temperature reaction in 2.5 hours is complete.System is poured into frozen water, pH value is adjusted to neutrality with 40% sodium hydroxide, is extracted three times with dichloromethane, merge organic phase, be spin-dried for obtaining the g of product 11.4, yield 93.6%.

(2) preparation of the fluoro- 1- nitroso-indols quinolines of 5-

In 250 mL round-bottomed flask, under ice bath, 5- fluoro indole quinolines（10 g, 72.9 mmol) it is dissolved in 75 mL glacial acetic acid, then it is added dropwise into solution dissolved with natrium nitrosum（5.5 g, 79.7 mmol) the 80 mL aqueous solution, control system temperature be no more than 20.C, LC-MS monitor reaction process, react 3 hours.PH value is adjusted to neutrality with 40% sodium hydroxide under ice bath, is extracted with ethyl acetate three times, merges organic phase, concentration, column chromatography（PE:EA=10:1) g of brown solid 10.5, yield 86.7% are obtained.

(3) preparation of 5- fluoro indole quinolines -1- amine

In the three-necked bottle that 500 mL are dried, the fluoro- 1- nitroso-indols quinolines of 5- are added（10 g, 60.2 mmol), the dry mL of tetrahydrofuran 150, system nitrogen displacement.System is placed in ice-water bath, adds in the 1M mL of Lithium Aluminium Hydride 90, ice-water bath and reacts 4 hours into system.After reaction completely, 120 mL ethyl acetate are added dropwise and are quenched, the mL of sodium hydroxide solution 100 that 40% is added dropwise after 1 hour is stirred 30 minutes, ethyl acetate extraction, point liquid , Nong Shrink organic phases, column chromatography (DCM:C¾OH=20:1) g of brown solid 6.3 is obtained, yield is 68.8%.

(4) preparation of (5) -1- (the chloro- 4- oxos -4H- benzos of 5- [[1,3] oxazine -2- bases) ethylcarbamate

In dry reaction bulb, 2- amino -6- chlorobenzoic acids (2 g, 11.7 mmol), (5) -2- (tertbutyloxycarbonyl ammonia are separately added into Base) propionic acid（2.4 g, 12.7 mmol), 20 mL B are than pyridine, triphenyl phosphite（3.63 g, 11.7 mmol), 55.Reacted 10 hours in C oil baths, be directly used in next step reaction.

(5) preparation of (5) -1- [the chloro- 3- of 5- (the small base of 5- fluoro indole quinolines) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Upwards in step reaction system, 5- fluoro indole quinoline -1- amine is added（1.78 g, 11.7 mmol), 100 °C of reactions are heated to, LC-MS monitoring reaction process reacts 16 hours most of raw materials and disappeared.Solvent is spin-dried for, the g of buff white solid 2 is obtained with preparation chromatographic isolation, in summary two step yields： 37.3%.

(6) preparation of the chloro- 3- of (5) -2- (1- amino-ethyls) -5- (5- fluoro indole quinoline -1- bases) quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb, by (5) small [the chloro- 3- of 5- (the small base of 5- fluoro indole quinolines) -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate（1 g, 2.2 mmol) it is dissolved in 20 mL Isosorbide-5-Nitraes-dioxane, hydrogen chloride gas is led into system, LC-MS monitoring reaction process, reaction in 4 hours is complete, and revolving removes solvent, obtains product（Hydrochloride）0.86 g, yield 99%.

(7) in the dry reaction bulb of the preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 3- of -5- (5- fluoro indole quinoline -1- bases) quinazoline -4 (3H) -one, 0S is added into the 30 mL tert-butyl alcohols) the chloro- 3- of -2- (l- amino-ethyls) -5- (5- fluoro indole quinoline -1- bases) (3H) the -one hydrochlorides of quinazoline -4 (0.2 g, 0.51 mmol) and DIEA (0.261 g, 2.02 mmol), then fast cry of certain animals (86 mg of the chloro- 9H- of 6- are added thereto, 0.56 mmol), reaction is reacted 18 hours under 90 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of faint yellow solid 35, yield 14.4%.

Mass spectrum（M+H): 476.8

'H-NMRC^-DMSO, 400 MHz):δ 12.90 (1 Η, br s), 8.25-7.97 (3H, m), 7.76-7.64 (1H, m), 7.61-7.45 (2H, m), 7.07 (1H, d), 6.81 (1H, t), 6.63-6.52 (1H, m), 5.84 (1H, m), 4.17-4.03 (1H, m), 4.03-3.88 (1H, m), 3.24-3.13 (1H, m), 3.05-2.86 (1H, m), 1.55 (3H, d)

(5-the 2- of embodiment 59【L- (9H- purine -6- bases amino) the chloro- 7- of ethyl 1-5- fluoro- 3- (anilino-) quinazolinone（Compound 72) preparation

(1) preparation of N- (the chloro- 5- fluorophenyls of 3-) -2- (hydroxyl imide) acetamide

In 2 L reaction bulb, chloral hydrate (6.19 g, 37.4 mmol) and anhydrous sodium sulfate（53 g, 373 mmol) it is dissolved in 100 mL water, add 2.6 mL concentrated hydrochloric acids.The chloro- 5- fluoroanilines of 3- (5.0 g, 34.3 mmol) are added in above-mentioned reaction solution, will be dissolved with hydroxylamine hydrochloride（7.3 g, 105 mmol) 30 mL solution be added in system, finish rear reaction solution and be warming up to the h of back flow reaction 2, then cooling down, is filtered when temperature is down to 50 °C, and flaxen filter cake is washed with clear water and dried after three times, obtain 5.5 g, yield 74.1%.

(2) preparation of the chloro- 6- fluoro indole quinolines -2,3- diketone of 4-

In dry reaction bulb, the mL of the concentrated sulfuric acid 20 is heated to 55 °C, by dry N- (the chloro- 5- fluorophenyls of 3-) -2- (hydroxyl imide) acetamide（5 g, 23.1 mmol) add in batches in upper reaction bulb, keep system temperature to be no more than 65 °C, 100 °C are warming up to after finishing and is reacted 1 hour, room temperature is then cooled to.It is poured into 200 mL frozen water and stirs half an hour, brown solid is separated out, is dried after filtering, obtain 3.2 g products, the % of yield 69.3.

(3) preparation of the chloro- 4- fluobenzoic acids of 2- amino -6-

42 mL 5% sodium hydroxide solution and 42 mL 30% hydrogen peroxide solution are added in dry reaction bulb, chloro- 6- fluoro indole quinolines -2, the 3- diketone of 4- is added in batches（3 g, 15 mmol) after be warming up to 50 °C reaction 1 h, then cool, filter, filtrate adjusts pH to 4, there is solid precipitation, filters, filtrate is extracted with ethyl acetate, it is spin-dried for, merges filter cake, be dried to obtain the g of faint yellow solid 1.7, yield 59.8%.

(4) preparation of (5) -1- (5- chloro- 7- fluorin-4-oxygens generation -4H- benzos [] [l, 3] oxazine -2- bases) ethylcarbamate

In dry reaction bulb, the chloro- 4- fluobenzoic acids of 2- amino -6- (1.5 g, 7.91 mmol), (5 are separately added into>2- (t-butoxycarbonyl amino) propionic acid（1.7 g, 8.99 mmol), 10 mL pyridines, triphenyl phosphite (2.4 g, 7.73 mmol), Reacted 10 hours in 55 °C of oil baths, be directly used in next step reaction.

(5) (5)-H5- chloro- 7- fluorin-4-oxygens generation -3- (anilino-) -3,4- dihydroquinazoline -2- bases] ethylcarbamate preparation

Upwards in step reaction system, hydrazinobenzene hydrochloride salt is added（1.27 g, 8.78 mmol), it is heated to 100 °C and reacts 8 hours.It is spin-dried for solvent, column chromatography (petroleum ether:Ethyl acetate 6:1) g of light yellow solid 2.0, two step yields are obtained： 58.4%.

(6) preparation of (5) -2- fluoro- 3- of (1- amino-ethyls) the chloro- 7- of -5- (anilino-)-quinazoline -4 (3H) -one hydrochloride

In dry reaction bulb, by CS)-l- [chloro- 7- fluorin-4-oxygens generation -3- (anilino-) -3, the 4- dihydroquinazoline -2- bases of 5-] ethylcarbamate（0.86 g, 2.0 mmol) it is dissolved in ethyl acetate（40 mL) in, hydrogen chloride gas is led into system until reaction is complete, revolving removes solvent, obtains the g of product 0.7, yield 95%.

(7) (in the reaction bulb of the preparation drying of 5 2- [l- (9H- purine -6- bases amino) ethyl] the chloro- 7- of -5- fluoro- 3- (anilino-) quinazoline -4 (3H) -one, (- 2- fluoro- the 3- of (1- amino-ethyls) the chloro- 7- of -5- (anilino-)-(3H) the -one hydrochloride of quinazoline -4 (0.7 g are added into the 30 mL tert-butyl alcohols, 1.9 mmol) and DIEA (0.98 g, 7.6 mmol), then chloro- 9H- purine (0.29 g of 6- are added thereto, 1.9 mmol), reaction is reacted two days under 90 °C, cooling, concentration, prepare chromatographic isolation and obtain the mg of white solid 120, yield 14.0%.

Mass spectrum（M+H): 451.1

¹H-NMR (^-DMSO, 400 MHz):δ 12.98 (1H, br s), 9.22,9.02 (IH, two singlets), and 8.25-8.08 (2H, m), 7.94-7.71 (1H, m), 7.61-7.51 (IH, m), 7.48-7.15 (3H, m), 7.10-6.71 (3H, m), 5.85,5.49 (IH, two br s), 1.65,1.46 (3H, two doublets)

The iS of embodiment 60>- 2-il-i9 purine -6- bases amino) ethyl 1-5- fluoro- 34 (4- luorobenzyls) (methyl) amino 1 quinazoline -4 (3H)-m (compound 73) preparation

(1) preparation of N- (4- luorobenzyls)-N- nitroso methylamines

By 1- (4- fluorophenyls) methyl methylamine（4.2 g, 30 mmol) it is dissolved in glacial acetic acid (60 mL), it is placed under ice bath and stirs 10 minutes.It is slowly dropped to after natrium nitrosum (9.0 g, 130 mmol) is dissolved in water (40 mL) in system, room temperature reaction 2 hours is moved to after completion of dropping.LC-MS monitoring reactions terminate, and system is directly used in next step.

(2) preparation of 1- (4- luorobenzyls) -1- methyl hydrazines

The reaction solution of previous step is moved under ice bath and stirred, and addition zinc powder (7.8 g, 119 mmol) slowly, feeding after finishing, stirring half an hour then moves to room temperature reaction 12 hours under ice bath.TLC monitoring reactions terminate.Suction filtration, filter cake is washed with ethyl acetate, and filtrate is spin-dried for, and obtains the g of white solid 2.3.Yield 49.7%.

(3) preparation of (5) -1- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate

The fluorine-based benzoic acid of 2- amino -6- (1.55 g are added in 100 dry mL reaction bulbs, 10.0 mmol), (5) -2- (t-butoxycarbonyl amino) propionic acid (2.37 g, 12.5 mmol), then the mL of pyridine 25 is added, triphenyl phosphite (3.40 g, 11.0 mmol) is eventually adding, is stirred 10 hours in 55 °C of oil bath.System is directly used in next step reaction.

(4) preparation of (5) -1- [the fluoro- 3- of 5- [(4- luorobenzyls) (methyl) amino] -4- oxo -3,4- dihydroquinazoline -2- bases] ethylcarbamate

Preparing CS)-l- (5- fluorin-4-oxygens generation -4H- benzos [[1,3] oxazine -2- bases) ethylcarbamate reaction solution in be directly added into 1- (4- luorobenzyls) -1- methyl hydrazines (1.85 g, 12.0 mmol), return stirring reacts 12 hours in 100 °C of oil bath, then cool down, be concentrated under reduced pressure, column chromatography（PE:EA=10:1) g of white solid 1.92 is purified to obtain, two step yields are 43.2%.

(5) preparation of the fluoro- 3- of (5) -2- (1- amino-ethyls) -5- [(4- luorobenzyls) (methyl) amino] quinazoline -4 (3H) -one

Added in dry lOO mL reaction bulbs (5-1- [the fluoro- 3- of 5- [(4- luorobenzyls) (methyl) amino]-4- oxo-3,4- dihydroquinazolines _₂- yl] ethylcarbamate (890 mg, 2.0 mmol) dissolved with 7.0 mL dichloromethane, the mL of trifluoroacetic acid 3.0 is added dropwise under conditions of ice bath, completion of dropping, room temperature continues to stir, and under TLC detections after raw material reaction completely, stops reaction, then it is concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(6) preparation of (5) -2- [l- (9H- purine -6- bases amino) ethyl] the fluoro- 3- of -5- [(4- luorobenzyls) (methyl) amino] quinazoline -4 (3H) -one

The fluoro- 3- of (5) -2- (1- amino-ethyls) -5- [(4- luorobenzyls) (methyl) amino] (3H) -one of quinazoline -4 obtained by previous step is dissolved with the 20.0 mL tert-butyl alcohols in the reaction bulb that 100 mL are dried, adjust pH to alkalescence system with DIEA, then add the fast cries of certain animals of the chloro- 9H- of 6-（308 mg, 2.0 mmol), back flow reaction 24 hours in 90 °C of oil bath.Then cooling is concentrated under reduced pressure, and prepares chromatographic isolation and obtains the g of white solid 0.260, two step yields 28.1%.

Mass spectrum（M+H): 463.3 1H-NMR( (i-DMSO, 400 MHz):5 12.94 (1H, s), 8.25-8.08 (2H, m), 7.97-7.60 (2H, m), 7.58-7.43 (2H, m), 7.39 (1H, t), 7.25 (1H, dd), 7.19 (1H, t), 7.06 (IH, t), 6.19-5.95 (1H, m), 4.72-4.41 (2H, m), 3.02-2.90 (3H, m), 1.54, (1.46 3H, two doublets)

Claims (1)

1. Claim

   1st, formula（I compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing shown in):

   Wherein：

   X¹, X², X³, X⁴, Y is separately N or CR³, R³For hydrogen, halogen, hydroxyl, carboxyl, trifluoromethyl .6 alkyl, C_1-6Alkoxy ,-N (R^A)(R^A'；), cyano group, alkenyl, alkynyl, carbamoyl, C^ alkyl formyl radicals, amino-sulfonyl, 3-14 yuan of rings protective embankments base, 6-14 members aryl, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases；

   L is covalent bond or-N (R^A)-_;

   When L is covalent bond, R¹For benzo C₃^ rings mono alkenyl, benzo C₄_₈Cycloalkadienyl, ring monoene and phenyl and C₄.₈Cyclic diolefine and phenyl, by（Phenyl or 5-6 unit monocycle heteroaryls）With（C₃.₈Ring mono alkenyl, cycloalkadienyl or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^BSubstitution,

   L is-N (R^A)-when, R¹For₆Protective embankment base, Cw protective embankment bases formoxyl, CL₆Alkyl sulphonyl, 3-14 yuan of rings protective embankments base, 6-14 members aryl, 6-14 member aryl C_MProtective embankment base, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^BSubstitution,

   R^A、 R^A' independently represent hydrogen, protective embankment base, CM alkenyls, C₂_₆Alkynyl, 3-14 yuan of rings protective embankment bases, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

   Z is -0-,-C (R⁴'R⁴)-or-N (R⁴)-;

   W is -0-,-C (R⁵'R⁵)-or-N (R⁵)-;

   R⁴, R⁴', R⁵, R⁵' it is separately hydrogen, C^ protective embankments base or 3-14 yuan of rings protective embankment bases unsubstituted or replaced by least one hydroxyl or at least one halogen；

   R²To be unsubstituted or by least one R^BSubstituted 6-10 membered bicyclic heterocycle protective embankments base, by（Phenyl or 5-6 unit monocycle heteroaryls）With（5-6 unit monocycle heteroaryls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases； R^bFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino, C_1-6Protective embankment base amido, two (Cw protective embankments base) amidos, carboxyl, amino-sulfonyl, carbamoyl, protective embankment base, C_1-6Protective embankment epoxide, halo C_1-6Alkyl, halo C_1-6Protective embankment epoxide, hydroxyl C_1-6Alkyl, amino C_1-6Protective embankment epoxide, carboxyl C_1-6Protective embankment base, carbamoyl C_1-6Alkyl .6 protective embankment base carbonyloxy groups, C_{1 -6}Protective embankment Epoxide carbonyl, C_1-6Alkyl-carbonyl, C_2-6Alkenyl, C₂Alkynyl, 3-14 yuan of rings protective embankment bases, 3-14 member cycloalkyl oxies, 6-14 member aryl, 6-14 member aryloxies, 3-14 circle heterocycles bases, 3-14 circle heterocycles base epoxides, 7-12 member loop coil bases or 7-12 member bridged ring bases.

   2nd, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing：Wherein-

   X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, C_1-6Alkyl, CL₆Alkoxy ,-N (R^A)(R^A'), cyano group, alkenyl, C₂Alkynyl, 3-8 unit monocycles cycloalkyl, phenyl or 3-8 unit monocycle heterocycle protective embankments base, 3-8 circle heterocycles alkenyl, 5-6 unit monocycle heteroaryls；

   Y is N;

   When L is covalent bond, R¹For benzo C_3-8Ring mono alkenyl, benzo cycloalkadienyl, ring monoene and phenyl and ^₈Cyclic diolefine and phenyl, by（Phenyl or 5-6 unit monocycle heteroaryls）With（C^ rings mono alkenyl, C cycloalkadienyls or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^BSubstitution,

   L is-N (R^A)-when, R¹For C_1-6Alkyl, C_1-6Alkyl formyl radical, C^ protective embankment bases sulfonyl, 3-14 yuan of rings protective embankments base, 6-14 members aryl, 6-14 member aryl CM alkyl, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^BSubstitution,

   R^A、 R^A' independently represent hydrogen, alkyl, alkenyl, C₂.₆Alkynyl, 3-14 member cycloalkyl, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

   Z is-C (R⁴'R⁴)-;

   W is-N (R⁵)-;

   R⁴, R⁴', R⁵It is separately hydrogen, that is unsubstituted or being replaced by least one hydroxyl or at least one halogen₆Protective embankment base or 3-14 yuan of rings protective embankment bases；

   R²To be unsubstituted or by least one R^BSubstituted 6-10 membered bicyclic heterocycle protective embankments base, by（Phenyl or 5-6 unit monocycle heteroaryls）With（5-6 unit monocycle heteroaryls）Condense obtained bicyclic heteroaryl, 7-12 member loop coil bases or 7-12 member bridged ring bases；

   R^BFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino, protective embankment base amido, two (- 6 protective embankment base) amidos, carboxyl, Amino-sulfonyl, carbamoyl, Cw alkyl, C_1-6Protective embankment epoxide, halo Cw protective embankment bases, halo C_1-6Protective embankment epoxide, hydroxyl.^ alkyl, amino C_1-6Protective embankment epoxide, carboxyl C_1-6Protective embankment base, carbamoyl C^ protective embankment bases, C_1-6Protective embankment base carbonyloxy group, C_1-6Protective embankment Epoxide carbonyl, C₆Alkyl-carbonyl, C_2-6Alkenyl, alkynyl, 3-8 member cycloalkyl, 3-8 yuan of rings protective embankment base epoxides, phenyl, phenyl epoxide, 3-8 unit monocycles Heterocyclylalkyl, 3-8 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 3-8 unit monocycle heterocycle protective embankment bases epoxide, 3-8 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

   3rd, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing, there is following structure：

   Wherein X¹, X², X³, X⁴, Y, L, R¹, R², R⁴And R⁵With implication as described in claim 1.

   4th, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing, wherein：

   X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, Q_₆Protective embankment base, C₆Alkoxy or amino；

   Y is N;

   L is covalent bond, R¹Serve as reasons（Phenyl or 5-6 unit monocycle heteroaryls）With（C^ rings mono alkenyl, C cycloalkadienyls or 3-8 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl or 7-12 member spiro heterocyclic radicals, and R¹Optionally by 1-3 R^bSubstitution,

   Z is-CH (R⁴)-;

   W is-N (R⁵)-;

   R⁴, R⁵It is separately hydrogen, d_ that is unsubstituted or being replaced by least one hydroxyl or at least one halogen₃Protective embankment base or 3-5 member cycloalkyl；

   R^bFor hydrogen, oxo, halogen, cyano group, C_1-3Alkyl, C_1-3Protective embankment epoxide, trifluoromethyl, amino or 3-8 unit monocycle heterocycle protective embankments base, 3-8 circle heterocycles alkenyl, 5-6 unit monocycle heteroaryls.

   5th, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing：Wherein：

   X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, fluorine, chlorine, trifluoromethyl or methyl；

   Y is N;

   L is covalent bond, R¹Serve as reasons（Phenyl or 5-6 unit monocycle heteroaryls）With（C^ rings mono alkenyl, C^ cycloalkadienyls or 5-6 circle heterocycles alkenyls）Condense obtained bicyclic heteroaryl or 7-12 member spiro heterocyclic radicals, and R¹Optionally by 1-3 R^BSubstitution,

   Z is-CH (R⁴)-, R⁴For hydrogen, d. that is unsubstituted or at least being replaced by a hydroxyl or fluorine₃Protective embankment base or cyclopropyl；W is-N R⁵)-, R⁵It is separately hydrogen or methyl；

   R^BFor halogen.

   6th, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing：Wherein-

   X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, C protective embankments base, CL₆Protective embankment epoxide ,-N (R^A)(R^A') or cyano group；

   Y is N;

   L is-N (R^A)-, R¹For alkyl, C^ protective embankment bases formoxyl, C alkyl sulphonyls, 3-6 yuan of rings protective embankments base, 6-14 members aryl, 6-14 member aryl C_1-3Protective embankment base, 3-14 circle heterocycles base, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^BSubstitution,

   R^a、 R^a' independently represent hydrogen, d.₆Protective embankment base, C alkenyls, C₂.₆Alkynyl, 3-14 member cycloalkyl, 6-14 member aryl, 3-14 circle heterocycles bases, 7-12 member loop coil bases or 7-12 member bridged ring bases；

   Z is-CH (R⁴)-;

   W is-N (R⁵)-;

   R⁴, R⁵It is separately hydrogen, C that is unsubstituted or being replaced by least one hydroxyl or at least one halogen_WProtective embankment base or 3-5 yuan of rings protective embankment bases；

   R^bFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino, C_1-6Protective embankment base amido, two (C₆Protective embankment base) amido, carboxyl, amino-sulfonyl, carbamoyl, C_1-6Wash epoxide, C_1-6Protective embankment base, halo C_1-6Protective embankment base, 3-6 member cycloalkyl, 3-6 member cycloalkyl oxies, 3-8 unit monocycle heterocycle protective embankments base, 3-8 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 3-8 unit monocycle heterocycle protective embankment bases epoxide, 3-8 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

   7th, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing-wherein-

   X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, halogen, hydroxyl, trifluoromethyl, C^ alkyl or d.₆Alkoxy；

   Y is N;

   L is-N (R^a)-, R¹For₃Alkyl, d-₃Protective embankment base formoxyl, Cw alkyl sulphonyls, 3-6 yuan of rings protective embankments base, 6-14 members aryl, 6-14 member aryl C_1-3Alkyl, 5-6 unit monocycle heterocycle protective embankments base, 5-6 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 6-10 membered bicyclics Heterocyclylalkyl, 7-12 member loop coil bases or 7-12 member bridged ring bases, and R¹Optionally by 1-3 R^bSubstitution,

   R^aRepresent hydrogen, Cw protective embankments base, 3-14 yuan of rings protective embankment bases or 6-14 member aryl；

   Z is-CH (R⁴)-, R⁴For hydrogen, that is unsubstituted or being replaced by least one hydroxyl or at least one halogen₃Protective embankment base or cyclopropyl；

   W is-N (R⁵)-, R⁵It is separately hydrogen or methyl；

   R^BFor hydrogen, oxo, halogen, cyano group, hydroxyl, amino, C alkyl amine groups, two (d.₆Protective embankment base) amido, Q_₆Alkoxy, _₆Alkyl, halo C_1-6Alkyl, 3-6 yuan of rings protective embankment bases, 3-6 yuan of rings protective embankment base epoxides, 5-6 unit monocycles Heterocyclylalkyl, 5-6 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 5-6 unit monocycle heterocycle protective embankment bases epoxide, 5-6 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

   8th, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing: Wherein-

   X¹, X², X³, X⁴It is separately CR³, R³For hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl；Y is N;

   L is-N (R^a)-, R¹For C_1-3Alkyl, acetyl group, methyl sulphonyl, phenyl, pyridine radicals, pyrimidine radicals, furyl, thienyl, pyrrole radicals, thiazolyl, imidazole radicals, pyrazolyl, imidazoles protective embankment base, pyrazoles protective embankment base, indyl, isoindolyl, indazolyl, benzimidazolyl, pyrido pyrazolyl, purine radicals, piperazinyl, quinolyl, THP trtrahydropyranyl, piperidyl, morpholinyl, pyrazinyl, pyridin-2-ones base, cyclohexyl, cyclopenta or benzyl, and R¹Optionally by 1-3 R^bSubstitution,

   R^aRepresent hydrogen, protective embankment base, 3-8 yuan of rings protective embankment bases or 6-14 member aryl；

   Z is-CH (R⁴)-, R⁴For hydrogen, Cw protective embankments base that is unsubstituted or being replaced by least one hydroxyl or at least one fluorine or cyclopropyl；

   W is-N (R⁵)-, R⁵It is separately hydrogen or methyl；

   R^bFor hydrogen, oxo, element, cyano group, hydroxyl, amino, alkyl amine group, two (d.₆Protective embankment base) amido, C_1-6Protective embankment epoxide, C_1-6Alkyl, halo C protective embankment bases, 3-6 yuan of rings protective embankment bases, 3-6 member cycloalkyl oxies, 5-6 unit monocycle heterocycle protective embankments base, 5-6 circle heterocycles alkenyl, 5-6 unit monocycles heteroaryl, 5-6 unit monocycle heterocycle protective embankment bases epoxide, 5-6 circle heterocycles alkenyls epoxide, 5-6 unit monocycle heteroaryl epoxides.

   9th, compound as claimed in claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing：Wherein：

   X¹, X², X³ , X⁴It is separately CR³, R³For hydrogen, fluorine, chlorine, hydroxyl, trifluoromethyl or methyl；Y is N;

   L is-N (R^a)-, R¹For C₃Protective embankment base, acetyl group, methyl sulphonyl, phenyl, pyridine radicals, pyridin-2-ones base, cyclohexyl, cyclopenta or benzyl, and R¹Optionally by 1-3 R^bSubstitution,

   R^aRepresent hydrogen, methyl, ethyl, cyclopropyl or phenyl；

   Z is-CH (R⁴)-, R⁴For hydrogen, Cw alkyl that is unsubstituted or being replaced by least one hydroxyl or at least one fluorine or cyclopropyl；

   W is-N (R⁵)-, R⁵It is separately hydrogen or methyl； > ¾

   R²For_NH,

   R^bFor hydrogen, oxo, m, cyano group, C_1-3Protective embankment base, C_1-3Protective embankment epoxide or trifluoromethyl., selected from following compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing:

   The ο ε Please ο ζ OA of ε 8

   fC6000/ClOZM3/X3d £SO£ZOItlOZ ΟΛλ

   The ο ε Please ο ζ OA of ε 8

   , selected from following compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing:

   6tl

   The ο ε Please ο ζ OA of ε 8

   OSl

   The ο ε Please ο ζ OA of ε 8

   1ST

   The ο ε Please Ο Ζ OA of ε 8

   The ο ε Please Ο Ζ OA of ε 8

   12nd, a kind of pharmaceutical composition, it includes compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing described in claim any one of 1-11, and one or more pharmaceutical carriers.

   13rd, described in any one of claim 1-11 composition described in compound, its pharmaceutically acceptable salt, its stereoisomer or its deuterated thing or claim 12 prepare be used to treat and/or prevent inflammatory disease and/or the medicine of tumour in purposes.

   14th, the purposes described in claim 13, wherein the inflammatory disease is selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, chronic obstructive pulmonary disease（COPD), lupus erythematosus, psoriasis, multiple sclerosis and end-stage renal disease, and the tumour is selected from leukaemia, lymthoma, myelosis disease, non Hodgkin lymphom and Chronic Spontaneous myelofibrosis.