CN109810111A

CN109810111A - A kind of pyrazolone miazines compound, preparation method and application

Info

Publication number: CN109810111A
Application number: CN201811382194.0A
Authority: CN
Inventors: 王倩; 夏广新; 霍国永; 舒思杰; 石辰; 张霖; 葛辉; 张智慧; 毛煜; 余建鑫; 刘彦君
Original assignee: Shanghai Pharmaceuticals Holding Co Ltd
Current assignee: Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2017-11-20
Filing date: 2018-11-20
Publication date: 2019-05-28
Anticipated expiration: 2038-11-20
Also published as: WO2019096322A1; CN109810111B

Abstract

The invention discloses a kind of pyrazolone miazines compound, preparation method and applications.The present invention provides a kind of pyrazolone miazines compound, its enantiomter, its diastereoisomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug shown in formula I, the compound is preferable to the inhibitory activity of WEE1 kinases.

Description

A kind of pyrazolone miazines compound, preparation method and application

Technical field

The present invention relates to a kind of pyrazolone miazines compound, preparation method and applications.

Background technique

Cell cycle and DNA damage repair process are closely related.Cell cycle refers to cell division entire mistake experienced Journey is divided into interphase in cell division (interphase) and division stage (mitotic phase, M) two stages.Cell cycle is examined Point (checkpoint) is a key point of cell cycle regulation, main function be guarantee in the period each event can on time and It orderly completes, and adjusts cell state and be adapted with external environment.The main check point of cell has: 1) G₁/ S check point: It is referred to as R (restriction) point in mammal, controls cell by static G₁Phase enters the DNA synthesis phase；2) S phase check point: Whether DNA replication dna is completed；3)G₂/ M check point: being the control point for adjusting cell and entering division stage；4) in-later period check point: Claim spindle assembly checkpoint that will cause the interruption of cell cycle if kinetochore is not connected on spindle correctly. If the certain processes of cell division cycle, which have abnormal such as DNA damage, check point, can incude in time and start reparation.P53 egg White is regulation G₁The important albumen of check point when DNA is damaged, prevents cell from entering the S phase, activates DNA repair mechanism, for dimension The integrality for protecting cellular genome is most important.But because often there is P53 mutation in tumour cell, so that G1 examines point defect, Therefore cell division cycle regulating relies on G in the cell of P53 mutation₂/ M check point.WEE1 kinases is a kind of Cycle Regulation Albumen, the phosphorylation shape of energy cell cycle regulation protein dependent kinase 1 (cyclin-dependent kinase 1, CDK1) State, so that the active regulation to realize cell cycle of CDK1 and cell periodic protein B (cyclinB) compound is adjusted, And there is important adjustment effect to DNA damage checkpoint.WEE1 is G₂The key gene that/M the phase blocks plays important monitoring Effect, is overexpressed in certain cancers, inhibits or lowers WEE1 kinases to cause mitosis disaster, therefore the suppression of WEE1 kinases Preparation has key effect in anticancer therapy, has become the research and development focus of anticancer agent at present.

International patent application WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, WO2004007499 etc. disclose part small molecule WEE1 kinase inhibitor, but at present There has been no the listings of small molecule WEE1 kinase inhibitor, and this field also needs to develop the WEE1 that new anticancer activity is good, highly-safe Kinase inhibitor.

Summary of the invention

The technical problem to be solved by the present invention is to inhibitory activity of the existing compound to WEE1 kinases is poor, so, The present invention provides a kind of pyrazolone miazines compound, preparation method and application, suppression of the compound to WEE1 kinases System activity is preferably.

The present invention provides a kind of pyrazolone miazines compound shown in formula I, its enantiomter, its is diastereomeric Before isomers, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its drug Body；

Wherein, X is N or CH；

M and n independently is 0,1,2 or 3, and m+n is 2,3 or 4 { for example, m+n is 2 or 3；In another example " m 0, n 2 ", " m 2, n 0 ", " m 1, n 1 ", " m 1, n 2 " or " m 2, n 1 " }；

Y is N or CH；

R¹For H, halogen, sulfydryl, nitro, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-C (=NR^1-11)R^1-5、-S (=O) R^1-6,-S (=O)₂R^1-7,-S (=NR^1-12)R^1-8,-S (=NR^1-13) (=NR^1-14)R^1-9,-S (=O) (=NR^1-15)R¹ ^-10, unsubstituted or R^1-16Substituted C₁~C₇Alkyl { wherein, R^1-16Number be one or more [such as 2,3 or 4], When there are multiple R^1-16When, the R^1-16It is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl, ethyl, n-propyl or different Propyl }, unsubstituted or R^1-17Substituted C₂~C₇Alkenyl { wherein, R^1-17Number be one or more [such as 2,3 or 4 It is a], when there are multiple R^1-17When, the R^1-17It is identical or different；Wherein, " the C₂~C₇Alkenyl " such as C₂~C₄Alkene Base, in another example 2- acrylic }, unsubstituted or R^1-18Substituted C₂~C₈Alkynyl { wherein, R^1-18Number be one or more [examples Such as 2,3 or 4], when there are multiple R^1-18When, the R^1-18It is identical or different；Wherein, " the C₂~C₇Alkynyl " Such as C₂~C₄Alkynyl, in another example 2-propynyl }, unsubstituted or R^1-19Substituted C₁~C₇Alkane silicon substrate { wherein, R^1-19Number be One or more [such as 2,3 or 4], when there are multiple R^1-19When, the R^1-19It is identical or different }, it is unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base { wherein, R^1-20Number be one or more [such as 2,3 or 4], it is more when existing A R^1-20When, the R^1-20It is identical or different；" the C₃~C₇Naphthenic base " such as cyclopropyl, cyclobutyl, cyclopenta or ring Hexyl, in another example cyclobutyl }, unsubstituted or R^1-21Replace " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { wherein, R^1-21Number be one or more [such as 2,3 Or 4], when there are multiple R^1-21When, the R^1-21It is identical or different；It is described that " hetero atom is boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " for example " hetero atom be nitrogen and/or oxygen, it is miscellaneous The C that atomicity is 1~2₃~C₅Heterocyclylalkyl ", in another example " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocycle Alkyl " or " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl ".It is described that " hetero atom is nitrogen, hetero atom The C that number is 1~2₃~C₅For example " hetero atom is nitrogen, the C that hetero atom number is 1~2 to Heterocyclylalkyl "₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with Y " or " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and it is miscellaneous Naphthenic base is connect by carbon atom with Y ".It is described that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with Y " for exampleIt is described that " hetero atom is nitrogen, hetero atom number For 1~2 C₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by carbon atom with Y " for example It is described that " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl " is for exampleNot Substitution or R^1-22Substituted C₆~C₁₀Aryl { wherein, R^1-22Number be one or more [such as 2,3 or 4], when depositing In multiple R^1-22When, the R^1-22It is identical or different }, unsubstituted or R^1-23Replace " hetero atom be boron, silicon, oxygen, sulphur, selenium, One of nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl " { wherein, R^1-23Number be one or more A [such as 2,3 or 4], when there are multiple R^1-23When, the R^1-23It is identical or different }, unsubstituted or R^1-24Replace C₁~C₇Alkoxy { wherein, R^1-24Number be one or more [such as 2,3 or 4], when there are multiple R^1-24When, institute The R stated^1-24It is identical or different } or unsubstituted or R^1-25Substituted C₁~C₇Alkane sulfydryl { wherein, R^1-25Number be one or Multiple [such as 2,3 or 4], when there are multiple R^1-25When, the R^1-25It is identical or different }；

All R^1-1、R^1-2And R^1-3It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2, unsubstituted or R^1-1-3Substituted C₁~ C₇Alkyl such as C₁~C₄Alkyl, in another example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tertiary fourth Base, in another example methyl, ethyl, n-propyl or isopropyl }, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is One of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Virtue Base or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl Base "；

All R^1-1-1、R^1-1-2And R^1-1-3It independently is C₁~C₇Alkyl, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9And R^1-10It independently is hydroxyl, C₁~C₇Alkyl such as C₁~C₄Alkane Base, in another example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl }, halogen The C that element replaces₁~C₇{ wherein, the number of halogen is one or more [such as 2,3 or 4] to alkyl, when there are multiple halogen When plain, the halogen is identical or different；" halogen " independently is fluorine, chlorine, bromine or iodine；" the C₁~C₇Alkyl " Such as C₁~C₄Alkyl, in another example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, and example Such as methyl；" the C that halogen replaces₁~C₇Alkyl " such as trifluoromethyl }, halogen, C₂~C₇Alkenyl, C₂~C₇Alkynyl { example Such as C₂~C₄Alkynyl, in another example 2-propynyl or 1- propinyl }, C₃~C₇Naphthenic base, C₁~C₇Alkoxy such as C₁~C₄Alcoxyl Base, in another example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary fourth oxygen Base, in another example methoxyl group }, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 A C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₁~C₇Heteroaryl " or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is hydrogen, C₁~C₇Alkyl such as C₁~C₄Alkyl, in another example methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl }, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃ ~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~ C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number For 1~4 C₁~C₇Heteroaryl "；

All R^1-11、R^1-12、R^1-13、R^1-14And R^1-15It independently is H, cyano, hydroxyl, C₁~C₇It is alkoxy, unsubstituted Or R^1-11-1Substituted C₁~C₇Alkyl { wherein, R^1-11-1Number be one or more [such as 2,3 or 4], work as presence Multiple R^1-11-1When, the R^1-11-1It is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl }, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or Person, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl Base "；

All R^1-11-1It independently is halogen, hydroxyl, cyano, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃ ~C₇Naphthenic base, C₁~C₇Heterocyclylalkyl, C₆~C₁₀Aryl, " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₁~C₇Heteroaryl " or C₁~C₇Alkoxy；

All R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24And R^1-25It independently is halogen { example Such as fluorine, chlorine, bromine or iodine, in another example fluorine }, nitro, cyano, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate Such as trimethyl silicon substrate, unsubstituted or R^1-16-7Substituted C₃~C₇Naphthenic base, unsubstituted or R^1-16-6Replace " hetero atom is One of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { wherein, R¹ ^-16-6Number be one or more [such as 2,3 or 4], when there are multiple R^1-16-6When, the R^1-16-6It is identical or not Together；It is described that " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇ For example " hetero atom is nitrogen and/or oxygen, the C that hetero atom number is 1~2 to Heterocyclylalkyl "₃~C₅Heterocyclylalkyl ", in another example " miscellaneous original Son is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl ", " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅ Heterocyclylalkyl " orIt is described that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl " such as " miscellaneous original Son is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl passes through nitrogen-atoms and other groups [such as C₁ ~C₇Alkyl] connection " or " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl passes through Carbon atom and other groups [such as C₁~C₇Alkyl] connection ".It is described that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~ C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with other groups " for example It is described that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl passes through carbon atom and other Group connection " is for exampleIt is described that " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅It is miscellaneous Naphthenic base " is for example}、C₆~C₁₀Aryl, " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus C one or more, that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R¹ ^-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6And R^1-16-7Independently be hydrogen, hydroxyl, halogen, cyano, C₁~C₇Alkyl such as C₁~C₄Alkyl, in another example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or Tert-butyl, in another example methyl }, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, sulphur, selenium, One of nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is One of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " Such as " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl, and it is connect by nitrogen-atoms with carbonyl ", in another example " hetero atom is one of oxygen, sulphur and nitrogen or a variety of, hetero atom The C that number is 1~2₃~C₇Heterocyclylalkyl, and it is connect by nitrogen-atoms with carbonyl ", also for example, halogenated " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { its In, " halogen " independently is fluorine, chlorine or bromine；The number of the halogen is one or more [such as 2,3 or 4 It is a], when there are multiple halogens, the halogen is identical or different；It is described " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and One of phosphorus is a variety of, the C that hetero atom number is 1~4₃~C₇For example " hetero atom is nitrogen to Heterocyclylalkyl ", and hetero atom number is 1 ~2 C₃~C₇Heterocyclylalkyl, and it is connect by nitrogen-atoms with carbonyl ".It is described " halogenated hetero atom be boron, silicon, oxygen, One of sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is for example}、C₆~C₁₀ Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl Base ",-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or R^1-16-5-1-1 Substituted C₁~C₇Alkyl { wherein, R^1-16-5-1-1Number be one or more [such as 2,3 or 4], when there are multiple R^1-16-5-1-1When, the R^1-16-5-1-1It is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl or ethyl }, C₂~C₇Alkene Base, C₂~C₇Alkynyl such as C₂~C₄Alkynyl, in another example 2-propynyl or 1- propinyl }, C₃~C₇Naphthenic base, " hetero atom is One of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Virtue Base or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl Base "；

All R^1-16-5-1-1It independently is halogen, hydroxyl, cyano, amino, C₁~C₇Alkyl, C₁~C₇Alkoxy, C₁~ C₇Alkane sulfydryl, C₁~C₇Alkane silicon substrate, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom For one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

Z is 0,1 or 2；

All R²It independently is halogen, hydroxyl, cyano, amino, unsubstituted or R^2-1Substituted C₁~C₇Alkyl is { wherein, R^2-1Number be one or more [such as 2,3 or 4], when there are multiple R^2-1When, the R^2-1It is identical or different }, Unsubstituted or R^2-2Substituted C₂~C₈Alkenyl { wherein, R^2-2Number be one or more [such as 2,3 or 4], when depositing In multiple R^2-2When, the R^2-2It is identical or different }, unsubstituted or R^2-3Substituted C₂~C₇Alkynyl { wherein, R^2-3Number be One or more [such as 2,3 or 4], when there are multiple R^2-3When, the R^2-3It is identical or different }, unsubstituted or R^2-4 Substituted C₁~C₇Alkane silicon substrate { wherein, R^2-4Number be one or more [such as 2,3 or 4], when there are multiple R^2-4 When, the R^2-4It is identical or different }, unsubstituted or R^2-5Substituted C₆~C₁₀Aryl { wherein, R^2-5Number be one or more A [such as 2,3 or 4], when there are multiple R^2-5When, the R^2-5It is identical or different }, unsubstituted or R^2-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl " { wherein, R^2-6Number be one or more [such as 2,3 or 4], when there are multiple R^2-6When, the R^2-6It is identical or It is different }, C₃~C₇Naphthenic base or unsubstituted or R^2-7Substituted C₁~C₇Alkoxy { wherein, R^2-7Number be one or more A [such as 2,3 or 4], when there are multiple R^2-7When, the R^2-7It is identical or different }；

{ when z is 2, two R²When being hydroxyl and being connected on same carbon atom, two R are indicated²It is connect with them Carbon atom carbonyl is collectively formed

All R^2-1、R^2-2、R^2-3、R^2-4、R^2-5、R^2-6And R^2-7It independently is halogen, nitro, cyano, C₁~C₇Alkyl, C₂ ~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus It is one or more, hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom be boron, silicon, oxygen, One of sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇ Alkane sulfydryl ,-NR^2-1-1R^2-1-2、-OR^2-1-3、-SR^2-1-4Or-(C=O) R^2-1-5；

All R^2-1-1、R^2-1-2、R^2-1-3And R^2-1-4It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃ ~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₁~C₇Heteroaryl "；

All R^2-1-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl "；

Alternatively, two R²It is connected on same carbon atom and unsubstituted or R is collectively formed^2-8Substituted C₃~C₇Naphthenic base { its In, R^2-8Number be one or more [such as 2,3 or 4], when there are multiple R^2-8When, the R^2-8It is identical or not Together } or unsubstituted or R^2-9Substituted C₁~C₇Heterocyclylalkyl { wherein, R^2-9Number be one or more [such as 2,3 It is a or 4], when there are multiple R^2-9When, the R^2-9It is identical or different；" the C₁~C₇Heterocyclylalkyl " such as " hetero atom For one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " }；

All R^2-8And R^2-9It independently is halogen, cyano, sulfydryl, hydroxyl, amino, C₁~C₇Alkoxy or C₁~C₇Alkane Sulfydryl.

In a certain technical solution, the compound I, its enantiomter, its diastereoisomer, its tautomerism The definition of each group in body, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug It can be as described below (not annotating as defined above any described):

X is CH.

M and n independently is 0,1,2 or 3, and m+n is 2 or 3.

M and n independently is 0,1,2 or 3, and m+n is 3.

M and n independently is 1 or 2, and m+n is 3.

" m 2, n 1 " or " m 1, n 2 ".

Y is N.

Y is N, and R¹In the atom that is connected with Y be not N.

Y is CH.

R¹For H, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁ ~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₈Alkynyl, C₃~C₇Naphthenic base or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ".

R¹For-NR^1-1R^1-2、R^1-16Substituted C₁~C₇Alkyl or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ".

All R^1-1、R^1-2And R^1-3It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or R^1-1-3Replace C₁~C₇Alkyl；

All R^1-1-1、R^1-1-2And R^1-1-3It independently is C₁~C₇Alkyl or C₆~C₁₀Aryl.

All R^1-1、R^1-2And R^1-3It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or C₆~C₁₀Aryl Substituted C₁~C₇Alkyl；

All R^1-1-1And R^1-1-2It independently is C₁~C₇Alkyl.

All R^1-1、R^1-2And R^1-3It independently is hydrogen or unsubstituted or C₆~C₁₀The C that aryl replaces₁~C₇Alkyl.

All R^1-1And R^1-2It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or C₆~C₁₀Aryl replaces C₁~C₇Alkyl；All R^1-1-1And R^1-1-2It independently is C₁~C₇Alkyl.

All R^1-1And R^1-2It independently is hydrogen or unsubstituted or C₆~C₁₀The C that aryl replaces₁~C₇Alkyl.

All R^1-4And R^1-7It independently is C₁~C₇The C that alkyl, halogen replace₁~C₇Alkyl, C₂~C₇Alkynyl, C₁~C₇ Alkoxy or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl.

All R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, unsubstituted or R^1-16-7Substituted C₃~C₇ Naphthenic base, unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6And R^1-16-7It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16-5Independently be hydroxyl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", halogenated " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ",-NR^1-16-5-1R^1-16-5-2Or-OR¹ ^-16-5-3；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁ ~C₇Alkyl, C₂~C₇Alkynyl or C₃~C₇Naphthenic base.

All R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, C₃~C₇Naphthenic base, unsubstituted or R^1-16-6 Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is miscellaneous Naphthenic base " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4And R^1-16-6It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, C₃~C₇Naphthenic base, unsubstituted or R^1-16-6 Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is miscellaneous Naphthenic base " ,-NR^1-16-1R^1-16-2、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-4And R^1-16-6It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16-5Independently be hydroxyl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ",Or-NR^1-16-5-1R^1-16-5-2；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁~C₇Alkane Base, C₂~C₇Alkynyl or C₃~C₇Naphthenic base.

All R^1-16And R^1-21It independently is C₁~C₇Alkyl, unsubstituted or R^1-16-6Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " ,-OR^1-16-3Or-(C= O)R^1-16-5；

All R^1-16-3And R^1-16-6It independently is C₁~C₇Alkyl；All R^1-16-5It independently is All R^1-16-5-4And R^1-16-5-5It independently is C₁~C₇Alkyl.

All R^1-16And R^1-21It independently is C₁~C₇Alkyl, unsubstituted or R^1-16-6Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " or-(C=O) R^1-16-5；

All R^1-16-6It independently is C₁~C₇Alkyl；All R^1-16-5It independently isAll R^1-16-5-4And R^1-16-5-5It independently is C₁~C₇Alkyl.

R¹For following any groups: hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, 2- hydroxyethyl, 2- methoxyl group Ethyl, 2- methylaminoethyl, 2- dimethyl aminoethyl, cyano methyl, cyano, acetyl group, 2- acrylic, 2-propynyl, Dimethylamino, 2- fluoro ethyl, 2,2,2- trifluoroethyl, methoxy acyl group, methylsulfonyl, 2,2,2- trifluoroacetyl group, cyclobutyl, ring Hydroxypropyl methyl, cyclopropyl, diethylamino, diη-propyl amino, dimethylaminomethyl, methoxyl group, hydroxyl, carboxymethyl,

Z is 0.

X is CH；

M and n independently is 0,1 or 2, and m+n is 2 or 3；

Y is N or CH；

R¹For H, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁ ~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₈Alkynyl, C₃~C₇Naphthenic base or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

All R^1-1-1、R^1-1-2And R^1-1-3It independently is C₁~C₇Alkyl or C₆~C₁₀Aryl；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁ ~C₇Alkyl, C₂~C₇Alkynyl or C₃~C₇Naphthenic base；

Z is 0.

X is CH；

M and n independently is 0,1 or 2, and m+n is 2 or 3；

Y is N or CH；

All R^1-1-1And R^1-1-2It independently is C₁~C₇Alkyl；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

Z is 0.

X is CH；

" m 1, n 2 " or " m 2, n 1 "；

Y is N or CH；

All R^1-1、R^1-2And R^1-3It independently is hydrogen or unsubstituted or C₆~C₁₀The C that aryl replaces₁~C₇Alkyl；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁~C₇Alkane Base, C₂~C₇Alkynyl or C₃~C₇Naphthenic base；

Z is 0.

X is CH；

M is 2, n 1；

Y is N or CH；

R¹For-NR^1-1R^1-2、R^1-16Substituted C₁~C₇Alkyl or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

All R^1-1And R^1-2It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or R^1-1-3Substituted C₁~C₇ Alkyl；All R^1-1-1、R^1-1-2And R^1-1-3It independently is C₁~C₇Alkyl or C₆~C₁₀Aryl；

All R^1-16-3And R^1-16-6It independently is C₁~C₇Alkyl；All R^1-16-5It independently is All R^1-16-5-4And R^1-16-5-5It independently is C₁~C₇Alkyl；

Z is 0.

X is CH；

M is 2, n 1；

Y is N or CH；

All R^1-1And R^1-2It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or C₆~C₁₀Aryl replaces C₁~C₇Alkyl；All R^1-1-1And R^1-1-2It independently is C₁~C₇Alkyl；

Z is 0.

X is CH；

M is 2, n 1；

Y is N or CH；

All R^1-1And R^1-2It independently is hydrogen or unsubstituted or C₆~C₁₀The C that aryl replaces₁~C₇Alkyl；

All R^1-16-6It independently is C₁~C₇Alkyl；All R^1-16-5It independently isAll R^1-16-5-4And R^1-16-5-5It independently is C₁~C₇Alkyl；

Z is 0.

Wherein, X is N or CH；

M and n independently is 0,1,2 or 3, and m+n be 2,3 or 4 for example, " m 0, n 2 ", " m 2, n 0 ", " m is 1, n 1 ", " m 1, n 2 " or " m 2, n 1 "；In another example m+n is 2 or 3 }；

Y is N or CH；

R¹For H, halogen, sulfydryl, nitro, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-C (=NR^1-11)R^1-5、-S (=O) R^1-6,-S (=O)₂R^1-7,-S (=NR^1-12)R^1-8,-S (=NR^1-13) (=NR^1-14)R^1-9,-S (=O) (=NR^1-15)R¹ ^-10, unsubstituted or R^1-16Substituted C₁~C₇Alkyl { wherein, R^1-16Number be one or more [such as 2,3 or 4], When there are multiple R^1-16When, the R^1-16It is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl, ethyl, n-propyl or different Propyl }, unsubstituted or R^1-17Substituted C₂~C₇Alkenyl { wherein, R^1-17Number be one or more [such as 2,3 or 4 It is a], when there are multiple R^1-17When, the R^1-17It is identical or different；Wherein, " the C₂~C₇Alkenyl " such as C₂~C₄Alkene Base, in another example 2- acrylic }, unsubstituted or R^1-18Substituted C₂~C₈Alkynyl { wherein, R^1-18Number be one or more [examples Such as 2,3 or 4], when there are multiple R^1-18When, the R^1-18It is identical or different；Wherein, " the C₂~C₇Alkynyl " Such as C₂~C₄Alkynyl, in another example 2-propynyl }, unsubstituted or R^1-19Substituted C₁~C₇Alkane silicon substrate { wherein, R^1-19Number be One or more [such as 2,3 or 4], when there are multiple R^1-19When, the R^1-19It is identical or different }, it is unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base { wherein, R^1-20Number be one or more [such as 2,3 or 4], it is more when existing A R^1-20When, the R^1-20It is identical or different；" the C₃~C₇Naphthenic base " such as cyclopropyl, cyclobutyl, cyclopenta or ring Hexyl, in another example cyclobutyl }, unsubstituted or R^1-21Replace " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { wherein, R^1-21Number be one or more [such as 2,3 Or 4], when there are multiple R^1-21When, the R^1-21It is identical or different；It is described that " hetero atom is boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇For example " hetero atom is nitrogen to Heterocyclylalkyl ", and hetero atom number is 1~2 C₃~C₅Heterocyclylalkyl ", in another example " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with Y ", also for example , unsubstituted or R^1-22Substituted C₆~C₁₀ Aryl { wherein, R^1-22Number be one or more [such as 2,3 or 4], when there are multiple R^1-22When, the R^1-22 It is identical or different }, unsubstituted or R^1-23Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₁~C₇Heteroaryl " { wherein, R^1-23Number be one or more [such as 2,3 or 4], when There are multiple R^1-23When, the R^1-23It is identical or different }, unsubstituted or R^1-24Substituted C₁~C₇Alkoxy { wherein, R^1-24's Number is one or more [such as 2,3 or 4], when there are multiple R^1-24When, the R^1-24It is identical or different } or Person, unsubstituted or R^1-25Substituted C₁~C₇Alkane sulfydryl { wherein, R^1-25Number be one or more [such as 2,3 or 4 It is a], when there are multiple R^1-25When, the R^1-25It is identical or different }；

All R^1-1、R^1-2And R^1-3It independently is hydrogen, C₁~C₇Alkyl such as C₁~C₄Alkyl, in another example methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl, ethyl, n-propyl or isopropyl Base }, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9And R^1-10It independently is hydroxyl, C₁~C₇Alkyl such as C₁~C₄Alkane Base, in another example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl }, halogen The C that element replaces₁~C₇{ wherein, the number of halogen is one or more [such as 2,3 or 4] to alkyl, when there are multiple halogen When plain, the halogen is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example methyl, ethyl, just Propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl；" the C that halogen replaces₁~C₇Alkane Base " such as trifluoromethyl }, halogen, C₂~C₇Alkenyl, C₂~C₇Alkynyl such as C₂~C₄Alkynyl, in another example 2-propynyl or 1- third Alkynyl }, C₃~C₇Naphthenic base, C₁~C₇Alkoxy such as C₁~C₄Alkoxy, in another example methoxyl group, ethyoxyl, positive propoxy, Isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, in another example methoxyl group }, " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀It is aryl, " miscellaneous Atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl " or NR^1-4-1R^1-4-2；

All R^1-11、R^1-12、R^1-13、R^1-14And R^1-15It independently is H, cyano, hydroxyl, C₁~C₇It is alkoxy, unsubstituted Or R^1-11-1Substituted C₁~C₇Alkyl { wherein, R^1-11-1Number be one or more [such as 2,3 or 4], work as presence Multiple R^1-11-1When, the R^1-11-1It is identical or different }, C₃~C₇Naphthenic base, " hetero atom is boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus One of or it is a variety of, hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, One of silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24And R^1-25It independently is halogen { example Such as fluorine, chlorine, bromine or iodine, in another example fluorine }, nitro, cyano, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate Such as trimethyl silicon substrate, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₃~C₇Heterocyclylalkyl " such as " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocycle alkane Base ", in another example " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl by nitrogen-atoms with Other groups, such as C₁~C₇Alkyl, connection ", also for example }、C₆~C₁₀Aryl, " hetero atom is One of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alcoxyl Base, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3And R^1-16-4It independently is hydrogen, C₁~C₇Alkyl such as C₁~C₄Alkyl, again Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl }, C₂~C₇Alkene Base, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " Such as " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl, and it is connect by nitrogen-atoms with carbonyl ", in another example " hetero atom is one of oxygen, sulphur and nitrogen or a variety of, hetero atom The C that number is 1~2₃~C₇Heterocyclylalkyl, and it is connect by nitrogen-atoms with carbonyl ", also for example, halogenated " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { its In, the number of the halogen is one or more [such as 2,3 or 4], when there are multiple halogens, the halogen It is identical or different；" halogen " independently is fluorine, chlorine or bromine；It is described that " hetero atom is boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus One of or it is a variety of, hetero atom number is 1~4 C₃~C₇For example " hetero atom is nitrogen to Heterocyclylalkyl ", and hetero atom number is 1~2 A C₃~C₇Heterocyclylalkyl, and it is connect by nitrogen-atoms with carbonyl "；It is described " halogenated hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is for example}、C₆~C₁₀Virtue Base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl Base " ,-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；

All R^1-16-5-1、R^1-16-5-2And R^1-16-5-3It independently is hydrogen, unsubstituted or R^1-16-5-1-1Substituted C₁~C₇Alkane Base { wherein, R^1-16-5-1-1Number be one or more [such as 2,3 or 4], when there are multiple R^1-16-5-1-1When, it is described R^1-16-5-1-1It is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example methyl, ethyl, n-propyl, different Propyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl or ethyl }, C₂~C₇Alkenyl, C₂~C₇Alkynyl such as C₂~C₄Alkynyl, in another example 2-propynyl or 1- propinyl }, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and One of phosphorus is a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

Z is 0,1 or 2；

Alternatively, two R²It is connected on same carbon atom and unsubstituted or R is collectively formed^2-8Substituted C₃~C₇Naphthenic base { its In, R^2-8Number be one or more [such as 2,3 or 4], when there are multiple R^2-8When, the R^2-8It is identical or not Together } or unsubstituted or R^2-9Substituted C₁~C₇Heterocyclylalkyl { wherein, R^2-9Number be one or more [such as 2,3 It is a or 4], when there are multiple R^2-9When, the R^2-9It is identical or different }；

X is CH.

M and n independently is 0,1,2 or 3, and m+n is 2 or 3.

M and n independently is 0,1,2 or 3, and m+n is 3 such as m is 2, n 1.

Y is N.

Y is CH.

R¹For H, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁ ~C₇Alkyl, C₃~C₇Naphthenic base or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ".

R¹For hydrogen ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁~C₇Alkane Base, C₃~C₇Naphthenic base or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ".

R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base does not take Generation or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ".

R¹For-NR^1-1R^1-2, unsubstituted or R^1-16Substituted C₁~C₇Alkyl or unsubstituted or R^1-21" the hetero atom replaced For one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

All R^1-1And R^1-2It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16It independently is C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₁~C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5。

R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl or unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base；

All R^1-16And R^1-20It independently is C₃~C₇Naphthenic base.

R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl ,-NR^1-1R^1-2Or " hetero atom is boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ".

All R^1-1、R^1-2And R^1-3It independently is hydrogen or C₁~C₇Alkyl.

All R^1-1And R^1-2It independently is hydrogen or C₁~C₇Alkyl.

All R^1-4And R^1-7It independently is C₁~C₇The C that alkyl, halogen replace₁~C₇Alkyl, C₁~C₇Alkoxy, C₂~ C₇Alkynyl or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl.

All R^1-4And R^1-7It independently is C₁~C₇The C that alkyl, halogen replace₁~C₇Alkyl, C₁~C₇Alkoxy or NR¹ ^-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl.

All R^1-16It independently is halogen, cyano, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇Ring Alkyl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heterocycle Alkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3And R^1-16-4It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16-5It independently is that " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous original The C that subnumber is 1~4₃~C₇Heterocyclylalkyl " or-NR^1-16-5-1R^1-16-5-2；

All R^1-16-5-1And R^1-16-5-2It independently is hydrogen, unsubstituted or R^1-16-5-1-1Substituted C₁~C₇Alkyl, C₂~C₇ Alkynyl or C₃~C₇Naphthenic base；

All R^1-16-5-1-1It independently is hydroxyl.

All R^1-16It independently is halogen, C₁~C₇Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2Or-(C= O)R^1-16-5；

All R^1-16-1And R^1-16-2It independently is C₁~C₇Alkyl；

All R^1-16-5-1-1It independently is hydroxyl.

All R^1-16It independently is C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₁~C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-5-1And R^1-16-5-2It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkynyl or C₃~C₇Naphthenic base.

Z is 0.

X is CH；

M and n independently is 0,1,2 or 3, and m+n is 2 or 3；

Y is N or CH；

R¹For H, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁ ~C₇Alkyl, C₃~C₇Naphthenic base or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl "；

All R^1-1、R^1-2And R^1-3It independently is hydrogen or C₁~C₇Alkyl；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

All R^1-16-5-1-1It independently is hydroxyl；

Z is 0.

X is CH；

M and n independently is 0,1,2 or 3, and m+n is 2 or 3；

Y is N or CH；

R¹For hydrogen ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁~C₇Alkane Base, C₃~C₇Naphthenic base or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl "；

All R^1-1、R^1-2And R^1-3It independently is hydrogen or C₁~C₇Alkyl；

All R^1-4And R^1-7It independently is C₁~C₇The C that alkyl, halogen replace₁~C₇Alkyl, C₁~C₇Alkoxy or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

All R^1-16-1And R^1-16-2It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16-5-1-1It independently is hydroxyl；

Z is 0.

X is CH；

M and n independently is 0,1,2 or 3, and m+n is 3 such as m is 2, n 1；

Y is N；

R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base does not take Generation or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl "；

All R^1-16、R^1-20And R^1-21It independently is halogen, nitro, cyano, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇ Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus C one or more, that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R¹ ^-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3And R^1-16-4It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynes Base, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₁~C₇Heteroaryl "；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", halogenated " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~ C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number For 1~4 C₁~C₇Heteroaryl " ,-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；

All R^1-16-5-1、R^1-16-5-2And R^1-16-5-3It independently is hydrogen, unsubstituted or R^1-16-5-1-1Substituted C₁~C₇Alkane Base, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

Z is 0.

X is CH；

M and n independently is 0,1,2 or 3, and m+n is 3 such as m is 2, n 1；

Y is CH；

All R^1-1And R^1-2It independently is hydrogen or C₁~C₇Alkyl；

All R^1-16It independently is C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-21It independently is halogen, nitro, cyano, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇ Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number is 1~ 4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R^1-16-2、-OR¹ ^-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

Z is 0.

X can be CH；

M+n can be 2 or 3；

Y can be CH or N；

R¹It can be H, cyano, nitro ,-NR^1-1R^1-2,-C (=O) R^1-4,-C (=NR^1-11)R^1-5,-S (=O) R^1-6, it is unsubstituted Or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-17Substituted C₂~C₇Alkenyl, unsubstituted or R^1-18Substituted C₂~C₇Alkynes Base, unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

All R^1-1And R^1-2Hydrogen, C can independently be₁~C₇Alkyl or C₃~C₇Naphthenic base；

All R^1-4、R^1-5And R^1-6It independently is C₁~C₇Alkyl, C₃~C₇Naphthenic base, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkoxy or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Cycloalkanes Base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base "；

R^1-11For H；

All R^1-16、R^1-17、R^1-18、R^1-20And R^1-21It independently is cyano ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR¹ ^-16-4、C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 A C₃~C₇Heterocyclylalkyl " or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3And R^1-16-4It independently is hydrogen, C₃~C₇Naphthenic base or C₁~C₇Alkyl；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl " ,-NR^1-16-5-1R^1-16-5-2Or OR^1-16-5-3；

Z can be 0.

X can be CH；

" m 2, n 0 ", " m 0, n 2 " " m 1, n 1 " or " m 2, n 1 "；

Y can be N；

R¹It can be H, cyano ,-NR^1-1R^1-2,-C (=O) R^1-4、R^1-16C substituted or unsubstituted₁~C₇Alkyl, C₂~C₇Alkenyl, Or C₂~C₇Alkynyl, R^1-20C substituted or unsubstituted₃~C₇Naphthenic base；

R^1-1And R^1-2C can independently be₁~C₇Alkyl；

R^1-4It independently is C₁~C₇Alkyl or C₂~C₇Alkynyl；

All R^1-16It independently is cyano ,-NR^1-16-1R^1-16-2、-OR^1-16-3Or C₃~C₇Naphthenic base；

All R^1-16-1、R^1-16-2And R^1-16-3It independently is hydrogen or C₁~C₇Alkyl；

Z can be 0.

X can be CH；

" m 2, n 0 ", " m 0, n 2 " " m 1, n 1 " or " m 2, n 1 "；

Y can be C；

R¹It can be H, cyano ,-NR^1-1R^1-2,-C (=O) R^1-4, unsubstituted or R^1-16Substituted C₁~C₇Alkyl, C₂~C₇Alkene Base, C₂~C₇Alkynyl, unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base or unsubstituted or R^1-21Replace " hetero atom be boron, One of silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl；

R^1-1And R^1-2C can independently be₁~C₇Alkyl；

R^1-4It independently is C₁~C₇Alkyl or C₂~C₇Alkynyl；

All R^1-16It independently is cyano ,-NR^1-16-1R^1-16-2、-OR^1-16-3Or hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl；

Z can be 0.

Wherein, X is N or CH；

Y is N or CH；

R¹For H, halogen, sulfydryl, nitro, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-C (=NR^1-11)R^1-5、-S (=O) R^1-6,-S (=O)₂R^1-7,-S (=NR^1-12)R^1-8,-S (=NR^1-13) (=NR^1-14)R^1-9,-S (=O) (=NR^1-15)R¹ ^-10、R^1-16C substituted or unsubstituted₁~C₇Alkyl { wherein, R^1-16Number be one or more [such as 2,3 or 4], when There are multiple R^1-16When, the R^1-16It is identical or different；" the C₁~C₇Alkyl " such as C₁~C₄Alkyl, in another example first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl, ethyl, n-propyl or different Propyl }, R^1-17C substituted or unsubstituted₂~C₇Alkenyl { wherein, R^1-17Number be one or more [such as 2,3 or 4 It is a], when there are multiple R^1-17When, the R^1-17It is identical or different；Wherein, " the C₂~C₇Alkenyl " such as C₂~C₄Alkene Base, in another example 2- acrylic }, R^1-18C substituted or unsubstituted₂~C₈Alkynyl { wherein, R^1-18Number be it is one or more [such as 2,3 or 4], when there are multiple R^1-18When, the R^1-18It is identical or different；Wherein, " the C₂~C₇Alkynyl " example Such as C₂~C₄Alkynyl, in another example 2-propynyl }, R^1-19C substituted or unsubstituted₁~C₇Alkane silicon substrate { wherein, R^1-19Number be one Or multiple [such as 2,3 or 4], when there are multiple R^1-19When, the R^1-19It is identical or different }, R^1-20Replace or does not take For C₃~C₇Naphthenic base { wherein, R^1-20Number be one or more [such as 2,3 or 4], when there are multiple R^1-20When, The R^1-20It is identical or different }, R^1-21It is substituted or unsubstituted that " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { wherein, R^1-21Number be one or more [such as 2,3 It is a or 4], when there are multiple R^1-21When, the R^1-21It is identical or different }, R^1-22C substituted or unsubstituted₆~C₁₀Aryl { its In, R^1-22Number be one or more [such as 2,3 or 4], when there are multiple R^1-22When, the R^1-22It is identical or It is different }, R^1-23It is substituted or unsubstituted that " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl " { wherein, R^1-23Number be one or more [such as 2,3 or 4], when there are multiple R^1-23When, the R^1-23It is identical or different }, R^1-24C substituted or unsubstituted₁~C₇Alkoxy { wherein, R^1-24Number be one Or multiple [such as 2,3 or 4], when there are multiple R^1-24When, the R^1-24It is identical or different } or R^1-25Replace Or unsubstituted C₁~C₇Alkane sulfydryl { wherein, R^1-25Number be one or more [such as 2,3 or 4], when there are multiple R^1-25When, the R^1-25It is identical or different }；

R^1-1、R^1-2And R^1-3It independently is hydrogen, C₁~C₇Alkyl such as C₁~C₄Alkyl, in another example methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl }, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇ Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is miscellaneous Naphthenic base ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1 ~4 C₁~C₇Heteroaryl "；

R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9And R^1-10It independently is hydroxyl, C₁~C₇Alkyl such as C₁~C₄Alkyl, again Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl, in another example methyl }, halogen, C₂ ~C₇Alkenyl, C₂~C₇Alkynyl such as C₂~C₄Alkynyl, in another example 2-propynyl or 1- propinyl }, C₃~C₇Naphthenic base, " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~ C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇ Heteroaryl " or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Cycloalkanes Base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl "；

R^1-11、R^1-12、R^1-13、R^1-14And R^1-15It independently is H, cyano, hydroxyl, C₁~C₇Alkoxy, R^1-11-1Replace or not Replace C₁~C₇Alkyl { wherein, R^1-11-1Number be one or more [such as 2,3 or 4], when there are multiple R^1-11-1 When, the R^1-11-1It is identical or different }, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24And R^1-25It independently is halogen, nitre Base, cyano, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom be boron, One of silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl "；

Z is 0,1 or 2；

All R²It independently is halogen, hydroxyl, cyano, amino, R^2-1C substituted or unsubstituted₁~C₇Alkyl { wherein, R^2-1 Number be one or more [such as 2,3 or 4], when there are multiple R^2-1When, the R^2-1It is identical or different }, R^2-2 C substituted or unsubstituted₂~C₈Alkenyl { wherein, R^2-2Number be one or more [such as 2,3 or 4], when there are multiple R^2-2When, the R^2-2It is identical or different }, R^2-3C substituted or unsubstituted₂~C₇Alkynyl { wherein, R^2-3Number be one or more A [such as 2,3 or 4], when there are multiple R^2-3When, the R^2-3It is identical or different }, R^2-4C substituted or unsubstituted₁~ C₇Alkane silicon substrate { wherein, R^2-4Number be one or more [such as 2,3 or 4], when there are multiple R^2-4When, it is described R^2-4It is identical or different }, R^2-5C substituted or unsubstituted₆~C₁₀Aryl { wherein, R^2-5Number be one or more [such as 2,3 It is a or 4], when there are multiple R^2-5When, the R^2-5It is identical or different }, R^2-6It is substituted or unsubstituted " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl " { wherein, R^2-6Number be One or more [such as 2,3 or 4], when there are multiple R^2-6When, the R^2-6It is identical or different } or R^2-7It takes Generation or unsubstituted C₁~C₇Alkoxy { wherein, R^2-7Number be one or more [such as 2,3 or 4], when there are multiple R^2-7When, the R^2-7It is identical or different }；

Alternatively, two R²It is connected on same carbon atom and R is collectively formed^2-8C substituted or unsubstituted₃~C₇Naphthenic base is { wherein, R^2-8Number be one or more [such as 2,3 or 4], when there are multiple R^2-8When, the R^2-8It is identical or different }, Or R^2-9C substituted or unsubstituted₁~C₇Heterocyclylalkyl { wherein, R^2-9Number be one or more [such as 2,3 or 4 It is a], when there are multiple R^2-9When, the R^2-9It is identical or different }；

X can be CH.

M+n can be 2 or 3.

M can be able to be 2 for 0, n.

M can be able to be 1 for 1, n.

M can be able to be 0 for 2, n.

M can be able to be 2 for 1, n.

M can be able to be 1 for 2, n.

Y can be N.

R¹It can be H, cyano, nitro ,-NR^1-1R^1-2,-C (=O) R^1-4,-C (=NR^1-11)R^1-5,-S (=O) R^1-6、R^1-16It takes Generation or unsubstituted C₁~C₇Alkyl, R^1-17C substituted or unsubstituted₂~C₇Alkenyl, R^1-18C substituted or unsubstituted₂~C₇Alkynyl or R^1-20C substituted or unsubstituted₃~C₇Naphthenic base, and can be H, cyano ,-NR^1-1R^1-2,-C (=O) R^1-4、R^1-16It is substituted or unsubstituted C₁~C₇Alkyl, C₂~C₇Alkenyl or C₂~C₇Alkynyl.

R^1-1And R^1-2Hydrogen, C can independently be₁~C₇Alkyl or C₃~C₇Naphthenic base, and C can independently be₁~C₇Alkyl.

R^1-4、R^1-5And R^1-6It independently is C₁~C₇Alkyl, C₃~C₇Naphthenic base, C₂~C₇Alkenyl or C₂~C₇Alkynyl；Again may be used It independently is C₁~C₇Alkyl or C₂~C₇Alkynyl.

R^1-11For H.

All R^1-16、R^1-17、R^1-18And R^1-20It independently is cyano ,-NR^1-16-1R^1-16-2Or-OR^1-16-3；

All R^1-16-1、R^1-16-2And R^1-16-3It independently is hydrogen, C₃~C₇Naphthenic base or C₁~C₇Alkyl；It again can be independently For hydrogen or C₁~C₇Alkyl.

Z can be 0.

Wherein, X CH；

Y is N or CH；

R¹For H, halogen, sulfydryl, nitro, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-C (=NR^1-11)R^1-5、-S (=O) R^1-6,-S (=O)₂R^1-7,-S (=NR^1-12)R^1-8,-S (=NR^1-13) (=NR^1-14)R^1-9,-S (=O) (=NR^1-15)R¹ ^-10、R^1-16C substituted or unsubstituted₁~C₇Alkyl { wherein, R^1-16Number be one or more [such as 2,3 or 4], when There are multiple R^1-16When, the R^1-16It is identical or different }, R^1-17C substituted or unsubstituted₂~C₇Alkenyl { wherein, R^1-17Number For one or more [such as 2,3 or 4], when there are multiple R^1-17When, the R^1-17It is identical or different }, R^1-18Replace Or unsubstituted C₂~C₈Alkynyl { wherein, R^1-18Number be one or more [such as 2,3 or 4], when there are multiple R¹ ^-18When, the R^1-18It is identical or different }, R^1-19C substituted or unsubstituted₁~C₇Alkane silicon substrate { wherein, R^1-19Number be one or Multiple [such as 2,3 or 4], when there are multiple R^1-19When, the R^1-19It is identical or different }, R^1-20It is substituted or unsubstituted C₃~C₇Naphthenic base { wherein, R^1-20Number be one or more [such as 2,3 or 4], when there are multiple R^1-20When, institute The R stated^1-20It is identical or different }, R^1-21It is substituted or unsubstituted " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " { wherein, R^1-21Number be one or more [such as 2,3 Or 4], when there are multiple R^1-21When, the R^1-21It is identical or different }, R^1-22C substituted or unsubstituted₆~C₁₀Aryl is { wherein, R^1-22Number be one or more [such as 2,3 or 4], when there are multiple R^1-22When, the R^1-22It is identical or not Together }, R^1-23It is substituted or unsubstituted that " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1 ~4 C₁~C₇Heteroaryl " { wherein, R^1-23Number be one or more [such as 2,3 or 4], when there are multiple R^1-23When, the R^1-23It is identical or different }, R^1-24C substituted or unsubstituted₁~C₇Alkoxy { wherein, R^1-24Number be one Or multiple [such as 2,3 or 4], when there are multiple R^1-24When, the R^1-24It is identical or different } or R^1-25Replace Or unsubstituted C₁~C₇Alkane sulfydryl { wherein, R^1-25Number be one or more [such as 2,3 or 4], when there are multiple R^1-25When, the R^1-25It is identical or different }；

R^1-1、R^1-2And R^1-3It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇It is naphthenic base, " miscellaneous Atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆ ~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~ C₇Heteroaryl "；

R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9And R^1-10It independently is hydroxyl, C₁~C₇Alkyl, halogen, C₂~C₇Alkenyl, C₂ ~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1 ~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₁~C₇Heteroaryl " or NR^1-4-1R^1-4-2；

Z is 0,1 or 2；

X can be CH；

M+n can be 2 or 3；

Y can be CH or N；

R¹It can be H, cyano, nitro ,-NR^1-1R^1-2,-C (=O) R^1-4,-C (=NR^1-11)R^1-5,-S (=O) R^1-6、R^1-16It takes Generation or unsubstituted C₁~C₇Alkyl, R^1-17C substituted or unsubstituted₂~C₇Alkenyl, R^1-18C substituted or unsubstituted₂~C₇Alkynyl or R^1-20C substituted or unsubstituted₃~C₇Naphthenic base；

R^1-1And R^1-2Hydrogen, C can independently be₁~C₇Alkyl or C₃~C₇Naphthenic base；

R^1-4、R^1-5And R^1-6It independently is C₁~C₇Alkyl, C₃~C₇Naphthenic base, C₂~C₇Alkenyl or C₂~C₇Alkynyl；

R^1-11For H；

All R^1-16-1、R^1-16-2And R^1-16-3It independently is hydrogen, C₃~C₇Naphthenic base or C₁~C₇Alkyl；

Z can be 0.

X can be CH；

" m 2, n 0 ", " m 1, n 1 " or " m 2, n 1 "；

Y can be N；

R¹It can be H, cyano ,-NR^1-1R^1-2,-C (=O) R^1-4、R^1-16C substituted or unsubstituted₁~C₇Alkyl, C₂~C₇Alkenyl, Or C₂~C₇Alkynyl；

R^1-1And R^1-2C can independently be₁~C₇Alkyl；

R^1-4It independently is C₁~C₇Alkyl or C₂~C₇Alkynyl；

All R^1-16It independently is cyano ,-NR^1-16-1R^1-16-2Or-OR^1-16-3；

Z can be 0.

In some scheme, the compound I, its enantiomter, its diastereoisomer, its tautomer, In its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, the compound I is Following any compound:

In general, method at least as described below, which can be used, prepares the compounds of this invention, but it is not limited to following reaction items Reagent and solvent in part.

The present invention also provides the preparation methods of above-mentioned compound I a kind of, are following either method:

Method one:

It includes the following steps: that compound 1A is aoxidized, and obtains compound 1B, and compound 1D is obtained after substitution, deprotection Obtain compound 1E；

Wherein, Y N.Described m, n, z and the R²Definition as described above；The condition of each step in reaction route is equal It can be the normal condition of such reaction of this field.

PG in the formula 1C compound represented can be the various conventional amino protecting groups in this field, preferably Boc, Purpose beWhen being reacted with compound 1B, it is not involved in certain reactive groups (such as amino) thereon Reaction；

The condition of the reaction of the deprotection base can be the conventional removing condition of the various protecting groups in this field, such as hydrolyze Condition, the condition of aminolysis reaction, condition of hydrogenation of reaction etc.；

The reaction of the deprotection base after, preferably, also can further include the operation of post-processing；It is described Post-processing method and condition can be the such post-reaction treatment routine in this field method and condition, preferably: will react System washed, dried, being filtered, solvent evaporated, and then column chromatographs；Alternatively, by reaction system be evaporated off solvent, washing, Filtering；Alternatively, solvent, thin-layer chromatography is evaporated off in reaction system；

Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field Normal condition carry out；

Method two:

It includes the following steps: that compound 1A is aoxidized, and obtains compound 1B, and compound 2B is obtained after reacting with 2A i.e. It can；

Wherein, described m, n, z, Y, R¹And R²Definition as described above；The condition of each step in reaction route Think the normal condition of such reaction of this field.

Method three:

Work as R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-17Substituted C₂~C₇It is alkenyl, unsubstituted Or R^1-18Substituted C₂~C₈Alkynyl or unsubstituted or R^1-20Substituted C₃~C₇When naphthenic base, chemical combination shown in the Formulas I The preparation method of object includes the following steps: in organic solvent (such as 1,2- dichloroethanes, methylene chloride, methanol and dioxane One of or it is a variety of) in, in the presence of reducing agent (such as sodium triacetoxy borohydride and/or sodium cyanoborohydride), By compound 1E and R¹- CHO carries out reductive amination process, obtains compound I；The condition of the reductive amination process can For the conventional condition of such reaction of this field；

Wherein, Y N, the R^1’-CH₂It is equal to R¹.Described m, n, z, the R¹、R²Definition as described above；Reaction The condition of each step in route all can be this field such reaction normal condition.

Method four:

Work as R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-17Substituted C₂~C₇It is alkenyl, unsubstituted Or R^1-18Substituted C₂~C₈Alkynyl, unsubstituted or R^1-20Substituted C₃~C₇When naphthenic base, cyano or acetyl group, the Formulas I The preparation method of compound represented includes the following steps: in organic solvent (such as in methanol, methylene chloride, acetonitrile and DMF It is one or more) in, in the presence of alkali (such as potassium carbonate, cesium carbonate, n,N-diisopropylethylamine or triethylamine), by chemical combination Object 1E and R¹-X¹Substitution reaction is carried out, compound I is obtained；The condition of the substitution reaction can be such reaction of this field Conventional condition；The X¹For halogen (such as chlorine or bromine)；

Wherein, Y N.Described m, n, z, the R¹、R²Definition as described above；The condition of each step in reaction route is equal It can be the normal condition of such reaction of this field.

Method five:

Work as R¹For-C (=O) R^1-4, and R^1-4For C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl or C₃~C₇Naphthenic base When, the preparation method of the Formulas I compound represented includes the following steps: in organic solvent (such as Isosorbide-5-Nitrae-dioxane, two One of chloromethanes and DMF are a variety of) in, in the presence of condensing agent (such as DMAP and EDCI), by compound 1E, withCondensation reaction is carried out, compound I is obtained；The condition of the condensation reaction can such reaction be normal for this field The condition of rule；

The present invention also provides one kind such as formula 1C, 1D or 2A compounds represented:

Wherein, PG, m, n, z, Y, R¹And R²Definition it is same as above.

The present invention also provides a kind of compound I as described above, its enantiomter, its diastereoisomer, its mutually Tautomeric, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug swash in preparation Application in enzyme (such as WEE1 kinases) inhibitor.

The present invention also provides a kind of compound I as described above, its enantiomter, its diastereoisomer, its mutually Tautomeric, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug are preparing medicine Application in object, the drug is for treating and/or preventing disease related with WEE1 kinases.

The disease such as cancer related with WEE1 kinases.The cancer such as cancer of the brain, head-neck carcinoma, esophagus Cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, gastric cancer, gall-bladder-cholangiocarcinoma, liver cancer, cancer of pancreas, colon Cancer, the carcinoma of the rectum, oophoroma, chorioepithelium cancer, carcinoma of uterine body, cervical carcinoma, renal plevis-carcinoma of ureter, bladder cancer, prostate cancer, yin Stem cancer, carcinoma of testis, embryonal carcinoma, the nephroblastoma, cutaneum carcinoma, malignant mela noma, neuroblastoma, osteosarcoma, Juventus Tumor, soft-tissue tumor, acute leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia or He Jiejin lymphomas, again Such as breast cancer, lung cancer, cancer of pancreas, colon cancer, oophoroma, acute leukemia, chronic lymphatic leukemia, chronic myeloid are white Blood disease, He Jiejin lymphomas, also such as colon cancer or oophoroma.

The present invention also provides a kind of compound I as described above, its enantiomter, its diastereoisomer, its mutually Tautomeric, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug are preparing medicine Application in object, the drug is for treatment and/or pre- anti-cancer.

The cancer such as cancer of the brain, head-neck carcinoma, cancer of the esophagus, thyroid cancer, small cell carcinoma, non-small cell carcinoma, mammary gland Cancer, lung cancer, gastric cancer, gall-bladder-cholangiocarcinoma, liver cancer, cancer of pancreas, colon and rectum carcinoma, oophoroma, chorioepithelium cancer, corpus uteri Cancer, cervical carcinoma, renal plevis-carcinoma of ureter, bladder cancer, prostate cancer, carcinoma of penis, carcinoma of testis, embryonal carcinoma, the nephroblastoma, skin Skin cancer, malignant mela noma, neuroblastoma, osteosarcoma, tumor Ewing, soft-tissue tumor, acute leukemia, chronic lymphatic are white Blood disease, chronic myelogenous leukemia or He Jiejin lymphomas, in another example breast cancer, lung cancer, cancer of pancreas, colon cancer, ovary Cancer, acute leukemia, chronic lymphatic leukemia, chronic myeloid leukemias, He Jiejin lymphomas, also for example colon cancer or Oophoroma.

The present invention also provides a kind of pharmaceutical composition, it includes compound I as described above, its enantiomter, its Diastereoisomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its Prodrug, and, (one or more) pharmaceutic adjuvant.

The present invention provides a kind of combination, it includes compound I as described above, its enantiomter, its is diastereomeric different Structure body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug And anticancer drug.

The anticancer drug can be anticancer drug conventional in the art, such as cancer resistance alkylating agent, cancer resistance generation It is derivative to thank antagonist, cancer resistance antibiotic, the anticancer agent from plant, cancer resistance iridium-platinum complex, cancer resistance camptothecine Object, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, interferon, biological respinse modifier, mitoxantrone, L- asparagus fern acyl Amine enzyme, procarbazine, Dacarbazine, hydroxycarbamide, Pentostatin, vitamin A acid, Ah method's Saite, A Fadabeiting, Anastrozole, according to Xi Meitan, Bicalutamide, Leuprorelin, Flutamide, fulvestrant, Macugen, denileukin diftitox, Aldesleukin, rush One of thyroxine α, arsenic trioxide, bortezomib, capecitabine and Goserelin are a variety of, in another example cancer resistance generation Thank to antagonist.

The cancer resistance alkylating agent can be this field routine cancer resistance alkylating agent, such as mustargen N- oxide, Cyclophosphamide, ifosfamide, Melphalan, busulfan, dibromannitol, carbaxilquinone, phosphinothioylidynetrisaziridine, Ranimustine, Ni Mosi One of spit of fland, Temozolomide and Carmustine are a variety of.

The cancer resistance metabolic antagonist can be this field routine cancer resistance metabolic antagonist, such as methotrexate (MTX), 6-MPR, mercaptopurine, 5 FU 5 fluorouracil, Tegafur, doxifluridine, Carmofur, cytarabine, cytarabine ten One of eight alkyl phosphoric acid sodium, enocitabine, S-1, gemcitabine, fludarabine and pemetrexed disodium are a variety of, and example Such as 5 FU 5 fluorouracil.

The cancer resistance antibiotic can be the cancer resistance antibiotic of this field routine, such as actinomycin D, how soft ratio The soft ratio of star, daunorubicin, neoearcinostain, bleomycin, Peplomycin, mitomycin C, Aclarubicin, pirarubicin, table One of star, Zinostatin stimalamer, idarubicin, sirolimus and valrubicin are a variety of.

The anticancer agent from plant can be new for the anticancer agent from plant of this field routine, such as Changchun One of alkali, vincaleukoblastinum, eldisine, etoposide, Sobuzoxane, docetaxel, taxol and vinorelbine are a variety of.

The cancer resistance iridium-platinum complex can be this field routine cancer resistance iridium-platinum complex, such as cis-platinum, One of carboplatin, Nedaplatin and oxaliplatin are a variety of.

The cancer resistance camptothecin derivative can be the cancer resistance camptothecin derivative of this field routine, such as Yi Li is replaced One of health, Hycamtin and camptothecine are a variety of.

The cancer resistance tyrosine kinase inhibitor can be the cancer resistance tyrosine kinase inhibitor of this field routine, example Such as one of Gefitinib, Imatinib and Erlotinib or a variety of.

The monoclonal antibody can be the monoclonal antibody of this field routine, such as Cetuximab, bevacizumab, benefit One of appropriate former times monoclonal antibody, alemtuzumab and trastuzumab are a variety of.

The interferon can be this field routine interferon, such as interferon-' alpha ', Intederon Alpha-2a, Interferon Alpha-2b, One of interferon beta, interferon gamma -1a and interferon gamma-n1 or a variety of.

The biological respinse modifier can be the biological respinse modifier of this field routine, such as coriolan, mushroom One of polysaccharide, sizofiran, Sapylin and ubenimex are a variety of.

Each component in the combination can be used simultaneously or be used separately (such as sequence uses)；When each in the combination Component is simultaneously in use, each component in the combination can uniformly mix (i.e. the mixture of each component).

Each component in the combination can be prepared into a single pharmaceutical composition while use, can also be by each group Single independent pharmaceutical composition (such as in the form of suit) is respectively prepared, these single independent pharmaceutical compositions can be same When using or be used separately (such as sequence use).

The present invention also provides combinations of the above preparation for prevent and/or the drug for the treatment of cancer in application.

In application of the present invention, above-mentioned compound I, its enantiomter, its diastereoisomer, its interconversion Isomers, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, and, it is above-mentioned Anticancer drug can simultaneously or separate administration (such as sequence apply).

The present invention also provides above-mentioned compound I, its enantiomter, its diastereoisomer, its tautomer, Its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, in preparation for " and above-mentioned Anti-cancer agent in combination " prevention and/or treating cancer drug in application.

The present invention also provides above-mentioned anticancer drug, preparation for " and above-mentioned compound I, its enantiomter, Its diastereoisomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or Application in the drug of its prodrug joint " prevention and/or treating cancer.

The present invention also provides a kind of pharmaceutical compositions, and it includes combinations of the above and (one or more) pharmaceutic adjuvant.

Described pharmaceutical composition can be made of the combination and the pharmaceutic adjuvant.

The present invention also provides a kind of Combined drug boxs, and it includes pharmaceutical composition As and pharmaceutical composition B；

The pharmaceutical composition A includes above-mentioned compound I, its enantiomter, its diastereoisomer, its interconversion Isomers, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, and, (it is a kind of or It is a variety of) pharmaceutic adjuvant；

The pharmaceutical composition B includes above-mentioned anticancer drug and (one or more) pharmaceutic adjuvant.

The Combined drug box can be made of the pharmaceutical composition A and the pharmaceutical composition B.

The pharmaceutical composition A can be by above-mentioned compound I, its enantiomter, its diastereoisomer, its interconversion Isomers, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, and, it is medicinal auxiliary Material composition；

The pharmaceutical composition B can be made of above-mentioned anticancer drug and pharmaceutic adjuvant.

Each pharmaceutical composition in the Combined drug box can simultaneously using or be used separately (such as sequence uses).

On the basis of without prejudice to field common sense, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention Example.

The reagents and materials used in the present invention are commercially available.

Unless otherwise indicated, the following term occurred in description of the invention and claims has the meaning that

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

Term " alkyl " refer to the linear chain or branched chain of the saturation with one to 12 carbon atom monovalent hydrocarbon (such as C₁-C₆Alkyl, in another example C₁-C₄Alkyl).The example of alkyl includes but are not limited to methyl, ethyl, 1- propyl, 2- propyl, 1- Butyl, 2-methyl-1-butene base, 2- butyl, 2- methyl-2-propyl, 1- amyl, 2- amyl, 3- amyl, 2- methyl -2- butyl, 3- Methyl-2- butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, 1- hexyl, 2- hexyl, 3- hexyl, 2- methyl-2- amyl, 3- Methyl -2- amyl, 4- methyl -2- amyl, 3- methyl -3- amyl, 2- methyl -3- amyl, 2,3- dimethyl -2- butyl, 3,3- Dimethyl -2- butyl, 1- heptyl and 1- octyl.

Term " alkenyl " refers to at least one unsaturation position i.e. carbon-to-carbon sp²Two to ten two carbon atoms of double bond Linear chain or branched chain monovalent hydrocarbon (such as C₂-C₆Alkenyl, in another example C₂-C₄Alkenyl), and it is " cis- " and " anti-including having The group of formula " orientation or " E " and " Z " orientation.The example includes but are not limited to the amyl- 1- alkene of vinyl, allyl, 1- ring The amyl- 2- alkenyl of base, 1- ring, the amyl- 3- alkenyl of 1- ring, 5- hexenyl, 1- hexamethylene -1- alkenyl, 1- hexamethylene -2- alkenyl and 1- hexamethylene - 3- alkenyl.

Term " alkynyl " refers to at least one unsaturated position i.e. two to ten two carbon atom of tri- key of carbon-to-carbon sp Univalence hydrocarbyl (such as the C of linear chain or branched chain₂-C₆Alkynyl, in another example C₂-C₄Alkynyl).The example includes but are not limited to acetenyl And propinyl.

Term " alkane silicon substrate " refers to the alkyl connected by silicon bridge；The alkyl is defined as above；C₁-C₇Alkane silicon substrate is Refer toWherein R^A、R^BAnd R^CIt independently is C₁-C₇Alkyl.

Term " naphthenic base " refers to the cyclic hydrocarbon atom of the saturation of the non-aromatic of the unit price with three to two ten carbon atoms Group (such as C₃-C₆Naphthenic base).Monocycle carboatomic ring atom group example include but are not limited to cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl and cyclo-dodecyl.Term " naphthenic base " further includes Polycyclic (for example, bicyclic and tricyclic) cyclic alkyl structure, the bicyclic carbocyclic with 7 to 12 atoms may be arranged to for example bicyclic [4,5], [5,5], [5,6] or [6,6] system, or it is arranged as example bis- [2.2.1] heptane of bridge joint loop system, bicyclic [2.2.2] Octane and bicyclic [3.2.2] nonane.

Term " Heterocyclylalkyl " refers to that the carbon ring group of the saturation with 3 to 12 annular atoms, wherein at least one ring are former Son is the hetero atom independently selected from boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, remaining annular atom is C.The group can be carbon-based group Or heteroatom group (namely it can be to be C- connection or N- connection, as long as it is possible).The example packet of heterocycle Include but be not limited only to pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, morpholine Base, 4- thio-morpholinyl, thiophene oxane base and piperazinyl.Spirocyclic moiety and bridged ring part are also included in the range of this definition. For example, the group as derived from nafoxidine can be nafoxidine -1- base (N- connection) or (the C- connection of nafoxidine -3- base ).E.g. 3-7 member ring monocycle (1-6 carbon atom and 1-3 hetero atom for being selected from N, O, P, B, Si, S and Se, in this N, B, P or Se is optionally obtained replaced one or more oxygen atoms as NO, BOH, PO, PO₂, the group of SeO；N can be optional Ground is quaternized；S atom can be obtained optionally replaced one or more oxygen atoms or nitrogen-atoms as SO, SO₂, S (=O) (=NR^a), S (=NR^b) or S (=NR^c)₂Group, meanwhile, R^a、R^bAnd R^cIt independently is cyano, C₁~C₇Alkyl, C₃~C₇Ring Alkyl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl ", " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇It is miscellaneous Aryl ", C₆~C₁₀Aryl or C₁~C₇Alkoxy；Meanwhile-CH₂Group can be optionally by-C (=O)-,-C (=S)-or-C (=NR^d)-substitution, R^dIt independently is cyano, C₁~C₇Alkyl, C₃~C₇Naphthenic base, " hetero atom is boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", " hetero atom be boron, silicon, oxygen, sulphur, selenium, One of nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₆~C₁₀Aryl or C₁~C₇Alkoxy； When the ring is a three-membered ring, only one of them hetero atom) or 7-10 former molecular bicyclic (4-9 carbon atom With selected from N, O, P, B, Si, the 1-3 hetero atom of S, in this N, S, B or P optionally must replaced one or more oxygen atoms To as NO, BOH, SO, SO₂, PO, PO₂, the group of SeO, meanwhile ,-CH₂Group can be substituted optionally by-C (=O) -).Depending on Depending on structure, heterocycle can be monoradical or bivalent group, i.e., sub- heterocycle.

Term " aryl " refers to any stable monocycle or bicyclic carbocyclic that may be up to 7 atoms in each ring, wherein At least one ring is aromatic rings.The example of above-mentioned aryl unit includes phenyl, naphthalene, tetralyl, indanyl, connection Phenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).It is appreciated that being two ring substituents in aryl substituent, and wherein In the case where one ring is non-aromatic ring, connection is carried out by aromatic ring.

Term " heteroaryl " refers to the stabilization monocycle or two rings that may be up to 7 atoms in each ring, wherein at least one ring It is aromatic rings and is selected from the hetero atom of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus containing 1-4.Heteroaryl within the range defined herein Including but not limited to: acridinyl, carbazyl, cinnoline base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thiophene Pheno base, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazine Base, pyridyl group, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline." heteroaryl " is it should also be understood that be the N- oxygen for including any nitrogenous heteroaryl Compound derivative.Wherein heteroaryl substituent be two ring substituents and a ring be non-aromatic ring or do not include hetero atom In the case where, it will be understood that connection is carried out by aromatic ring respectively.Simultaneously aromatic ring, Bicyclic heteroaromatic rings system can be with condensed for hetero-aromatic ring Form cyclization.Wherein, N, S, B, P or Se are optionally obtained replaced one or more oxygen atoms as NO, SO, SO₂、BOH、 PO、PO₂, SeO group, N atom can be quaternized.Heteroaryl can be connected to main knot on any hetero atom or carbon atom To form stable compound on structure.Depending on structure, heteroaryl can be monoradical or bivalent group, i.e. inferior heteroaryl.

Term " alkoxy " refers to the alkyl connected by oxygen bridge；The alkyl is defined as above.

Term " alkane sulfydryl " refers to the alkyl connected by sulphur bridge；The alkyl is defined as above.

Term " pharmaceutically acceptable salt " refers to by suitable non-toxic organic, inorganic acid, organic base or inorganic base The salt formed with compound I retains the bioactivity of compound I.The organic acid can for this field it is conventional can be at salt Various organic acids, preferably methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, first One of acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalene sulfonic acids and salicylic acid or It is a variety of.The inorganic acid can for this field it is conventional can be at the various inorganic acids of salt, preferably one in hydrochloric acid, sulfuric acid and phosphoric acid Kind is a variety of.The organic base can for this field it is conventional can be at the various organic bases of salt, preferably pyridines, imidazoles, pyrrole One of piperazine class, indoles, fast quinoline class, tertiary amines and phenyl amines are a variety of.The preferred triethylamine of tertiary amines organic base And/or N, N- diisopropylethylamine.The preferred N of phenyl amines organic base, accelerine.The pyridines organic base It is preferred that one of pyridine, picoline, 4-dimethylaminopyridine and 2- methyl -5- ethylpyridine or a variety of.Described is inorganic Alkali can for this field it is conventional can be at the various inorganic bases of salt, preferred as alkali hydride, the hydroxide of alkali metal, alkali metal One of alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, saleratus and sodium bicarbonate or a variety of.It is described The preferred sodium hydride of alkali metal hydride and/or hydrofining.The preferred sodium hydroxide of the hydroxide of the alkali metal, hydroxide One of potassium and lithium hydroxide are a variety of.The preferred sodium methoxide of the alkoxide of the alkali metal, sodium ethoxide, potassium tert-butoxide and One of sodium tert-butoxide is a variety of.

Term " solvate " refers to the substance that compound I and suitable solvent are formed.The solvent be, for example, water or Organic solvent.

Term " component " refers to the component in present invention combination, i.e. compound I, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, Or anticancer drug.

Term " pharmaceutic adjuvant ", which refers to, those of is widely used auxiliary material in drug production field.Auxiliary material is mainly used for offer one A safe and stable and functional pharmaceutical composition, can be with providing method, and active constituent is after so that subject is received administration with institute Expected rate dissolution, or promote subject to receive active constituent after composition is administered and effectively absorbed.The pharmaceutic adjuvant Can be inert filler, or certain function be provided, for example, stable the composition whole pH value or prevent composition active The degradation of ingredient.The pharmaceutic adjuvant may include one of following auxiliary material or a variety of: adhesive, suspending agent, emulsifier, Diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antitack agent, glidant, wetting agent, gelling agent, absorption Delayed-action activator, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, colorant, corrigent and sweetener.

Term " active constituent " refers to the active constituent in pharmaceutical composition of the present invention or Combined drug box, i.e. compound I, its Enantiomter, its diastereoisomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, Its metabolite or its prodrug, anticancer drug, alternatively, they are formed by said combination.

The positive effect of the present invention is that: the compound of the present invention is preferable to the inhibitory activity of WEE1 kinases.

Specific embodiment

The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.

The structure of all compounds of the present invention can by nuclear magnetic resonance (¹H NMR) and/or Mass Spectrometer Method (MS) identification.¹H Nmr chemical is displaced (δ) with PPM record (10^-6).NMR is carried out by Bruker AVANCE-400 spectrometer.

LC-MS is measured by Agilent 1200HPLC/6120 mass spectrograph.

Thin layer silica gel plate is good minister silicon source HSGF254 or Qingdao GF254 silica gel plate.Column chromatography generally uses the Yantai Huanghai Sea 200-300 mesh silica gel is as carrier.

Embodiment 1

Step 1:

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- methyl mercapto pyrazolo [3,4-d] Pyrimidine -3- ketone (270mg, 0.75mmol) (such as formula 1A compound represented) and 4- chloroperoxybenzoic acid (143mg, 0.83mmol) It is dissolved into toluene (20ml), is stirred at room temperature 1 hour, n,N-diisopropylethylamine (291mg, 2.26mmol) and 6- is then added Amino -3,4- dihydro -1H- isoquinolin -2- carboxylic acid tert-butyl ester (243mg, 0.98mmol) (compound as shown in Equation 2) continues Be stirred at room temperature 16 hours, reaction solution concentration, through silica gel column chromatography (petrol ether/ethyl acetate=100% to 50%) purify as [[2- allyl-1- [6- (1- hydroxyl-1- methyl-ethyl)-2- the pyridyl group]-3- oxygen of compound tert-butyl group 6-shown in Formulas I-1-a Generation-pyrazolo [3,4-d] pyrimidine -6- base] amino] -3,4- dihydro -1H- isoquinolin -2- carboxylic acid, ethyl ester (270mg, 0.48mmol)。LC-MS:m/z:(M+H)⁺=558.3,¹H NMR(400MHz,CDCl₃) δ 8.88 (s, 1H), 7.91 (t, J= 7.9Hz, 1H), 7.85-7.70 (m, 2H), 7.63-7.47 (m, 1H), 7.42 (d, J=7.6Hz, 1H), 7.37 (s, 1H), 7.11 (d, J=8.3Hz, 1H), 5.73 (dq, J=10.2,6.1Hz, 1H), 5.08 (d, J=10.1Hz, 1H), 4.96 (d, J= 17.0Hz, 1H), 4.79 (d, J=6.2Hz, 2H), 4.59 (s, 2H), 3.70 (d, J=4.5Hz, 2H), 2.86 (t, J= 5.5Hz,2H),1.62(s,6H),1.53(s,9H)。

Step 2:

By tert-butyl 6- [[2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -3- oxo-pyrazoles And [3,4-d] pyrimidine -6- base] amino] -3,4- dihydro -1H- isoquinolin -2- carboxylic acid, ethyl ester (250mg, 0.45mmol) (such as Formulas I - 1-a compound represented) it is dissolved in methylene chloride (10ml), the dioxane solution (2ml, 4M) of hydrochloric acid is added, is stirred at room temperature 16 hours, filtering, filtrate was concentrated and dried to obtain [6- (1- hydroxyl -1- the methyl-second of the compound 2- allyl -1- as shown in Formulas I -1 Base) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline -6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (200mg, 0.44mmol)。LC-MS:m/z:(M+H)⁺=458.2,¹H NMR(400MHz,DMSO-d₆)δ10.37(s,1H),9.48(s, 2H), 8.96-8.90 (m, 1H), 8.08 (t, J=7.9Hz, 1H), 7.80 (d, J=7.8Hz, 2H), 7.66 (d, J=7.6Hz, 1H), 7.51 (d, J=8.3Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 5.69 (qd, J=11.1,5.7Hz, 1H), 5.02 (d, J=10.4Hz, 1H), 4.84 (d, J=17.0Hz, 1H), 4.72 (d, J=5.6Hz, 2H), 4.23 (s, 4H), 3.39 (d, J= 5.0Hz, 2H), 3.04 (t, J=6.0Hz, 2H), 1.49 (s, 6H).

Embodiment 2

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into first In alcohol (5ml), the aqueous solution (0.1ml, 40%) and Sodium triacetoxyborohydride (46mg, 0.22mmol) of formaldehyde is then added, It is stirred at room temperature 4 hours.Reaction solution concentration, is dissolved, saturated sodium bicarbonate with the mixed liquor (10/1,20ml) of methylene chloride and methanol It washes twice, after organic layer is dried over anhydrous sodium sulfate, filtering is concentrated to give such as -2 compound represented 2- allyl -1- [6- of Formulas I (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- [(2- methyl -3,4- dihydro -1H- isoquinolin -6- base) amino] pyrazolo [3,4-d] pyrimidine -3- ketone (40mg, 0.085mmol).LC-MS:m/z:(M+H)⁺=472.3,¹H NMR(400MHz,DMSO- d₆) δ 10.23 (s, 1H), 8.89 (s, 1H), 8.05 (t, J=7.9Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.66 (m, 2H), 7.40 (d, J=7.6Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 5.75-5.63 (m, 1H), 5.35 (s, 1H), 5.02 (d, J=10.2Hz, 1H), 4.84 (d, J=17.5Hz, 1H), 4.72 (d, J=5.8Hz, 2H), 3.46 (s, 2H), 2.84 (t, J =5.5Hz, 2H), 2.62 (t, J=5.8Hz, 2H), 2.36 (s, 3H), 1.49 (s, 6H).

Embodiment 5

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into two In chloromethanes (5ml), acetone (0.1ml, 40%) and Sodium triacetoxyborohydride (46mg, 0.22mmol), heating is then added To flowing back and stir 48 hours.Reaction solution concentration, through silica gel column chromatography (methylene chloride/methanol=100% to 10%, then two Chloromethanes/methanol/methanolic ammonia solution=100/10/1.5) purify such as -5 compound represented 2- allyl -1- [6- (1- of Formulas I Hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- [(2- isopropyl -3,4- dihydro -1H- isoquinolin -6- base) amino] pyrazolo [3,4-d] pyrimidine -3- ketone (30mg, 0.06mmol).LC-MS:m/z:(M+H)⁺=496.2,¹H NMR(400MHz,MeOD-d₄) δ 8.87 (s, 1H), 8.05 (t, J=7.8Hz, 1H), 7.86-7.76 (m, 2H), 7.70 (d, J=7.8Hz, 1H), 7.51 (d, J =7.6Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 5.74 (dq, J=11.0,6.2Hz, 1H), 5.06 (d, J=10.1Hz, 1H), 4.95 (s, 1H), 4.84 (d, J=6.1Hz, 2H), 4.26 (s, 2H), 3.58-3.49 (m, 1H), 3.42 (t, J= 5.8Hz, 2H), 3.16 (t, J=5.8Hz, 2H), 1.60 (s, 6H), 1.42 (d, J=6.6Hz, 6H).

Embodiment 11

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into two Then ethylene bromohyrin (43mg, 0.34mmol) and potassium carbonate is added in chloromethanes (5ml) and methanol (5ml) in the mixed solvent (72mg, 0.52mmol), 60 DEG C are stirred 16 hours.Reaction solution concentration, prepares plate (methylene chloride: methanol through tlc silica gel =10:1) purify such as -11 compound represented of Formulas I (18mg, 0.036mmol).Yield 41%.LC-MS:m/z:(M+H)⁺= 502.3,¹H NMR(400MHz,MeOD-d₄) δ 8.84 (s, 1H), 8.00 (t, J=7.9Hz, 1H), 7.85-7.79 (m, 1H), 7.70-7.60 (m, 2H), 7.38 (dd, J=8.3,2.0Hz, 1H), 7.05 (d, J=8.4Hz, 1H), 5.72 (ddt, J= 16.3,10.2,6.1Hz, 1H), 5.05 (dd, J=10.2,1.1Hz, 1H), 4.96-4.89 (m, 1H), 4.85 (s, 2H), 3.83 (s,2H),3.80(s,2H),2.97(s,4H),2.82(s,2H),1.59(s,6H)。

Embodiment 12

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into N, In dinethylformamide (5ml), be then added 2- bromo-ethyl-methyl ether (48mg, 0.34mmol) and potassium carbonate (72mg, 0.52mmol), it stirs 16 hours for 75 DEG C.Reaction solution concentration, prepares plate (methylene chloride: methanol=10:1) through tlc silica gel Purify such as -12 compound represented of Formulas I (8mg, 0.016mmol).Yield 18%.LC-MS:m/z:(M+H)⁺=516.3,¹H NMR(400MHz,MeOD-d₄) δ 8.84 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.68 (d, J=7.7Hz, 1H), 7.63 (s, 1H), 7.38 (d, J=8.4Hz, 1H), 7.04 (d, J=8.4Hz, 1H), 5.80-5.66 (m, 1H), 5.06 (d, J=10.2Hz, 1H), 4.95 (d, J=1.1Hz, 1H), 4.83 (s, 2H), 3.75 (s, 2H), 3.68 (t, J=5.5Hz, 2H), 3.41 (s, 3H), 2.94 (dd, J=12.2,4.8Hz, 4H), 2.83 (t, J=5.6Hz, 2H), 1.60 (s, 6H)。

Embodiment 14

Step 1:

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (110mg, 0.24mmol) (such as -1 compound represented of Formulas I) and N-Boc- Methylamino acetaldehyde (83mg, 0.48mmol) (compound as shown in Equation 3) is dissolved into methanol (5ml), is stirred at room temperature 1 hour, Then be added sodium triacetoxy borohydride (127mg, 0.60mmol), continue to be stirred at room temperature 16 hours, reaction solution be concentrated to give as [2- [6- [[2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- the pyridyl group] -3- oxygen of compound N-shown in Formulas I -14-a Generation-pyrazolo [3,4-d] pyrimidine -6- base] amino] -3,4- dihydro -1H- isoquinolin-2-yl] ethyl]-N- methyl-carbamic acid The tert-butyl ester (150mg, 0.24mmol).LC-MS:m/z:(M+H)⁺=615.4.

Step 2:

By N- [2- [6- [[2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -3- oxo-pyrazoles And [3,4-d] pyrimidine -6- base] amino] -3,4- dihydro -1H- isoquinolin-2-yl] ethyl]-N- methyl-t-butyl carbamate (140mg, 0.23mmol) (such as Formulas I -14-a compound represented) is dissolved in the aqueous solution (6ml, 2M) of hydrochloric acid, and it is small to be stirred at room temperature 16 When, adding saturated aqueous solution of sodium bicarbonate tune pH value is 7, with the mixed solution (DCM/CH of methylene chloride and methanol₃OH=10/1) Extraction, organic layer are dried over anhydrous sodium sulfate, and are filtered, and filtrate is concentrated and dried to obtain the compound 2- allyl -1- as shown in Formulas I -14 [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- [[2- [2- (methylamino) ethyl] -3,4- dihydro -1H- isoquinoline Quinoline -6- base] amino] pyrazolo [3,4-d] pyrimidine -3- ketone (90mg, 0.17mmol).LC-MS:m/z:(M+H)⁺=515.3,¹H NMR(400MHz,DMSO-d₆) δ 10.26 (s, 1H), 8.90 (s, 1H), 8.05 (t, J=7.9Hz, 1H), 7.80 (d, J= 8.1Hz, 1H), 7.67 (m, 2H), 7.39 (d, J=8.5Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 5.69 (dq, J=11.7, 6.1Hz, 1H), 5.37 (s, 1H), 5.01 (d, J=10.1Hz, 1H), 4.84 (d, J=17.2Hz, 1H), 4.72 (d, J= 5.6Hz, 2H), 3.54 (s, 2H), 2.83 (t, J=5.2Hz, 2H), 2.70 (t, J=6.0Hz, 4H), 2.57 (t, J=6.3Hz, 2H),2.34(s,3H),1.48(s,6H)。

Embodiment 15

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- [[2- [2- (methylamino) second Base] -3,4- dihydro -1H- isoquinolin -6- base] amino] pyrazolo [3,4-d] pyrimidine -3- ketone (40mg, 0.116mmol) is (such as formula I-14 compound represented) it is dissolved into methanol (5ml), the aqueous solution (0.1ml, 40%) and triacetyl oxygen of formaldehyde is then added Base sodium borohydride (61mg, 0.30mmol) is stirred at room temperature 4 hours.Reaction solution concentration, with the mixed liquor of methylene chloride and methanol (10/1,20ml) it dissolving, saturated sodium bicarbonate is washed twice, and organic layer is dried over anhydrous sodium sulfate, column chromatography (silica gel, UV254, DCM/CH₃OH=100% to 10%, then DCM/CH₃OH/NH₃.CH₃OH=100/10/1.5) purify as shown in Formulas I -15 Compound 2- allyl -6- [[2- (2- dimethylaminoethyl) -3,4- dihydro -1H- isoquinolin -6- base] amino] -1- [6- (1- Hydroxyl -1- methyl-ethyl) -2- pyridyl group] pyrazolo [3,4-d] pyrimidine -3- ketone (30mg, 0.057mmol).LC-MS:m/z: (M+H)⁺=529.2,¹H NMR(400MHz,DMSO-d₆)δ10.35–10.16(m,1H),8.92–8.86(m,1H),8.07– 8.01(m,1H),7.82–7.76(m,1H),7.74–7.63(m,2H),7.45–7.37(m,1H),7.05–7.00(m,1H), 5.74–5.64(m,1H),5.36(s,1H),5.05–4.98(m,1H),4.88–4.80(m,1H),4.75–4.67(m,2H), 3.63–3.58(m,2H),2.87–2.81(m,2H),2.78–2.69(m,4H),2.69–2.63(m,2H),2.44–2.32(m, 6H),1.52–1.44(m,6H)。

Embodiment 21

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into two In chloromethanes (5ml) and DMF (1ml), be then added chloroacetic chloride (6.8mg, 0.087mmol) and triethylamine (17.7mg, 0.175mmol), it is stirred at room temperature 16 hours.Reaction solution concentration, after being diluted with water, filtering, solid is through dry as shown in Formulas I -21 Compound 6- [(2- acetyl group -3,4- dihydro -1H- isoquinolin -6- base) amino] -2- allyl -1- [6- (1- hydroxyl -1- first Base-ethyl) -2- pyridyl group] pyrazolo [3,4-d] pyrimidine -3- ketone (40mg, 0.085mmol).LC-MS:m/z:(M+H) += 500.3,¹H NMR(400MHz,DMSO-d₆)δ10.29(s,1H),8.90(s,1H),8.11–8.02(m,1H),7.82–7.73 (m, 2H), 7.65 (d, J=7.5Hz, 1H), 7.46 (t, J=8.1Hz, 1H), 7.15 (d, J=8.2Hz, 1H), 5.74-5.62 (m, 1H), 5.35 (s, 1H), 5.01 (dd, J=10.3,1.3Hz, 1H), 4.83 (dd, J=17.3,1.3Hz, 1H), 4.71 (d, J=7.7Hz, 2H), 4.61 (s, 1H), 4.56 (s, 1H), 3.68 (t, J=5.8Hz, 2H), 2.87 (t, J=6.2Hz, 1H), 2.76 (t, J=6.5Hz, 1H), 2.11 (d, J=4.5Hz, 3H), 1.48 (s, 6H).

Embodiment 28

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (30mg, 0.066mmol) (such as -1 compound represented of Formulas I) is dissolved into N, In dinethylformamide (5ml), 3- bromopropene (8mg, 0.66mmol) and potassium carbonate (14mg, 0.1mmol), room is then added Temperature stirring 16 hours.Reaction solution concentration, prepares plate (methylene chloride: methanol=10:1) through tlc silica gel and purifies such as Formulas I- 28 compounds represented (5mg, 0.016mmol).Yield 15%.¹H NMR(400MHz,MeOD-d₄)δ8.84(s,1H),8.03 (t, J=7.9Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.69 (d, J=7.7Hz, 2H), 7.41 (dd, J=8.3,1.8Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 6.10-5.93 (m, 1H), 5.73 (ddd, J=17.0,6.1,4.1Hz, 1H), 5.42 (dd, J=23.2,5.8Hz, 2H), 5.05 (dd, J=10.2,1.1Hz, 1H), 4.98-4.92 (m, 1H), 4.84 (d, J= 6.1Hz, 2H), 3.84 (s, 2H), 3.43 (d, J=6.8Hz, 2H), 3.02 (s, 4H), 1.60 (s, 6H) .LC-MS:m/z:(M+ H)⁺=498.3.

Embodiment 37

Step 1:

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- methyl mercapto pyrazolo [3,4-d] Pyrimidine -3- ketone (such as formula 1A compound represented) (100mg, 0.28mmol) and 4- chloroperoxybenzoic acid (53mg, 0.31mmol) It is dissolved into toluene (20ml), is stirred at room temperature 1 hour, 2- amino -7,8- dihydro -5H-1,6- benzodiazine -6- carboxylic is then added Tert-butyl acrylate (243mg, 0.98mmol) is warming up to 100 DEG C and stirs 16 hours, reaction solution concentration, through silica gel column chromatography (petroleum Ether/ethyl acetate=100% to 0%) it purifies and then purifies to obtain the compound tert-butyl group 2- as shown in Formulas I -6-a through preparing liquid phase [[2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -3- oxo-pyrazolo [3,4-d] pyrimidine -6- base] Amino] -7,8- dihydro -5H-1,6- benzodiazine -6- carboxylic acid, ethyl ester (28mg, 0.05mmol).LC-MS:m/z:(M+H)⁺= 559.3。

Step 2:

By tert-butyl 2- [[2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -3- oxo-pyrazoles And [3,4-d] pyrimidine -6- base] amino] -7,8- dihydro -5H-1,6- benzodiazine -6- carboxylic acid, ethyl ester (28mg, 0.05mmol) (such as Formulas I -37-a compound represented) is dissolved in methylene chloride (10ml), and the dioxane solution (2ml, 4M) of hydrochloric acid is added, It is stirred at room temperature 16 hours, filters, filtrate is concentrated and dried to obtain [6- (1- hydroxyl -1- the first of the compound 2- allyl -1- as shown in Formulas I -6 Base-ethyl) -2- pyridyl group] -6- (5,6,7,8- tetrahydro -1,6- benzodiazine -2- base amino) pyrazolo [3,4-d] pyrimidine -3- Ketone (200mg, 0.44mmol).¹H NMR(400MHz,MeOD-d₄) δ 9.28 (s, 1H), 8.11 (t, J=7.0Hz, 2H), 7.82 (d, J=7.4Hz, 2H), 7.43 (d, J=8.9Hz, 1H), 5.76 (dq, J=11.2,6.5Hz, 1H), 5.07 (d, J= 9.5Hz, 1H), 4.95 (s, 1H), 4.90 (d, J=8.0Hz, 2H), 4.50 (s, 2H), 3.74 (s, 2H), 3.49 (s, 2H), 1.59(s,6H).LC-MS:m/z:(M+H)⁺=459.2.

Embodiment 44

Step 1:

By bromo- 3,4- dihydronaphthalene -2 (1H) -one (1.8g, 8mmol) (such as Formulas I -44-a compound represented) of 6- and acetic acid Ammonium (6.2g, 81mmol) is added in the methanol of 80ml, and 2h is stirred at room temperature.Then be added sodium cyanoborohydride (600mg, 0.984mmol), it is stirred overnight at room temperature.30ml water is added after being concentrated under reduced pressure in reaction solution, and is adjusted to pH value with the hydrochloric acid of 1mol/L Acidity is extracted twice with the methylene chloride of 30ml every time.PH value is adjusted to alkali (pH=with the sodium hydroxide solution of 1mol/L by water phase 10-11).Every time three times with the methylene chloride extraction of 40ml.Organic phase is washed with 30ml saturated salt solution, uses anhydrous slufuric acid It is concentrated after sodium is dry, gained crude product is directly used in next step.Obtain rufous liquid 900mg, yield 50%.LC-MS:m/z:(M +H)⁺=226.

Step 2:

The bromo- 1,2,3,4- naphthane -2- amine (900mg, 3.98mmol) (such as Formulas I -44-b compound represented) of 6- is molten Solution is heated to reflux 4h into the formaldehyde and 16ml formic acid of 10ml37%.Evaporated under reduced pressure solvent, gained crude product are dissolved in 30ml water, PH value is adjusted to alkalinity by the sodium bicarbonate solution that saturation is then added, and is extracted in two times with 120ml methylene chloride, organic layer nothing Aqueous sodium persulfate is dry, concentration, and gained crude product is brown oil 800mg, is directly used in and reacts in next step.Yield 79%.LC- MS:m/z:(M+H)⁺=254.

Step 3:

By the bromo- N of 6-, N- dimethyl -1,2,3,4- naphthane -2- amine (600mg, 2.36mmol) is (as shown in Formulas I -44-c Compound), benzophenone imine (470mg, 2.594mmol), sodium tert-butoxide (480mg, 5mmol), Pd₂(dba)₃(70mg, 0.0765mmol), BINAP (150mg, 0.241mmol) is added in 30ml toluene, is taken a breath three times, is then heated in argon gas 120 spend night.Reaction solution concentration, gained crude product cross column purification (methanol: methylene chloride=0-10%), obtain brown oil 600mg, yield 71%.LC-MS:m/z:(M+H)⁺=355.

Step 4:

By 6- ((diphenyl methylene) amino)-N, N- dimethyl -1,2,3,4- naphthane -2- amine (as shown in Formulas I -44-d Compound) (600mg, 1.693mmol) be dissolved in 30ml methanol, sodium acetate (560mg, 6.83mmol) and hydrochloric acid is then added Azanol (350mg, 5.04mmol) is heated to 60 degree and reacts 3 hours.Reaction solution filtering and concentrating, gained crude product cross column purification (first Alcohol: methylene chloride=0-20%), obtain brown solid 300mg, yield 93%.LC-MS:m/z:(M+H)⁺=191.

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (such as formula 1A compound represented) (72mg, 0.2mmol) is added azoles in the solution of 15ml toluene Metachloroperbenzoic acid (50mg, 0.22mmol), acquired solution are stirred at room temperature 1h and obtain 2- allyl -1- (6- (2- hydroxyl third Alkane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone is (such as formula 1B Compound represented) toluene solution.N, N- dimethyl -1,2,3,4- naphthanes -2,6- bis- are added in above-mentioned acquired solution Amine (such as Formulas I -44-e compound represented) (40mg, 0.21mmol) and 0.5mlN, N- diisopropylethylamine, were stirred at room temperature Then night is placed at room temperature for 16 days.It is concentrated under reduced pressure, gained crude product first isolates and purifies (7M ammonia methanol: dichloromethane with thin layer chromatography Alkane=0-10%), then it is prepared again with efficient liquid phase such as -44 compound represented 10mg of Formulas I, white solid, yield 9%.LC-MS:m/z:(M+H)⁺=500,¹H NMR(400MHz,MeOD-d₄)δ8.81(s,1H),8.54(s,1H),8.02(t, J=7.9Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.69 (d, J=7.7Hz, 1H), 7.62 (s, 1H), 7.39 (d, J= 7.9Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 5.73 (ddd, J=17.0,6.0,4.2Hz, 1H), 5.05 (d, J=9.2Hz, 1H), 4.94 (d, 1H), 4.83 (d, J=6.0Hz, 2H), 3.59 (s, 1H), 3.19 (d, J=12.3Hz, 1H), 3.07-2.87 (m,9H),2.35(m,1H),1.92(m,1H),1.60(s,6H)。

Embodiment 49

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (20mg, 0.044mmol) (such as -1 compound represented of Formulas I) is distributed to two In chloromethanes (5ml), tetrolic acid (3.7mg, 0.44mmol), EDCI (17mg, 0.088mmol), 4- dimethylamino is then added Pyridine (1mg, 0.008mmol) is stirred at room temperature 16 hours.Reaction solution concentration, through tlc silica gel prepare plate (methylene chloride: Methanol=10:1) purify such as -49 compound represented of Formulas I (6mg, 0.011mmol).Yield 26%.LC-MS:m/z:(M+H )⁺=524.3,¹H NMR(400MHz,MeOD-d₄) δ 8.86 (s, 1H), 8.11-7.98 (m, 1H), 7.82 (d, J=8.1Hz, 1H), 7.70 (s, 2H), 7.48 (d, J=8.4Hz, 1H), 7.21-7.08 (m, 1H), 5.74 (ddt, J=16.3,10.2, 6.1Hz, 1H), 5.05 (dd, J=10.2,1.1Hz, 1H), 4.94 (d, J=1.3Hz, 1H), 4.92 (s, 1H), 4.84 (d, J= 6.1Hz, 2H), 4.70 (s, 1H), 4.06 (t, J=5.9Hz, 1H), 3.84 (t, J=6.1Hz, 1H), 2.92 (dt, J=24.8, 5.9Hz,2H),2.11(s,3H),1.60(s,6H)。

Embodiment 54

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into first In alcohol (6ml), cyclobutanone (9.2mg, 0.131mmol) and Sodium triacetoxyborohydride (37mg, 0.175mmol) is then added, It is stirred at room temperature 4 hours.Reaction solution concentration, is dissolved, saturated sodium bicarbonate with the mixed liquor (10/1,20ml) of methylene chloride and methanol It washes twice, after organic layer is dried over anhydrous sodium sulfate, filtering, concentration gained crude product isolates and purifies (7M ammonia with thin layer chromatography Methanol: methylene chloride=0-10%) obtain target compound such as -54 compound represented of Formulas I (12mg, 0.023mmol), yield 27%.LC-MS:m/z:(M+H)⁺=512.3,¹H NMR (400MHz, MeOD) δ 8.86 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.81 (d, J=7.6Hz, 1H), 7.75-7.62 (m, 2H), 7.44 (dd, J=8.3,1.9Hz, 1H), 7.10 (d, J= 8.4Hz, 1H), 5.81-5.65 (m, 1H), 5.05 (dd, J=10.2,1.1Hz, 1H), 4.92 (dd, J=17.1,1.2Hz, 1H), 4.83 (s, 2H), 3.80 (s, 2H), 3.29 (d, J=7.8Hz, 0H), 2.99 (dt, J=11.7,6.1Hz, 4H), 2.36- 2.23 (m, 1H), 2.13 (dd, J=15.4,6.1Hz, 1H), 1.92-1.80 (m, 1H).

Embodiment 55

By 2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- (1,2,3,4- tetrahydroisoquinoline - 6- base amino) pyrazolo [3,4-D] pyrimidine -3- ketone (40mg, 0.087mmol) (such as -1 compound represented of Formulas I) is dissolved into first In alcohol (6ml), be then added cyclopropyl formaldehyde (9.2mg, 0.131mmol) and Sodium triacetoxyborohydride (37mg, 0.175mmol), it is stirred at room temperature 4 hours.Reaction solution concentration, is dissolved with the mixed liquor (10/1,20ml) of methylene chloride and methanol, Saturated sodium bicarbonate is washed twice, after organic layer is dried over anhydrous sodium sulfate, filtering, and concentration gained crude product thin layer chromatography point From purifying (7M ammonia methanol: methylene chloride=0-10%) obtain target compound such as -55 compound represented of Formulas I (14mg, 0.023mmol), yield 31%.1H NMR (400MHz, MeOD) δ 8.85 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.81 (d, J=7.5Hz, 1H), 7.75-7.59 (m, 2H), 7.39 (dd, J=8.3,1.9Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 5.74 (ddt, J=16.4,10.3,6.1Hz, 1H), 5.05 (dd, J=10.2,1.2Hz, 1H), 4.92 (dd, J=17.1, 1.3Hz, 1H), 4.83 (s, 2H), 3.80 (s, 2H), 2.97 (d, J=4.0Hz, 4H), 2.55 (d, J=6.7Hz, 2H), 1.70- 1.49 (m, 6H), 1.04 (dd, J=13.2,6.4Hz, 1H), 0.71-0.58 (m, 2H), 0.27 (q, J=4.7Hz, 2H) .LC- MS:m/z:(M+H)⁺=512.3.

Embodiment 56

Step 1:

By 6- nitro -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salt (100mg, the 0.47mmol) (change as shown in Formulas I -55-a Close object) it is dissolved in 10mL methanol, 1- ethyoxyl -1- trimethylsilyl cyclopropane (98mg, 0.56mmol) and cyano is then added Sodium borohydride (29mg, 0.46mmol), 60 DEG C are stirred to react 16h.It is concentrated under reduced pressure after reaction, gained crude product is chromatographed with column Method isolates and purifies (ethyl acetate: petroleum ether=0-15%), obtains target compound, 56mg, yellow solid, yield 46%.¹H NMR(400MHz,CDCl₃) δ 8.00 (d, J=7.5Hz, 2H), 7.21 (d, J=8.5Hz, 1H), 3.91 (s, 2H), 3.01 (s, 4H), 1.87 (s, 1H), 0.61 (d, J=6.0Hz, 4H) .LC-MS:m/z:(M+H)⁺=219.1.

Step 2:

By 2- cyclopropyl -6- nitro -1,2,3,4- tetrahydroisoquinoline (56mg, 0.26mmol) (as shown in Formulas I -55-b Compound) and palladium carbon (10mg) be dissolved in 10ml methanol, room temperature room temperature is stirred to react 4h under hydrogen balloon.Diatomite after reaction Filtering obtains yellow solid (48mg, 0.26mmol) and is directly used in next step, yield 100%.LC-MS:m/z:(M+H)⁺= 189.1。

Step 3:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (86mg, 0.24mmol) (such as formula 1A compound represented) is added azoles in the solution of 10ml methanol Metachloroperbenzoic acid (65mg, 0.29mmol), acquired solution are stirred at room temperature 3h and obtain 2- allyl -1- (6- (2- hydroxyl third Alkane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone is (such as formula 1B Compound represented) dichloromethane solution.Four isoquinolin -6- of 2- cyclopropyl -1,2,3,4- is added in above-mentioned acquired solution Amine (48mg, 0.26mmol) (such as Formulas I -55-c compound represented) and 0.13ml n,N-diisopropylethylamine, are stirred at room temperature 18h.It is concentrated under reduced pressure, gained crude product isolates and purifies (7M ammonia methanol: methylene chloride=0-10%) with thin layer chromatography and obtains I- Target compound 12mg shown in 56, yellow solid, yield 10%.LC-MS:m/z:(M+H)⁺=498.3,¹H NMR(400MHz, CDCl₃) δ 8.88 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 7.39 (d, J= 7.8Hz, 1H), 7.30 (s, 1H), 7.05 (d, J=7.2Hz, 1H), 5.72 (s, 1H), 5.07 (d, J=9.5Hz, 1H), 4.96 (d, J=17.8Hz, 1H), 4.78 (s, 2H), 3.92 (s, 3H), 3.03 (d, J=36.6Hz, 4H), 1.98 (s, 1H), 1.28 (s,6H),0.65(s,4H)。

Embodiment 57

Step 1:

5- nitro indenes -2- ketone (280mg, 1.58mmol) (such as Formulas I -57-a compound represented) is dissolved into 5ml methanol, 2ml (methanol solution of 2M) dimethylamine is added, the cyano hydroboration of 298mg (4.74mmol) is added after being stirred at room temperature about 2 hours Sodium continues to be stirred at room temperature 16 hours, concentration, is dissolved with the aqueous hydrochloric acid solution of 2N, methylene chloride extraction, the hydroxide of water layer 2N Sodium water solution adjusts PH=8, is extracted with dichloromethane, dichloromethane layer with anhydrous sodium sulfate it is dry after, filtered, be concentrated to give as Compound N shown in Formulas I -57-b, N- dimethyl -5- nitro dihydroindene -2- amine 60mg, yield 18%, tan solid.LC-MS: m/z:[M+1]⁺=207.1

Step 2:

N, N- dimethyl -5- nitro dihydroindene -2- amine (60mg, 0.29mmol) (such as Formulas I -57-b compound represented) It is dissolved into 5ml methanol, 50mg (0.76mmol) zinc powder is added, 2ml saturated aqueous ammonium chloride is then added, is stirred at room temperature about After 2 hours, concentration is added 5ml 2N aqueous hydrochloric acid solution, is extracted with dichloromethane, water layer uses the ammonium hydroxide aqueous solution tune of 2N again PH value is saved to 8, is then extracted with dichloromethane, dichloromethane layer is dried over anhydrous sodium sulfate, and filtering is concentrated to give such as Formulas I -57-c Shown compound N 2, N2- dimethyl indenes -2,5- diamines 50mg, yield 97%, tan solid.LC-MS:m/z:[M+1]⁺= 177.2

Step 3:

2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- methyl mercapto pyrazolo [3,4-d] is phonetic Pyridine -3- ketone (20mg0.056mmol) (such as formula 1A compound represented) is dissolved into 10ml methylene chloride, and 10.6mg is added (0.062mmol) metachloroperbenzoic acid is stirred at room temperature about 1 hour, 10mg (0.056mmol) N2, N2- dimethyl is then added Indenes -2,5- diamines (such as Formulas I -57-c compound represented) and 14mg (0.11mmol) DIPEA, after being stirred at room temperature 4 days, reaction solution It is washed with water, organic layer is dried over anhydrous sodium sulfate, concentration, and (silica gel, UV, petrol ether/ethyl acetate=100% arrive column chromatography 40%) the compound 2- allyl -6- as shown in Formulas I -57 [[2- (dimethylamino) indane -5- base] amino] -1- [6- is purified to obtain (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] pyrazolo [3,4-d] pyrimidine -3- ketone 15mg, yield 55%, yellow solid. LC-MS:m/z:[M+1]⁺=486.2,1H NMR (400MHz, MeOD) δ 8.85 (s, 1H), 8.46 (s, 1H), 8.03 (t, J= 7.9Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=7.7Hz, 1H), 7.49 (dd, J=8.2, 1.8Hz, 1H), 7.23 (d, J=8.2Hz, 1H), 5.73 (ddt, J=16.3,10.2,6.1Hz, 1H), 5.05 (dd, J= 10.2,1.2Hz, 1H), 4.92 (dd, J=17.1,1.3Hz, 1H), 4.83 (d, J=6.1Hz, 2H), 4.03 (p, J=7.8Hz, 1H), 3.40 (dt, J=15.8,7.8Hz, 2H), 3.17 (td, J=15.0,7.5Hz, 2H), 2.88 (s, 6H), 1.59 (s, 6H).

Embodiment 58

Step 1:

6- nitro 1-Indanone (1g, 5.64mmol) (such as Formulas I -58-a compound represented) is dissolved into 10ml methanol, is added Enter 2ml (methanol solution of 2M) dimethylamine, the sodium cyanoborohydride of 1.06g (16.9mmol) be added after being stirred at room temperature about 2 hours, It is warming up to 100 degrees Celsius under microwave condition and stirs 1 hour, concentration is dissolved with the aqueous hydrochloric acid solution of 2N, methylene chloride extraction It takes, water layer adjusts PH=8 with the sodium hydrate aqueous solution of 2N, is extracted with dichloromethane, and dichloromethane layer is dry with anhydrous sodium sulfate It after dry, is filtered, is concentrated to give the compound N as shown in Formulas I -58-2, N- dimethyl -6- nitro dihydroindene -1- amine 500mg is produced Rate 43%, brown oil.LC-MS:m/z:[M+1]⁺=207.1.

Step 2:

N, N- dimethyl -6- nitro dihydroindene -1- amine (500mg, 2.42mmol) (chemical combination as shown in Formulas I -58-b Object) it is dissolved into 30ml methanol, 476mg (7.27mmol) zinc powder is added, 5ml saturated aqueous ammonium chloride, room temperature is then added After stir about 2 hours, concentration is added 5ml 2N aqueous hydrochloric acid solution, is extracted with dichloromethane, water layer uses the ammonium hydroxide water of 2N again Solution adjusts pH value to 8, is then extracted with dichloromethane, and dichloromethane layer is dried over anhydrous sodium sulfate, and filtering is concentrated to give such as formula Compound N 1 shown in I-58-c, N1- dimethyl indenes -1,6- diamines 420mg, yield 100%, yellow oil.LC-MS:m/z: [M+1]⁺=177.2

Step 3:

2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] -6- methyl mercapto pyrazolo [3,4-d] is phonetic Pyridine -3- ketone (60mg, 0.17mmol) (such as formula 1A compound represented) is dissolved into 20ml methylene chloride, and 32mg is added (0.18mmol) metachloroperbenzoic acid is stirred at room temperature about 1 hour, and N1, N1- dimethyl indenes -1,6- diamines is then added (30mg, 0.17mmol) (such as Formulas I -58-c compound represented) and (65mg, 0.50mmol) DIPEA, after being stirred at room temperature 4 days, Reaction solution is washed with water, and organic layer is dried over anhydrous sodium sulfate, and concentration is prepared through efficient liquid phase after purification again through thin layer chromatography (methylene chloride/methanol=10/1) purifies to obtain [[3- (dimethylamino) indane-of the compound 2- allyl -6- as shown in Formulas I -58 5- yl] amino] -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridyl group] pyrazolo [3,4-d] pyrimidine -3- ketone 4mg, yield 5%, yellow solid.LC-MS:m/z:[M+1]⁺=486.2,1H NMR (400MHz, MeOD) δ 8.88-8.83 (m, 1H), 8.02–7.96(m,1H),7.83–7.78(m,1H),7.76–7.71(m,1H),7.70–7.65(m,1H),7.64–7.59(m, 1H),7.28–7.22(m,1H),5.79–5.67(m,1H),5.08–5.02(m,1H),4.96–4.89(m,1H),4.83–4.80 (m, 2H), 4.51-4.44 (m, 1H), 3.06-2.96 (m, 1H), 2.93-2.83 (m, 1H), 2.37 (s, 6H), 2.25 (dd, J= 13.8,6.7Hz,2H),1.59(s,6H).

Embodiment 59

Step 1:

By bromo- 3,4- dihydronaphthalene -2 (1H) -one (0.7g, 3mmol) (such as Formulas I -59-a compound represented) of 6- and acetic acid Ammonium (2.4g, 31mmol) is added in the methanol of 20ml, and 2h is stirred at room temperature.Then be added sodium cyanoborohydride (230mg, 3.77mmol), it is stirred overnight at room temperature.20ml water is added after being concentrated under reduced pressure in reaction solution, and is adjusted to pH value with the hydrochloric acid of 1mol/L Acidity is extracted twice with the methylene chloride of 30ml every time.PH value is adjusted to alkali (PH=with the sodium hydroxide solution of 2mol/L by water phase 10-11).Every time three times with the methylene chloride extraction of 40ml.Organic phase is washed with 30ml saturated salt solution, uses anhydrous slufuric acid It is concentrated after sodium is dry, gained crude product is directly used in next step.Obtain rufous liquid 300mg, yield 40%.LC-MS:m/z:(M +H)⁺=226.

Step 2:

By the bromo- 1,2,3,4- naphthane -2- amine (300mg, 1.33mmol) (such as Formulas I -59-b compound represented) of 6-, 0.65mlN, N- diisopropylethylamine and tert-butoxycarbonyl tert-butyl carbonate (400mg, 1.83mmol), were stirred at room temperature Night.Evaporated under reduced pressure solvent, gained crude product cross column purification (ethyl acetate: petroleum ether=0-15%), obtain white solid 400mg. Yield 92%.LC-MS:m/z:(M+Na)⁺=348.

Step 3:

By (the bromo- 1,2,3,4- naphthane -2- base of 6-) t-butyl carbamate (600mg, 2.36mmol) (such as Formulas I -59-c Compound represented), benzophenone imine (270mg, 1.49mmol), sodium tert-butoxide (145mg, 1.51mmol), Pd₂(dba)₃ (30mg, 0.033mmol), BINAP (35mg, 0.056mmol) are added in 20ml toluene, argon gas ventilation three times, then plus Heat spends night to 110.Reaction solution concentration, gained crude product cross column purification (methanol: methylene chloride=0-10%), obtain brown oil Shape object 170mg, yield 40%.LC-MS:m/z:(M+H)⁺=427.

Step 4:

By (6-((diphenylmethylene) amino)-1,2,3,4- naphthane-2- base) t-butyl carbamate (170mg, 0.4mmol) (such as Formulas I -59-d compound represented) is dissolved in 20ml methanol, and sodium acetate (110mg, 1.34mmol) then is added With hydroxylamine hydrochloride (60mg, 0.86mmol), it is heated to 60 degree of reactions overnight.Reaction solution filtering and concentrating, it is pure that gained crude product crosses column Change (methanol: methylene chloride=0-20%), obtains colorless oil 90mg, yield 86%.LC-MS:m/z:(M-55)⁺=207.

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (107mg, 0.3mmol) (such as formula 1A compound represented) is added azoles in the solution of 15ml toluene Metachloroperbenzoic acid (76mg, 0.34mmol), acquired solution are stirred at room temperature 1h and obtain 2- allyl -1- (6- (2- hydroxyl third Alkane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone.This solution It is directly used in and reacts in next step.LC-MS:m/z:(M+H)⁺=374.

In above-mentioned acquired solution be added (6- amino -1,2,3,4- naphthane -2- base) t-butyl carbamate (90mg, 0.34mmol) (such as Formulas I -59-e compound represented) and 1ml N, N- diisopropylethylamine, are stirred overnight at room temperature.It depressurizes dense Contracting, gained crude product obtain white with thin layer chromatography { methanol: (methylene chloride: ethyl acetate=2:1)=1:10) } Solid 110mg, yield 64%.LC-MS:m/z:(M+H)⁺=572.

Step 6:

By (6- ((2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -3- oxo -2,3- dihydro -1H- Pyrazoles [3,4] tert-butyl-d] pyrimidine -6- base) amino) -1,2,3,4- tetrahydro-naphthalene -2- base) carbamic acid (110mg, 0.19mmol) (such as Formulas I -59-f compound represented) is dissolved into the mixed solvent of 5ml methylene chloride and 2ml methanol composition, The hydrochloric acid dioxane of the 4mol/L of 10ml is added, 2h is stirred at room temperature.30ml methanol and methylene chloride group are added after reduced pressure At mixed solvent (methanol: methylene chloride=10:1) and 10ml saturation aqueous sodium carbonate, 20min is stirred at room temperature, it is organic Column purification { methanol: (methylene chloride: ethyl acetate=2:1)=0-20%) } is crossed after the dry concentration of layer, and it is solid to obtain 40mg white Body, yield 44%.

LC-MS:m/z:(M+H)⁺=472,1H NMR (400MHz, CDCl3:MeOD=2:1) δ 8.85 (d, J=4.9Hz, 1H), 7.93 (dd, J=10.3,5.5Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.57 (d, J=7.7Hz, 1H), 7.53 (s, 1H), 7.38-7.31 (m, 1H), 7.06 (d, J=8.3Hz, 1H), 5.70 (dq, J=10.4,6.0Hz, 1H), 5.05 (d, J= 10.2Hz, 1H), 4.93 (d, J=17.1Hz, 1H), 4.82 (d, J=5.9Hz, 2H), 3.28-3.16 (m, 1H), 3.03 (dd, J =15.9,4.6Hz, 1H), 2.91 (dd, J=7.7,4.8Hz, 2H), 2.60 (dd, J=15.6,9.6Hz, 1H), 2.10 (d, J =9.5Hz, 1H), 1.74-1.63 (m, 1H), 1.61 (d, J=4.8Hz, 6H)

Embodiment 60

By 2- allyl -6- [(6- amino -5,6,7,8- Tetrahydronaphthyridderivates -2- base) amine] -1- [6- (2- hydroxypropyl -2- Base) pyridine -2- base] -1,2- dihydro -3H- pyrazolo [3,4-D] pyrimidine -3- ketone (20mg, 0.042mmol) is (as shown in Formulas I -59 Compound) be dissolved into methanol (6ml), be then added 40% acetaldehyde solution (1mL) and Sodium triacetoxyborohydride (45mg, 0.212mmol), it is stirred at room temperature 4 hours.Reaction solution concentration, is dissolved with the mixed liquor (10/1,20ml) of methylene chloride and methanol, Saturated sodium bicarbonate is washed twice, after organic layer is dried over anhydrous sodium sulfate, filtering, and concentration gained crude product thin layer chromatography point From purifying (7M ammonia methanol: methylene chloride=0-10%) obtain target compound such as -60 compound represented of Formulas I (4mg, 0.008mmol), yield 18%.LC-MS:m/z:(M+H)⁺=528.3,¹H NMR(400MHz,MeOD)δ8.83(s,1H), 8.01 (t, J=7.9Hz, 1H), 7.81 (d, J=7.8Hz, 1H), 7.68 (d, J=7.7Hz, 1H), 7.56 (s, 1H), 7.34 (d, J=8.2Hz, 1H), 7.06 (d, J=8.3Hz, 1H), 5.73 (ddt, J=16.3,10.2,6.1Hz, 1H), 5.10-5.02 (m, 1H), 4.92 (dd, J=17.1,1.2Hz, 1H), 4.82 (s, 2H), 3.14 (d, J=10.8Hz, 0H), 2.92 (dt, J= 16.3,14.4Hz, 1H), 2.79 (t, J=12.2Hz, 5H), 2.17 (d, J=10.2Hz, 0H), 1.70 (dd, J=11.7, 6.5Hz, 0H), 1.60 (s, 6H), 1.17 (t, J=7.2Hz, 6H).

Embodiment 61

Step 1:

Bromo- 3,4- dihydronaphthalene -2 (1H) -one (400mg, 1.78mmol) (such as Formulas I -61-a compound represented) of 6- is molten In 18mL methanol, (1368mg, 17.8mmol) ammonium acetate is then added, (120mg, 1.91mmol) is added after 2h is stirred at room temperature Reaction 16h is stirred at room temperature in sodium cyanoborohydride.30ml water is added in reaction solution after being concentrated under reduced pressure, and with the hydrochloric acid of 1mol/L by pH Value is adjusted to acidity, is extracted twice every time with the methylene chloride of 30ml.PH value is adjusted to by water phase with the sodium hydroxide solution of 1mol/L Alkali (pH=10-11).Every time three times with the methylene chloride extraction of 40ml.Organic phase is washed with 30ml saturated salt solution, is used It is concentrated after anhydrous sodium sulfate is dry, gained crude product is directly used in next step.Rufous grease is obtained (to change as shown in Formulas I -61-b Close object) (200mg, 0.84mmol), yield 50%.LC-MS:m/z:(M+H)⁺=226.0,228.0.

Step 2:

By the bromo- 1,2,3,4- naphthane -2- amine (200mg, 0.84mmol) (such as Formulas I -61-b compound represented) of 6- and Sodium cyanoborohydride (280mg, 4.46mmol) is dissolved in 10ml methanol, and 0.5mL propionic aldehyde is added, and room temperature room temperature is stirred to react 16h. 30ml water is added after being concentrated under reduced pressure in reaction solution, and pH value is adjusted to acidity with the hydrochloric acid of 1mol/L, uses the dichloromethane of 30ml every time Alkane is extracted twice.PH value is adjusted to alkali (pH=10-11) with the sodium hydroxide solution of 1mol/L by water phase.The dichloro of 40ml is used every time Methane extracts three times.Organic phase is washed with 30ml saturated salt solution, and with being concentrated after anhydrous sodium sulfate drying, gained crude product is straight It connects in next step.Obtain rufous grease (190mg, 0.61mmol) (compound as shown in Formulas I -61-c), yield 69%. LC-MS:m/z:(M+H)⁺=310.1,312.1.

Step 3:

By the bromo- N of 6-, N- dimethyl -1,2,3,4- naphthane -2- amine (190mg, 0.61mmol) is (as shown in Formulas I -61-c Compound), benzophenone imine (122mg, 0.67mmol), sodium tert-butoxide (118mg, 1.22mmol), Pd₂(dba)₃ (28mg, 0.03mmol), BINAP (38mg, 0.06mmol) are added in 10ml toluene, are taken a breath three times in argon gas, are then heated To 100 DEG C of reaction 18h.Reaction solution concentration, gained crude product cross column purification (methanol: methylene chloride=0-10%), obtain brown Grease (220mg, 0.54mmol) (compound as shown in Formulas I -61-d), yield 87%.LC-MS:m/z:(M+H)⁺= 411.3。

Step 4:

By 6- ((diphenyl methylene) amino)-N, N- dipropyl -1,2,3,4- naphthane -2- amine (220mg, 0.54mmol) (such as Formulas I -61-d compound represented) is dissolved in 10ml methanol, and acetic acid sodium trihydrate (220mg, 1.62mmol) then is added With hydroxylamine hydrochloride (82mg, 1.18mmol), it is heated to 60 degree and reacts 5 hours.Reaction solution filtering and concentrating, it is pure that gained crude product crosses column Change (methanol: methylene chloride=0-20%), obtains brown oil (130mg, 0.53mmol) (chemical combination as shown in Formulas I -61-e Object), yield 98%.LC-MS:m/z:(M+H)⁺=247.2,¹H NMR(400MHz,CDCl₃) δ 6.91 (d, J=8.2Hz, 1H), 6.54 (dd, J=8.2,2.1Hz, 1H), 6.46 (s, 1H), 3.62 (s, 1H), 3.24-3.02 (m, 4H), 2.92-2.85 (m, 2H), 2.57 (d, J=9.7Hz, 1H), 2.13-1.82 (m, 8H), 1.03 (t, J=7.3Hz, 6H).

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Azoles is between simultaneously [3,4-d] pyrimidine -3- ketone (72mg, 0.2mmol) (compound as shown in formula 1A) is added in the solution of 15ml toluene Chloroperoxybenzoic acid (50mg, 0.22mmol), acquired solution are stirred at room temperature 1h and obtain 2- allyl -1- (6- (2- hydroxy propane - 2- yl) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone toluene it is molten Liquid.N is added in above-mentioned acquired solution, N- dipropyl -1,2,3,4- naphthane -2,6- diamines (65mg, 0.27mmol) are (such as formula Compound shown in I-61-e) and 0.1ml N, N- diisopropylethylamine, 18h is stirred at room temperature.It is concentrated under reduced pressure, gained crude product is first used Thin layer chromatography isolates and purifies (7M ammonia methanol: methylene chloride=0-10%) and obtains target compound (such as Formulas I -61 shown in I-61 Shown compound) 45mg, yellow solid, yield 40%.LC-MS:m/z:(M+H)⁺=556.3,¹H NMR(400MHz,CDCl₃) δ 8.87 (s, 1H), 7.90 (t, J=7.8Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.39 (d, J=7.6Hz, 1H), 7.27 (s, 1H), 7.09 (d, J=8.3Hz, 1H), 5.72 (ddd, J=16.4,11.3, 5.0Hz, 1H), 5.07 (d, J=10.2Hz, 1H), 4.96 (d, J=17.1Hz, 1H), 4.78 (d, J=6.2Hz, 2H), 3.91 (s, 1H), 3.06 (s, 1H), 2.87 (d, J=30.3Hz, 4H), 2.57 (s, 4H), 2.13 (s, 2H), 1.61 (s, 6H), 1.57 (s, 4H), 0.94 (t, J=7.3Hz, 6H).

Embodiment 62

Step 1:

6- amino-DHN 1,4 dihydronaphthalene -1 (2H) -1 (148.9mmol) (compound as shown in Formulas I -62-a) is dissolved in dichloro Methane (200mL) is added n,N-diisopropylethylamine (446.7mmol) into reaction solution, reaction solution is cooled to 0 DEG C, on the contrary It answers and is slowly added in liquid chloroacetic chloride (223.3mmol), reaction solution stirs 12 hours at room temperature.Reaction solution is evaporated to obtain crude product, slightly Product are washed with ethyl acetate, filtering, and filter cake is target compound N- (5- oxygen -5-, 6-, 7-, 8- naphthane -2- base) acetamide (compound as shown in Formulas I -62-b) (26.5g), yield: 87.6%, gray solid.LC-MS:m/z:[M+1]⁺=204.

Step 2:

By N- (5- oxygen -5-, 6-, 7-, 8- naphthane -2- base) acetamide (25mmol) (compound as shown in Formulas I -62-b) It is dissolved in 1,1- dimethoxy-N, N- dimethyl methylamine (60mL), reaction solution is heated to flowing back, is stirred 18 hours.By reaction solution It is evaporated to obtain crude product, crude product is washed with ethyl acetate, filtering, and filter cake is target compound (E)-N- (6- ((dimethylamino) methylene Base) -5- oxo -5-, 6-, 7-, 8- naphthane -2- base) acetamide (compound as shown in Formulas I -62-c) (5.8g, 91%), ash Color solid.LC-MS:m/z:[M+1]⁺=259.

Step 3:

By (E)-N- (6- ((dimethylamino) methylene) -5- oxo -5-, 6-, 7-, 8- naphthane -2- base) acetamide (3.96mmol) (compound as shown in Formulas I -62-c) is dissolved in methanol (15mL), and palladium carbon (500mg) and concentrated hydrochloric acid (1mL) is added, Reaction solution is heated to flowing back, is stirred 24 hours.By reaction solution unsaturated carbonate aqueous solutions of potassium tune pH=9, filtering, filtrate second Acetoacetic ester extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate are dried, filtered, are evaporated, column chromatographic purifying (methylene chloride/ Methanol=20/1) target compound 6- ((dimethylamino) methyl) -5-, 6-, 7-, 8- naphthane -2- amine is (such as Formulas I -62-d institute Show compound) (150mg, 19%), yellow oil.LC-MS:m/z:[M+1]⁺=205.

Step 4:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-D] pyrimidine -3- ketone (0.56mmol) (compound as shown in formula 1A) is dissolved in 1,2- dichloroethanes (10mL) to azoles, between addition Chloroperoxybenzoic acid (0.62mmol), reaction solution stir 0.5 hour at room temperature, and 6- ((dimethylamino) first is added into reaction solution Base) -5-, 6-, 7-, 8- naphthane -2- amine (0.56mmol) (compound as shown in Formulas I -62-d) and N, N- diisopropylethylamine Reaction solution is heated to 70 DEG C, stirred 16 hours by (1.68mmol).Reaction solution is evaporated to obtain crude product, crude product prepares the purifying of TLC plate Obtain target compound 2- allyl -6- ((6- ((dimethylamino) methyl) -5-, 6-, 7-, 8- naphthane -2- base) amino) -1- (3- (2- hydroxy propane -2- base) phenyl) -1,2- dihydro -3H- pyrazolo [3,4-D] pyrimidine -3- ketone (chemical combination as shown in Formulas I -62 Object) (31mg, 10.8%), white solid.LC-MS:m/z:[M+1]⁺=514.1H NMR(400MHz,CDCl3)δ8.87(s, 1H), 7.93-7.81 (m, 2H), 7.47 (s, 1H), 7.40-7.36 (m, 1H), 7.26 (dd, J=8.2,2.2Hz, 1H), 7.09 (d, J=8.2Hz, 1H), 5.73 (ddt, J=16.4,10.2,6.2Hz, 1H), 5.01 (ddd, J=18.3,13.6,1.2Hz, 2H), 4.78 (d, J=6.2Hz, 2H), 3.91 (s, 1H), 2.96 (dd, J=16.7,4.8Hz, 1H), 2.86 (dd, J=7.8, 4.3Hz, 2H), 2.44 (dd, J=16.2,10.4Hz, 1H), 2.31 (s, 8H), 2.01 (s, 2H), 1.61 (s, 6H)

Embodiment 63

Step 1:

Bromo- 3,4- dihydronaphthalene -2 (1H) -one (400mg, 1.78mmol) (compound as shown in Formulas I -63-a) of 6- is dissolved in In 18mL methanol, ammonium acetate (1368mg, 17.8mmol) then is added, sodium cyanoborohydride is added after 2h is stirred at room temperature Reaction 16h is stirred at room temperature in (120mg, 1.91mmol).30ml water is added after being concentrated under reduced pressure in reaction solution, and with the hydrochloric acid of 1mol/L PH value is adjusted to acidity, is extracted twice every time with the methylene chloride of 30ml.Water phase is with the sodium hydroxide solution of 1mol/L by pH value It is adjusted to alkali (pH=10-11).Every time three times with the methylene chloride extraction of 40ml.Organic phase is washed with 30ml saturated salt solution It washs, with being concentrated after anhydrous sodium sulfate drying, gained crude product is directly used in next step.Obtain rufous grease (such as Formulas I -63-2 Shown compound) (150mg, 0.84mmol), yield 37%.LC-MS:m/z:(M+H)⁺=226.0,228.0.

Step 2:

By the bromo- 1,2,3,4- naphthane -2- amine (150mg, 0.67mmol) (compound as shown in Formulas I -63-b) of 6- and cyanogen Base sodium borohydride (209mg, 3.3mmol) is dissolved in 10ml methanol, and 0.5mL acetone is added, and room temperature room temperature is stirred to react 16h.Instead 30ml water is added after answering liquid to be concentrated under reduced pressure, and pH value is adjusted to acidity with the hydrochloric acid of 1mol/L, uses the methylene chloride of 30ml every time It is extracted twice.PH value is adjusted to alkali (pH=10-11) with the sodium hydroxide solution of 1mol/L by water phase.The dichloromethane of 40ml is used every time Alkane extracts three times.Organic phase is washed with 30ml saturated salt solution, and with being concentrated after anhydrous sodium sulfate drying, gained crude product is direct For in next step.Obtain rufous grease (170mg, 0.55mmol) (compound as shown in Formulas I -63-c), yield 83%. LC-MS:m/z:(M+H)⁺=268.1,270.1.

Step 3:

By bromo- N- isopropyl -1,2,3,4- naphthane -2- amine (170mg, the 0.5mmol) (chemical combination as shown in Formulas I -63-c of 6- Object) and Boc₂O (137mg, 0.55mmol) is dissolved in 10ml methylene chloride, and 0.16mL n,N-diisopropylethylamine, room temperature is added 16h is stirred to react to 40 DEG C.It is concentrated under reduced pressure after reaction, gained crude product isolates and purifies (ethyl acetate: stone with column chromatography Oily ether=0-10%) obtain target compound (compound as shown in Formulas I -63-d) 176mg, yellow solid, yield 76%.LC- MS:m/z:(M+H)⁺=368.1,370.1.

Step 4:

By (the bromo- 1,2,3,4- tetrahydronaphthalene amine -2- base of 6-) (isopropyl) t-butyl carbonate (176mg, 0.48mmol) (such as formula Compound shown in I-63-d), benzophenone imine (94mg, 0.52mmol), sodium tert-butoxide (91mg, 0.95mmol), Pd₂ (dba)₃(22mg, 0.02mmol), BINAP (30mg, 0.05mmol) are added in 10ml toluene, are taken a breath three times, so in argon gas After be heated to 100 DEG C of reaction 18h.Reaction solution concentration, gained crude product are crossed column purification (methanol: methylene chloride=0-10%), are obtained To yellow solid (compound as shown in Formulas I -63-e) (180mg, 0.38mmol), yield 81%.LC-MS:m/z:(M+H)⁺= 469.3。

Step 5:

By (6- ((diphenyl methylene) amino) -1,2,3,4- tetrahydronaphthalene amine -2- base) (isopropyl) t-butyl carbonate (180mg, 0.38mmol) (compound as shown in Formulas I -63-e) is dissolved in 10ml methanol, and acetic acid sodium trihydrate is then added (157mg, 1.15mmol) and hydroxylamine hydrochloride (82mg, 0.85mmol) is heated to 60 degree and reacts 5 hours.Reaction solution filtering and concentrating, Gained crude product crosses column purification (methanol: methylene chloride=0-20%), obtains yellow solid (compound as shown in Formulas I -63-f) (102mg, 0.34mmol), yield 87%.¹H NMR(400MHz,CDCl₃) δ 6.91 (d, J=8.1Hz, 1H), 6.59 (dd, J= 8.1,2.2Hz, 1H), 6.55 (s, 1H), 3.15 (s, 1H), 2.95-2.76 (m, 2H), 2.66 (d, J=11.0Hz, 1H), 2.18 (dt, J=44.1,12.4Hz, 2H), 1.83 (d, J=10.1Hz, 1H), 1.50 (s, 9H), 1.26 (d, J=16.4Hz, 6H) .LC-MS:m/z:(M+H)⁺=305.3.

Step 6:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Azoles is between simultaneously [3,4-d] pyrimidine -3- ketone (compound as shown in formula 1A) (108mg, 0.3mmol) is added in the solution of 15ml toluene Chloroperoxybenzoic acid (82mg, 0.47mmol), acquired solution are stirred at room temperature 1h and obtain 2- allyl -1- (6- (2- hydroxy propane - 2- yl) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone toluene solution (compound as shown in formula 1B).(6- amino -1,2,3,4- tetrahydronaphthalene amine -2- base) (isopropyl) is added in above-mentioned acquired solution T-butyl carbonate (102mg, 0.33mmol) (compound as shown in Formulas I -63-g) and 0.16ml N, N- diisopropylethylamine, room Temperature stirring 18h.It is concentrated under reduced pressure, gained crude product first isolates and purifies (7M ammonia methanol: methylene chloride=0- with thin layer chromatography 10%) target compound (compound as shown in Formulas I -63-g) 85mg, yellow solid, yield 46% are obtained.LC-MS:m/z:(M+ H)⁺=614.3.

Step 7:

By (6- ((2- allyl -1- (6- (2- hydroxyisopropyl -2- base) pyridine -2- base) -3- ketone -2,3- dihydro -1H- Pyrazolo [3,4-d] pyrimidine -6- base) amino) -1,2,3,4- tetrahydronaphthalene amine -2- base) (isopropyl) t-butyl carbonate (85mg, 0.3mmol) (compound as shown in Formulas I -63-g) is dissolved in 10ml methylene chloride, and 4N hydrogen chloride dioxane solution is added 4h is stirred at room temperature in 0.5mL.It is concentrated under reduced pressure, gained crude product is first dissolved with water, methylene chloride extraction.Layer of fetching water is molten with 2N NaOH Liquid is adjusted to pH=10, and target compound shown in I-63 (compound as shown in Formulas I -63) 70mg, yellow solid, yield is obtained by filtration 98%.LC-MS:m/z:(M+H)⁺=514.3,¹H NMR(400MHz,CDCl₃) δ 8.87 (s, 1H), 7.90 (t, J=7.8Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=7.6Hz, 1H), 7.32-7.29 (m, 1H), 7.07 (d, J=8.3Hz, 1H), 5.84-5.64 (m, 1H), 5.06 (d, J=10.2Hz, 1H), 4.95 (d, J=17.1Hz, 1H), 4.78 (d, J=6.2Hz, 2H), 3.94 (s, 1H), 3.25-2.99 (m, 3H), 2.90 (s, 2H), 2.70-2.56 (m, 1H), 2.12 (s, 1H), 1.61 (s, 6H), 1.16 (d, J=6.1Hz, 6H).

Embodiment 64

Step 1:

Bromo- 3,4- dihydronaphthalene -2 (1H) -one (0.5g, 2.22mmol) (such as Formulas I -64-a compound represented) of 6- is added Into the methanol of 15ml, sodium borohydride (100mg, 2.65mmol) is added under ice bath, 1h is stirred at room temperature.Reaction solution is concentrated under reduced pressure The aqueous ammonium chloride solution of 10ml saturation is added afterwards, every time three times with the ethyl acetate extraction of 15ml.Combined organic phase is with anhydrous It is concentrated after sodium sulphate is dry, gained crude product crosses column purification (ethyl acetate: petroleum ether=0-50%).Colourless liquid 380mg is obtained, Yield 75%.LC-MS:m/z:(M+Na)⁺=249.

Step 2:

By powdered potassium hydroxide (470mg, 8.39mmol) and the bromo- 1,2,3,4- naphthane -2- alcohol of 6- (380mg, 1.67mmol) (such as Formulas I -64-b compound represented) is added in 7ml anhydrous dimethyl sulfoxide, and 15min is stirred at room temperature.Then plus Enter iodomethane (700mg, 4.93mmol), is stirred overnight at room temperature.20ml saturated salt solution, methylene chloride extraction are added in reaction solution (3*20ml) three times.Organic layer wash three times (3*15ml), evaporated under reduced pressure solvent, gained crude product cross column purification (ethyl acetate: Petroleum ether=0-10%), obtain colorless oil 340mg.Yield 84%.LC-MS:m/z:(M+Na)⁺=263.

Step 3:

By the bromo- 2- methoxyl group of 6- -1,2,3,4-tetralin (340mg, 1.41mmol) (chemical combination as shown in Formulas I -64-c Object), benzophenone imine (300mg, 1.66mmol), sodium tert-butoxide (220mg, 2.29mmol), Pd₂(dba)₃(45mg, 0.05mmol), BINAP (90mg, 0.14mmol) is added in 20ml toluene, is taken a breath three times in argon gas, is then heated to 110 degree Overnight.Reaction solution concentration, gained crude product cross column purification (ethyl acetate: petroleum ether=0-30%), obtain brown oil 450mg, yield 93%.1H NMR (400MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.47 (t, J=7.2Hz, 1H), 7.41 (t, J=7.4Hz, 2H), 7.33-7.29 (m, 3H), 7.15 (dd, J=7.3,2.2Hz, 2H), 6.84 (d, J=8.0Hz, 1H), 6.54 (s, 1H), 6.45 (dd, J=8.0,2.0Hz, 1H), 3.60 (m, 1H), 3.42 (s, 3H), 3.00 (dd, J=16.3, 4.9Hz, 1H), 2.78 (dt, J=16.9,5.7Hz, 1H), 2.65 (m, 2H), 2.04 (m, 1H), 1.80-1.68 (m, 1H)

Step 4:

By N- (6- methoxyl group -5,6,7,8- naphthane -2- base), -1,1- benzophenone imine (450mg, 1.3mmol) is (such as Formulas I -64-d compound represented) it is dissolved in 20ml methanol, sodium acetate (340mg, 4.15mmol) and hydroxylamine hydrochloride is then added (210mg, 3mmol) is heated to 60 degree of reactions overnight.Reaction solution filtering and concentrating, gained crude product cross column purification (ethyl acetate: Petroleum ether=0-30%), obtain white solid 220mg, yield 94%.LC-MS:m/z:(M+H)⁺=178.

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (107mg, 0.3mmol) (such as formula 1A compound represented) is added azoles in the solution of 25ml toluene Metachloroperbenzoic acid (76mg, 0.34mmol), acquired solution are stirred at room temperature 1h and obtain 2- allyl -1- (6- (2- hydroxyl third Alkane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone.This solution It is directly used in and reacts in next step.LC-MS:m/z:(M+H)⁺=374.

6- methoxyl group -5,6,7,8- naphthane -2- amine (55mg, 0.31mmol) is added in above-mentioned acquired solution (such as formula I-64-e compound represented) and 1ml N, N- diisopropylethylamine, it is stirred overnight at room temperature.It is concentrated under reduced pressure, gained crude product is first Column purification { methanol: (methylene chloride: ethyl acetate=2:1)=1:15 } is crossed, then isolated and purified with thin layer chromatography methanol: (methylene chloride: ethyl acetate=2:1)=0-15%) }, obtain white solid 25mg, yield 17%.LC-MS:m/z:(M+H)⁺ =487,1H NMR (400MHz, DMSO) δ 10.18 (s, 1H), 8.87 (s, 1H), 8.02 (t, J=7.9Hz, 1H), 7.78 (d, J =8.0Hz, 1H), 7.64 (d, J=7.7Hz, 2H), 7.41-7.33 (m, 1H), 7.02 (d, J=8.3Hz, 1H), 5.75-5.60 (m, 1H), 5.32 (s, 1H), 5.00 (dd, J=10.3,1.2Hz, 1H), 4.83 (dd, J=17.1,1.3Hz, 1H), 4.70 (d, J=5.9Hz, 2H), 3.64 (m, 1H), 3.32 (s, 3H), 2.97 (dd, J=16.4,4.5Hz, 1H), 2.88-2.59 (m, 3H), 2.08–1.96(m,1H),1.83–1.68(m,1H),1.47(s,6H).。

Embodiment 65

Step 1:

Bromo- 3,4- dihydronaphthalene -2 (1H) -one (0.6g, 2.66mmol) (such as Formulas I -64-a compound represented) of 6- is added Into the methanol of 15ml, sodium borohydride (110mg, 2.91mmol) is added under ice bath, 1h is stirred at room temperature.Reaction solution is concentrated under reduced pressure The aqueous ammonium chloride solution of 10ml saturation is added afterwards, every time three times with the ethyl acetate extraction of 15ml.Combined organic phase is with anhydrous It is concentrated after sodium sulphate is dry, gained crude product crosses column purification (ethyl acetate: petroleum ether=0-50%).Colourless liquid 460mg is obtained, Yield 75%.LC-MS:m/z:(M-OH)⁺=209.

Step 2:

By imidazoles (330mg, 4.85mmol) and the bromo- 1,2,3,4- naphthane -2- alcohol (440mg, 1.94mmol) of 6- (such as formula I-64-b compound represented) it is added in the N,N-dimethylformamide of 5ml, tert-butyl chloro-silicane is then added (360mg, 2.39mmol), is stirred overnight at room temperature.30ml ethyl acetate is added in reaction solution.Organic layer washes twice of (2* 15ml), saturated common salt washes one time (15ml), evaporated under reduced pressure solvent, and gained crude product crosses column purification (ethyl acetate: petroleum ether =0-10%), obtain colorless oil 540mg.Yield 81%.1H NMR(400MHz,CDCl3)δ7.23–7.18(m,2H), (6.91 d, J=8.0Hz, 1H), 4.14-4.01 (m, 1H), 2.97-2.83 (m, 2H), 2.80-2.60 (m, 2H), 1.98-1.85 (m,1H),1.84–1.68(m,1H),0.92–0.84(m,9H),0.14–0.02(m,6H)。

Step 3:

By ((the bromo- 1,2,3,4- naphthane -2- base of 6-) oxygroup) (tert-butyl) dimethylsilane (540mg, 1.58mmol) (such as Formulas I -65-c compound represented), benzophenone imine (330mg, 1.82mmol), sodium tert-butoxide (240mg, 2.5mmol),Pd₂(dba)₃(45mg, 0.05mmol), BINAP (95mg, 0.15mmol) is added in 20ml toluene, in argon gas Ventilation three times, is then heated to 110 and spends night.Reaction solution concentration, gained crude product cross column purification (ethyl acetate: petroleum ether= 0-30%), brown oil 600mg, yield 85% are obtained.

Step 4:

By N- [2- [tert-butyl (dimethyl) silicyl] oxygen naphthane -6- base] -1,1- diphenyl-azomethine (600mg, 1.36mmol) (such as Formulas I -65-d compound represented) is dissolved in 30ml methanol, then be added sodium acetate (340mg, 4.15mmol) with hydroxylamine hydrochloride (210mg, 3mmol), it is heated to 60 degree of reaction 2h.Reaction solution filtering and concentrating, gained crude product mistake Column purification (ethyl acetate: petroleum ether=0-30%), obtains white solid 350mg, yield 92%.LC-MS:m/z:(M+H)⁺= 278。

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (120mg, 0.33mmol) (such as formula 1A compound represented) adds azoles in the solution of 25ml toluene Enter metachloroperbenzoic acid (85mg, 0.38mmol), 1h is stirred at room temperature in acquired solution.6- ((uncle is added in above-mentioned acquired solution Butyldimethylsilane base) oxygroup) -5,6,7,8- naphthane -2- amine (100mg, the 0.36mmol) (change as shown in Formulas I -64-e Close object) and 1ml N, N- diisopropylethylamine, it is stirred overnight at room temperature.Be concentrated under reduced pressure, gained crude product first cross column purification methanol: (methylene chloride: ethyl acetate=2:1)=1:15 }, then { methanol: (methylene chloride: acetic acid is isolated and purified with thin layer chromatography Ethyl ester=2:1)=0-15%), obtain white solid 110mg, yield 55%.LC-MS:m/z:(M+H)⁺=587.

Step 6:

By 2- allyl -6- ((6- ((t-butyldimethylsilyi) oxygroup) -5,6,7,8- naphthane -2- base) ammonia Base) -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone (100mg, 0.17mmol) (such as Formulas I -65-f compound represented) and 1ml tetra-n-butyl ammonium fluoride (1mol/L in THF) add Enter into 5ml tetrahydrofuran, 35 degree are stirred overnight.Be concentrated under reduced pressure, gained crude product first cross column purification methanol: (methylene chloride: Ethyl acetate=2:1)=0-20% }, white solid 28mg, yield 34% then is prepared with efficient liquid phase.LC-MS:m/ z:(M+H)⁺=473.1H NMR (400MHz, DMSO) δ 10.16 (s, 1H), 8.86 (s, 1H), 8.02 (t, J=7.9Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 7.64 (dd, J=7.7,0.6Hz, 1H), 7.60 (s, 1H), 7.36 (dd, J=8.3,1.9Hz, 1H), 7.00 (d, J=8.3Hz, 1H), 5.67 (ddt, J=16.2,10.3,5.9Hz, 1H), 5.32 (s, 1H), 5.00 (dd, J =10.3,1.3Hz, 1H), 4.83 (dd, J=17.1,1.4Hz, 1H), 4.76 (s, 1H), 4.70 (d, J=5.9Hz, 2H), 3.91 (s, 1H), 2.86 (ddd, J=16.6,13.7,5.1Hz, 2H), 2.79-2.66 (m, 1H), 2.56 (dd, J=16.1, 8.1Hz, 1H), 1.98-1.88 (m, 1H), 1.65 (ddd, J=12.5,9.0,3.4Hz, 1H), 1.47 (s, 6H)

Embodiment 66

Step 1:

6- acetylaminohydroxyphenylarsonic acid 1,2,3,4- tetrahydro -1- naphthalenone (2000mg, 9.8406mmol) (is changed as shown in formula 1-66-a Close object) it is dissolved in toluene (40mL), glyoxylic acid ethyl ester (2equiv., 19.681mmol, 50mass%) (such as Formulas I-is then added Shown in 66-b), magnesium sulfate (5equiv., 49.203mmol) and p-methyl benzenesulfonic acid (0.1equiv., 0.98406mmol).Instead 120 DEG C should be heated to stir 12 hours.Add water 20ml extraction to go out, 2x20ml is extracted with ethyl acetate, merges organic phase and washed with salt 1x20ml is dried, filtered with anhydrous sodium sulfate, is concentrated to get crude product.Crude product is through purification on normal-phase silica gel column separating purification (eluent EA/PE=0% to 60%, 12CV) obtains target compound (such as Formulas I -66-c compound represented) 2.0g, and yellow solid is received Rate 61%.LC-MS:m/z:(M+H)⁺=288.0.

Step 2:

By ethyl (E) -2- (- 2 (1 hydrogen)-methylene of 6- acetamido -1- oxygen -3,4- dihydro naphthalenone) acetic acid esters (2000mg, 6.961mmol) (such as Formulas I -66-c compound represented) is dissolved in ethyl alcohol (20mL), and sulfuric acid solution is then added (1mL, 70mass%) and Pd/C (200mg, 10mass%).Reaction is stirred at room temperature 12 hours under an atmosphere of hydrogen.Filtering, is used in combination Saturated sodium bicarbonate solution adjusts filtrate pH value to 7-8.2x20ml is extracted with ethyl acetate in solution, merges organic phase and is washed with salt 1x20ml is dried, filtered with anhydrous sodium sulfate, is concentrated to get crude product.Crude product is through purification on normal-phase silica gel column separating purification (eluent EA/PE=8% to 60%, 12CV) obtains target compound (such as Formulas I -66-d compound represented) 0.7g, and yellow solid is received Rate 36%.1H NMR (400MHz, MeOD) δ 7.27 (s, 1H), 7.23 (dd, J=8.2,2.2Hz, 1H), 6.98 (d, J= 8.2Hz, 1H), 4.11 (t, J=7.1Hz, 2H), 2.87 (d, J=4.5Hz, 1H), 2.81 (dd, J=8.2,4.3Hz, 2H), 2.44 (dd, J=15.8,10.1Hz, 1H), 2.38 (d, J=7.1Hz, 2H), 2.20 (d, J=7.8Hz, 1H), 2.11 (s, 3H), 2.01-1.90 (m, 1H), 1.47 (dd, J=12.8,10.8Hz, 1H), 1.29 (t, J=5.1Hz, 3H)

Step 3:

By ethyl -2- (6- acetamide -1,2,3,4- dihydronaphthalene -2- base) acetic acid esters (700mg, 2.436mmol) (such as Formulas I - 66-d compound represented) it is dissolved in ethyl alcohol (20mL) solution, sulfuric acid solution (2mL, 70mass%) then is added.Reaction heating To flowing back and stir 12 hours.2x20ml is extracted with ethyl acetate, merges organic phase with salt and washes 1x20ml, use anhydrous sodium sulfate It dries, filters, is concentrated to get target compound (such as Formulas I -66-e compound represented) 0.56g, brown oil, yield 99%.¹H NMR (400MHz, MeOD) δ 6.79 (d, J=8.0Hz, 1H), 6.57-6.44 (m, 2H), 4.21-4.11 (m, 2H), 2.80-2.66 (m, 3H), 2.44-2.27 (m, 3H), 2.16 (dddd, J=14.9,10.4,4.7,2.9Hz, 1H), 1.96- 1.86(m,1H),1.49–1.37(m,1H),1.35–1.21(m,3H).

Step 4:

2- allyl -1- [6- (1- hydroxyl -1- methyl-ethyl) -2- pyridine] -6- first sulphur-pyrazoles [3,4-d] pyrimidine -3- ketone (70mg, 0.1959mmol) (such as formula 1A compound represented) is dissolved in dichloroethanes (2mL), and mCPBA is then added (1.3equiv., 0.2546mmol, 77mass%).Reaction is stirred at room temperature 2 hours.Later, be added DIPEA (3equiv., 0.5876mmol) and ethyl 2- (6- amine -1,2,3,4- naphthane -2- base) acetic acid esters (such as Formulas I -66-e compound represented) (3equiv.,0.5876mmol,).Reaction is stirred at room temperature 12 hours.Add saturation sodium hydrogensulfite 20ml extraction to go out, uses dichloro Methane extracts 2x20ml, merges organic phase with salt and washes 1x20ml, is dried, filtered with anhydrous sodium sulfate, be concentrated to get crude product. Crude product isolates and purifies (eluent acetonitrile/water (formic acid 0.1%)=30% to 60%) through Pre-HPLC and obtains target compound (such as -66 compound represented of Formulas I) 25mg, white solid, yield 23.5%.1H NMR(400MHz,DMSO)δ10.19(s, 1H), 8.87 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.63 (d, J=7.7Hz, 2H), 7.36 (d, J=8.1Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 5.67 (dd, J=17.1,10.3Hz, 1H), 5.33 (s, 1H), 5.00 (dd, J=10.3,1.3Hz, 1H), 4.83 (dd, J=17.1,1.3Hz, 1H), 4.70 (d, J=5.8Hz, 2H), 4.11 (q, J=7.1Hz, 2H), 2.80 (dd, J=16.0,4.2Hz, 3H), 2.44-2.38 (m, 3H), 2.11 (s, 1H), 1.90 (s, 1H), 1.47 (s, 6H), 1.45-1.35 (m, 1H) 1.22 (t, J=7.1Hz, 3H) .LC-MS:m/z:(M+H)⁺=543.

Embodiment 67

By 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- oxygen -2,3- dihydro -1H- pyrrole Azoles [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetic acid esters (520mg, 0.9583mmol) (such as Formulas I -66 Compound represented) it is dissolved in methanol (5ml) and tetrahydrofuran (5ml) in the mixed solvent, then plus lithium hydroxide aqueous solution (1mol/L,5ml).Reaction is being heated to 50 ° of 50 DEG C of stirrings 2 hours.Reaction is gone out with 1N hydrochloric acid extraction and is adjusted to reacting liquid pH value 6-7, a large amount of white solids are precipitated in the process, white solid are obtained by filtration, and elute 2 times to obtain product with petroleum ether 5ml.It should Product further refines (condition is acetonitrile/water (0.1% formic acid)=30%-60%12CV) through Pre-HPLC and obtains target chemical combination Object (such as -67 compound represented of Formulas I) 400mg, white solid, yield 81.1%.1H NMR(400MHz,DMSO)δ10.21 (s, 1H), 8.87 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.78 (d, J=7.9Hz, 0H), 7.64 (d, J=7.5Hz, 2H), 7.35 (d, J=7.9Hz, 1H), 7.01 (d, J=8.4Hz, 1H), 5.67 (dd, J=17.1,10.3Hz, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2Hz, 1H), 4.82 (d, J=17.1Hz, 1H), 4.70 (d, J=5.9Hz, 1H), 2.81 (dd, J=21.9,4.6Hz, 3H), 2.39 (dd, J=16.6,10.4Hz, 1H), 2.29 (d, J=7.0Hz, 2H), 2.08 (s, 1H), 1.92(s,1H),1.58–1.32(m,7H).LC-MS:m/z:(M+H)⁺=515.

Embodiment 68

By ethyl 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- oxygen -2,3- dihydro - 1H- pyrazoles [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetic acid (40mg, 0.07773mmol) (such as Formulas I - 67 compounds represented) it is dissolved in DMF (2ml), HATU (1equiv., 0.07773mmol) and DIPEA is then added (2equiv., 0.1555mmol) is eventually adding ethamine (2equive., 0.1555mmol).It is small that reaction is stirred at room temperature 12 When.Add water 20ml extraction to go out, and is extracted twice with ethyl acetate 20ml.Organic layer is washed twice with salt water 20ml, dry with sodium sulphate, Filtering is concentrated to get thick production mouth.The crude product further refined through Pre-HPLC (condition be acetonitrile/water (0.1% formic acid)= 30%-60%12CV) obtain target (such as -68 compound represented of Formulas I) 18mg, white solid, yield 41.5%).NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.03 (t, J=7.9Hz, 0H), 7.85 (t, J=5.3Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.63 (d, J=7.5Hz, 2H), 7.35 (d, J=8.5Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 5.67 (ddd, J=23.0,10.3,5.9Hz, 1H), 5.34 (s, 1H), 5.00 (d, J=10.3Hz, 1H), 4.90-4.76 (m, 1H), 4.70 (d, J=5.8Hz, 2H), 3.16-3.04 (m, 2H), 2.74 (dd, J=23.4,14.8Hz, 3H), 2.43- 2.30 (m, 1H), 2.10 (d, J=12.8Hz, 2H), 1.88 (d, J=12.7Hz, 1H), 1.47 (s, 6H), 1.38 (s, 1H), 1.04 (t, J=7.2Hz, 3GH) .LC-MS:m/z:(M+H)⁺=542.

Embodiment 69

Using ibid compound ethyl 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- Oxygen -2,3- dihydro-1 h-pyrazole [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetamide is (such as -67 institute of Formulas I The compound shown) target compound 18mg, white solid, yield 41.5% is made in identical method.1H NMR(400MHz, DMSO) δ 10.19 (s, 1H), 8.91-8.84 (m, 1H), 8.03 (t, J=7.9Hz, 1H), 7.87 (s, 1H), 7.78 (d, J= 7.9Hz, 1H), 7.64 (d, J=7.7Hz, 2H), 7.35 (d, J=9.6Hz, 1H), 6.99 (d, J=8.3Hz, 1H), 5.67 (dd, J=16.9,10.2Hz, 1H), 5.37-5.32 (m, 1H), 5.00 (d, J=11.4Hz, 1H), 4.82 (d, J=17.2Hz, 1H), 4.73-4.65 (m, 2H), 3.42 (dd, J=11.8,6.1Hz, 2H), 3.16 (d, J=5.7Hz, 2H), 2.81-2.67 (m, 3H), 2.42-2.28 (m, 3H), 2.14 (s, 2H), 2.14-2.05 (m, 1H), 1.87 (s, 1H), 1.44 (t, J= 18.7Hz,6H),1.45-1.30(m,1H).LC-MS:m/z:(M+H)⁺=558.

Embodiment 70

Using ibid compound ethyl 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- Oxygen -2,3- dihydro-1 h-pyrazole [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetamide is (such as -67 institute of Formulas I The compound shown) target compound (such as -70 compound represented of Formulas I) 20mg, white solid, yield is made in identical method 46.7%.1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.93 (d, J=3.8Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.64 (d, J=7.6Hz, 2H), 7.35 (d, J=8.1Hz, 1H), 7.00 (d, J=8.1Hz, 1H), 5.73-5.62 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.3Hz, 1H), 4.82 (d, J= 18.6Hz, 1H), 4.70 (d, J=5.9Hz, 2H), 2.76 (s, 3H), 2.69-2.61 (m, 1H), 2.32 (d, J=10.5Hz, 3H), 2.2-2.09 (m, 1H), 2.09 (s, 2H), 1.85 (s, 1H), 1.47 (s, 6H), 1.37 (s, 1H), 0.62 (dd, J= 7.0,2.1Hz, 2H), 0.40 (dd, J=8.4,5.8Hz, 2H) .LC-MS:m/z:(M+H)⁺=554.

Embodiment 71

Using ibid compound ethyl 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- Oxygen -2,3- dihydro-1 h-pyrazole [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetamide is (such as -67 institute of Formulas I The compound shown) target compound (as shown in Formulas I -71) 15mg, white solid, yield 35.0% is made in identical method.1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.33 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.78 (d, J=8.1Hz, 1H), 7.64 (d, J=7.6Hz, 2H), 7.35 (d, J=8.2Hz, 1H), 6.99 (d, J=8.6Hz, 1H), 5.67 (dd, J=16.9,10.4Hz, 1H), 5.33 (s, 1H), 5.00 (d, J=10.3Hz, 1H), 4.83 (d, J=17.1Hz, 1H), 4.70 (d, J=5.4Hz, 2H), 3.89 (d, J=5.2Hz, 2H), 3.12 (t, J=2.5Hz, 1H), 2.82-2.66 (m, 3H),2.42–2.29(m,3H),2.2-2.1(m,3H),1.87(s,1H),1.43(s,6H),1.45-1.31(m,1H).LC- MS:m/z:(M+H)⁺=552.

Embodiment 72

Using ibid compound ethyl 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- Oxygen -2,3- dihydro-1 h-pyrazole [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetamide is (such as -67 institute of Formulas I The compound shown) target compound 15mg, white solid, yield 31.1% is made in identical method.1H NMR(400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.02 (t, J=7.9Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.63 (d, J =7.7Hz, 2H), 7.35 (d, J=8.4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 5.75-5.59 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.4Hz, 1H), 4.82 (d, J=17.0Hz, 1H), 4.70 (d, J=5.6Hz, 2H), 4.33 (s, 4H), 3.41 (d, J=5.8Hz, 4H), 2.79 (d, J=17.1Hz, 3H), 2.44-2.31 (m, 3H), 2.08 (s, 1H), 1.89 (s, 1H),1.85–1.65(m,4H),1.47(s,6H),1.45-1.35(m,1H)..LC-MS:m/z:(M+H)⁺=624.

Embodiment 73

Using ibid compound ethyl 2- (6- ((2- allyl -1- (6- (2- hydroxypropyl alkane -2- base) pyridine -2- base) -3- oxygen -2,3- two Hydrogen -1H- pyrazoles [3,4-d] pyrimidine -6- base) amine) -1,2,3,4- naphthane -2- base) acetamide (chemical combination as shown in Formulas I -67 Object) target (such as -73 compound represented of Formulas I) compound 15mg, white solid, yield 31.2% is made in identical method.1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.63 (d, J=7.6Hz, 2H), 7.35 (d, J=8.3Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 5.73-5.62 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.7Hz, 1H), 4.82 (d, J=16.9Hz, 1H), 4.70 (d, J=5.8Hz, 2H), 3.60 (s, 4H), 2.89-2.72 (m, 3H), 2.46-2.33 (m, 3H), 2.13 (s, 1H), 1.97 (d, J=32.9Hz, 3H), 1.47(s,6H),1.45-1.35(m,1H).LC-MS:m/z:(M+H)⁺=618.

Embodiment 74

Step 1:

By bromo- 3,4- dihydronaphthalene -2 (1H) -one (855mg, 3.8mmol) (such as Formulas I -74-a compound represented) of 6- and (400mg, 5.6mmol) pyrrolidines is dissolved in 20mL methylene chloride, then addition (1.6g, 7.6mmol) acetic acid sodium borohydride, and 65 DEG C tube sealing is stirred overnight.It is gone out with 5ml water quenching, successively with the aqueous sodium carbonate of saturation and the brine It of saturation, anhydrous sulphur Crude product is concentrated under reduced pressure to obtain after sour sodium is dry, crude product is dissolved in 20ml ethyl acetate, 4M hydrochloric acid dioxane solution is added dropwise until No solid is precipitated from ethyl acetate.Pale solid 1g is obtained by filtration, yield: 83%.LC-MS:m/z:[M+1]⁺=280.

Step 2:

By 1- (the bromo- 1,2,3,4- naphthane -2- base of 6-) pyrrolidine hydrochloride (1g, 3.16mmol) (such as Formulas I -74-b institute The compound shown), benzophenone imine (620mg, 3.4mmol), sodium tert-butoxide (450mg, 4.69mmol), Pd₂(dba)₃ (100mg, 0.11mmol), BINAP (150mg, 0.241mmol) are added in 20ml toluene, argon gas ventilation three times, then plus Heat spends night to 110.Reaction solution concentration, gained crude product cross column purification (7M ammonia methanol: methylene chloride=0-20%), obtain palm fibre Color grease 1g, yield 83%.LC-MS:m/z:(M+H)⁺=381.

Step 3:

By 1,1- diphenyl-N- (6- (pyrrolidin-1-yl) -5,6,7,8- naphthane -2- base) azomethine (1g, 2.63mmol) (such as Formulas I -74-c compound represented) is dissolved in 30ml methanol, and sodium acetate (0.7g, 8.5mmol) then is added With hydroxylamine hydrochloride (370mg, 5.32mmol), it is heated to 60 degree of reactions overnight.Reaction solution filtering and concentrating, it is pure that gained crude product crosses column Change (7M ammonia methanol: methylene chloride=0-20%), obtains brown solid 220mg, yield 38%.LC-MS:m/z:(M+H)⁺= 217。

Step 4:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (120mg, 0.336mmol) (such as formula 1A compound represented) adds azoles in the solution of 15ml toluene Enter metachloroperbenzoic acid (82mg, 0.367mmol), acquired solution is stirred at room temperature 2h and obtains 2- allyl -1- (6- (2- hydroxyl Propane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone.This is molten Liquid is directly used in react in next step.

In 10ml methylene chloride be added 6- (pyrrolidin-1-yl) -5,6,7,8- naphthane -2- amine (100mg, 0.46mmol) (such as Formulas I -74-d compound represented) and 0.5mlN, N- diisopropylethylamine, stirring to solution are clarified, then It is added in above-mentioned resulting toluene solution, 40h is stirred at room temperature.It is concentrated under reduced pressure, gained crude product is first separated with thin layer chromatography It purifies { 7M ammonia methanol: (methylene chloride: ethyl acetate=5:1)=1:12 }, white then is prepared admittedly with efficient liquid phase again Body 16mg, yield 7%.LC-MS:m/z:(M+H)⁺=526,¹H NMR(400MHz,MeOD)δ8.85(s,1H),8.40(s, 2H), 8.14 (s, 1H), 7.92 (t, J=7.7Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.54-7.32 (m, 3H), 7.08 (d, J=7.9Hz, 1H), 5.81-5.62 (m, 1H), 5.07 (d, J=10.0Hz, 1H), 4.95 (d, J=16.9Hz, 1H), 4.77 (d, J=5.5Hz, 2H), 3.37 (m, 5H), 3.19 (d, J=7.6Hz, 2H), 2.95 (m, 2H), 2.37 (s, 1H), 2.13 (s,5H),1.62(s,6H).

Embodiment 75

Step 1:

By bromo- 3,4- dihydronaphthalene -2 (1H) -one (900mg, 4mmol) (such as Formulas I -75-a compound represented) of 6-, hydrochloric acid Azetidine (750mg, 8mmol) and 20ml water are added in 60mL methanol, and (1.31g, 16mmol) sodium acetate is then added, 1h is stirred at room temperature under nitrogen protection.

(1.5g, 16mmol) acetic acid and (500mg, 8.2mmol) sodium cyanoborohydride are added in above-mentioned reactant, nitrogen It is stirred overnight at room temperature under gas shielded.After be concentrated under reduced pressure, be added 20ml saturation aqueous sodium carbonate, be extracted with dichloromethane three times Crude product is concentrated under reduced pressure to obtain after organic phase anhydrous sodium sulfate is dry in (3*30ml), and crude product crosses column purification { 7M ammonia methanol: (dichloromethane Alkane: EA=2:1)=0-15% }, obtain brown oil 700mg yield: 65%.LC-MS:m/z:[M+1]⁺=266.

Step 2:

By 1- (the bromo- 1,2,3,4- naphthane -2- base of 6-) azetidine (0.7g, 2.63mmol) (such as Formulas I -75-b institute The compound shown), benzophenone imine (530mg, 2.92mmol), sodium tert-butoxide (410mg, 4.27mmol), Pd₂(dba)₃ (80mg, 0.087mmol), BINAP (165mg, 0.265mmol) are added in 35ml toluene, with argon gas ventilation three times, then plus Heat spends night to 110.Reaction solution concentration, gained crude product cross column purification { 7M ammonia methanol: (methylene chloride: EA=2:1)=0- 10% }, brown oil 0.85g, yield 88% are obtained.LC-MS:m/z:(M+H)⁺=367.

Step 3:

By 1,1- diphenyl-N- (6- (azetidine -1- base) -5,6,7,8- naphthane -2- base) azomethine (1g, 2.53mmol) (such as Formulas I -75-c compound represented) is dissolved in 40ml methanol, then be added sodium acetate (0.61g, 7.44mmol) with hydroxylamine hydrochloride (340mg, 4.89mmol), it is heated to 60 degree of reactions overnight.Reaction solution filtering and concentrating, gained are thick Product crosses column purification (7M ammonia methanol: methylene chloride=0-10%), obtains brown solid 450mg, yield 95%.LC-MS:m/z: (M+H)⁺=203.

Step 4:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (150mg, 0.42mmol) (such as formula 1A compound represented) adds azoles in the solution of 25ml toluene Enter metachloroperbenzoic acid (110mg, 0.49mmol), acquired solution is stirred at room temperature 2h and obtains 2- allyl -1- (6- (2- hydroxyl Propane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone.

Will above-mentioned reaction solution concentration after be added 6- (azetidine -1- base) -5,6,7,8- naphthane -2- amine (100mg, 0.49mmol) (such as Formulas I -75-d compound represented), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide, 60 degree of stirrings are for 24 hours.

The aqueous sodium carbonate and 25ml water of 10ml saturation are added into above-mentioned reaction solution, is extracted with dichloromethane three times (3*20ml) merges organic phase, is washed respectively with the sodium chloride solution that 20ml water and 20ml are saturated, dense after anhydrous sodium sulfate is dry Contract to obtain crude product, and gained crude product first crosses column purification { 3M ammonia methanol: (methylene chloride: ethyl acetate=1:1)=0-15% }, then Brown solid 100mg, yield 39% is prepared with efficient liquid phase again.LC-MS:m/z:(M+H)⁺=512,1H NMR (400MHz, CDCl3) δ 8.84 (s, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 7.89 (t, J=7.9Hz, 1H), 7.76 (d, J =7.6Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=7.6Hz, 1H), 7.32 (dd, J=8.3,2.1Hz, 1H), 7.03 (d, J =8.3Hz, 1H), 5.71 (ddt, J=16.4,10.2,6.2Hz, 1H), 5.05 (dd, J=10.2,1.1Hz, 1H), 4.94 (dd, J=17.1,1.2Hz, 1H), 4.76 (d, J=6.2Hz, 2H), 4.01 (t, J=7.8Hz, 4H), 3.19-3.06 (m, 1H), 3.06-2.75 (m, 4H), 2.48 (p, J=7.5Hz, 2H), 2.13 (d, J=10.0Hz, 1H), 1.93-1.75 (m, 1H), 1.61(s,6H).

Embodiment 76

Step 1:

By bromo- 3,4- dihydronaphthalene -2 (1H) -one (1g, 4.44mmol) (such as Formulas I -76-a compound represented) of 6-, piperidines (760mg, 8.93mmol) and p-methyl benzenesulfonic acid (90mg, 0.52mmol) are added in 40mL toluene, and one is fixed on reaction flask A water segregator, 155 DEG C are stirred at reflux overnight.

40ml methanol is added after solvent toluene in reaction is removed under reduced pressure, be slowly added under ice bath (0.85g, 23mmol) sodium borohydride removes ice bath and 2h is stirred at room temperature.It is concentrated under reduced pressure, the salt of 40ml ethyl acetate and 30ml 1mol/L is added Acid, organic layer wash twice (2*20ml) with the hydrochloric acid of 1mol/L, with the sodium hydroxide of 5mol/L by the acid solution after merging Alkalization, methylene chloride extract three times (3*30ml), and crude product 900mg brown oil is concentrated under reduced pressure to obtain after organic phase anhydrous sodium sulfate is dry Shape object, crude product are directly used in next step, yield: 70%.LC-MS:m/z:[M+1]⁺=294.

Step 2:

By (the change as shown in Formulas I -76-b of 1- (the bromo- 1,2,3,4- naphthane -2- base of 6-) piperidines (0.9g, 3.06mmol) Close object), benzophenone imine (620mg, 3.42mmol), sodium tert-butoxide (470mg, 4.89mmol), Pd₂(dba)₃(90mg, 0.1mmol), BINAP (190mg, 0.3mmol) is added in 35ml toluene, three times with argon gas ventilation, is then heated to 110 degree Overnight.Reaction solution concentration, gained crude product cross column purification (7M ammonia methanol: methylene chloride=0-10%), obtain brown oil 1g, yield 82.8%.LC-MS:m/z:(M+H)⁺=395.

Step 3:

By 1,1- diphenyl-N- (6- (piperidin-1-yl) -5,6,7,8- naphthane -2- base) azomethine (1g, 2.53mmol) (such as Formulas I -76-c compound represented) is dissolved in 40ml methanol, and sodium acetate (1g, 12.2mmol) and hydroxylamine hydrochloride is then added (360mg, 5.18mmol) is heated to 60 degree of reactions overnight.Reaction solution filtering and concentrating, gained crude product cross column purification (7M ammonia first Alcohol: methylene chloride=0-20%), obtain brown solid 500mg, yield 90%.LC-MS:m/z:(M+H)⁺=231.

Step 4:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (179mg, 0.5mmol) (such as formula 1A compound represented) is added azoles in the solution of 35ml toluene Metachloroperbenzoic acid (122mg, 0.546mmol), acquired solution are stirred at room temperature 2h and obtain 2- allyl -1- (6- (2- hydroxyl third Alkane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone.

Will above-mentioned reaction solution concentration after be added 6- (piperidin-1-yl) -5,6,7,8- naphthane -2- amine (130mg, 0.564mmol) (such as Formulas I -76-d compound represented), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide, 60 degree of stirrings are for 24 hours. The aqueous sodium carbonate and 25ml water of 10ml saturation are added into above-mentioned reaction solution, (3*20ml) three times is extracted with dichloromethane, Merge organic phase, washed respectively with the sodium chloride solution that 20ml water and 20ml are saturated, is concentrated to give crude product after anhydrous sodium sulfate is dry, Gained crude product first crosses column purification { 3M ammonia methanol: (methylene chloride: ethyl acetate=1:1)=0-15% }, then again with efficient Brown solid 130mg, yield 41% is prepared in liquid phase.LC-MS:m/z:(M+H)⁺=540,¹H NMR(400MHz,CDCl₃)δ 8.84 (s, 1H), 8.56 (s, 1H), 7.96 (s, 1H), 7.90 (t, J=7.9Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.48 (s, 1H), 7.42 (d, J=7.6Hz, 1H), 7.31 (dd, J=8.4,2.0Hz, 1H), 7.06 (d, J=8.3Hz, 1H), 5.71 (ddt, J=16.4,10.2,6.2Hz, 1H), 5.11-5.02 (dd, J=10.2,1.1Hz, 1H), 4.94 (dd, J=17.1, 1.1Hz, 1H), 4.77 (d, J=6.1Hz, 2H), 3.54 (m, 1H), 3.04 (m, 8H), 2.41 (d, J=11.9Hz, 1H), 1.99 (s,4H),1.87(m,1H),1.63(d,8H).

Embodiment 82

Step 1:

By (E)-N- (6- ((dimethylamino) methylene) -5- oxo -5-, 6-, 7-, 8- naphthane -2- base) acetamide (4.6mmol) (such as Formulas I -82-a compound represented) is dissolved in ethyl alcohol (20mL), and piperidines (14mmol) is added into reaction solution, will Reaction solution is heated to flowing back, and reaction solution stirs 16 hours.Reaction solution is evaporated to obtain crude product, crude product is washed with ethyl acetate, filtering, Filter cake is target compound (E)-N- (5- oxo -6- (piperidines -1- methylene) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (950mg, 69%), gray solid.1H NMR (400MHz, CDCl3) δ 7.98 (d, J=8.4Hz, 1H), 7.73 (s, 1H), 7.65 (d, J=29.8Hz, 2H), 7.16 (d, J=8.3Hz, 1H), 3.47 (s, 4H), 2.90-2.76 (m, 4H), 2.21 (s, 3H),1.67(s,6H).

Step 2:

By (E)-N- (5- oxo -6- (piperidines -1- methylene) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (3.18mmol) (such as Formulas I -82-b compound represented) is dissolved in anhydrous methanol (20mL), and Pd/C is added into reaction solution (300mg) and the concentrated sulfuric acid (0.5mL), reaction solution is heated to flowing back in hydrogen, is stirred 18 hours.Use saturated sodium carbonate solution By reaction solution tune pH=9, filtering removes Pd/C, reaction solution is evaporated, and is layered with water and ethyl acetate, organic phase saturated salt solution Washing, anhydrous sodium sulfate are dried, filtered, are evaporated, and reaction solution is evaporated to obtain crude product by crude product, and crude product is washed with ethyl acetate, filtering, Column chromatographic purifying (petrol ether/ethyl acetate=100/0-50/50) obtains target compound 6- (piperidines -1- methyl) -5-, 6-, 7-, 8- naphthane -2- amine (250mg, 32.1%), yellow oil.LC-MS:m/z:[M+1]⁺=245.

Step 3:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-D] pyrimidine -3- ketone (0.56mmol) (such as formula 1A compound represented) is dissolved in toluene (15mL) azoles, and m-chloro peroxide is added Benzoic acid (0.62mmol), reaction solution stir 0.5 hour at room temperature, reaction solution are evaporated, and gained sulfoxide intermediate is dissolved in diformazan 6- (piperidines -1- methyl) -5-, 6-, 7- is added in sulfoxide (10mL), and 8- naphthane -2- amine (0.67mmol) is (such as Formulas I -82-c institute The compound shown) and trifluoroacetic acid (0.5mL), reaction solution is heated to stirring 16 hours at 60 DEG C.Reaction solution unsaturated carbonate Water (50mL) ethyl acetate (50mL), layering, organic phase saturated common salt water washing, anhydrous sodium sulfate is added in sodium solution tune pH=9 It dries, filters, is evaporated, target compound 2- allyl -1- (6- (the 2- hydroxyl of column chromatographic purifying (methylene chloride/methanol=20/1) Base propane -2- base) pyridine -2- base) -6- ((6- (piperidines -1- methyl) -5,6,7,8- naphthane -2- base) amino) -1,2- dihydro 3H- pyrazoles [3,4-d] pyrimidine -3- ketone (182.4mg, 58.9%), gray solid.LC-MS:m/z:[M+1]⁺=554.1H NMR (400MHz,CDCl3)δ8.86(s,1H),7.95-7.70(m,3H),7.46(s,1H),7.41-7.35(m,1H),7.24(dd, J=8.2,2.1Hz, 1H), 7.08 (d, J=8.3Hz, 1H), 5.72 (dd, J=17.0,10.3Hz, 1H), 5.06 (dd, J= 10.2,1.0Hz, 1H), 4.95 (dd, J=17.1,1.1Hz, 1H), 4.78 (d, J=6.2Hz, 2H), 3.99 (s, 1H), 2.90 (d, J=4.6Hz, 1H), 2.84 (dd, J=8.0,4.2Hz, 2H), 2.43 (dd, J=15.5,10.4Hz, 4H), 2.32 (d, J =6.9Hz, 2H), 2.09-1.98 (m, 3H), 1.68-1.58 (m, 10H), 1.53-1.40 (m, 3H)

Embodiment 87

Step 1:

By 6- nitro -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salt (215mg, the 1mmol) (chemical combination as shown in Formulas I -87-a Object) and N, N- diisopropylethylamine (0.2ml) be added in the methylene chloride of 15ml, stir to clarify.Then 1- methyl-is added Piperidin-4-one (170mg, 1.5mmol), acetic acid sodium borohydride (422mg, 2mmol) and 0.3ml acetic acid, are stirred at room temperature 40h.It will The concentrated column of reaction solution { 3mol/L ammonia methanol: (methylene chloride: ethyl acetate=5:1)=0-15% } obtains the production of brown target Object 185mg.Yield: 67%.LC-MS:m/z:[M+1]⁺=276.

Step 2:

By 2- (1- methyl piperidine -4- base) -6- nitro -1,2,3,4- Tetrahydroisoquinoli- (180mg, 0.65mmol) (such as Formulas I - 87-b compound represented) and Raney nickel (0.2g) be added in 30ml ethyl alcohol, hydrazine hydrate is then slowly added dropwise into solution 2h is stirred at room temperature after being added dropwise in (0.5ml).Reaction solution filtering and concentrating is obtained into crude product 150mg, is directly used in next step.Yield: 93%.LC-MS:m/z:[M+1]⁺=246.

Step 3:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (such as formula 1A compound represented) (160mg, 0.45mmol) adds azoles in the solution of 15ml toluene Enter metachloroperbenzoic acid (110mg, 0.49mmol), 2h is stirred at room temperature in acquired solution.

2- (1- methyl piperidine -4- base) -1,2,3,4- tetrahydroisoquinoline -6- amine will be added after the concentration of above-mentioned reaction solution (150mg, 0.61mmol) (such as Formulas I -87-c compound represented), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide, 60 degree are stirred It mixes for 24 hours.The aqueous sodium carbonate and 15ml water of 10ml saturation are added into above-mentioned reaction solution, (3* three times is extracted with dichloromethane 20ml), merge organic phase, washed respectively with the sodium chloride solution that 20ml water and 20ml are saturated, is concentrated after anhydrous sodium sulfate is dry Crude product, gained crude product first with thin layer chromatography board separation it is primary 3M ammonia methanol: (methylene chloride: ethyl acetate=1:1)=1: 10 }, yellow solid 110mg, yield 44% then is prepared with efficient liquid phase again.LC-MS:m/z:(M+H)⁺=555,¹H NMR (400MHz, MeOD) δ 8.84 (s, 1H), 8.37 (s, 2H), 8.02 (t, J=7.9Hz, 1H), 7.81 (d, J=7.6Hz, 1H), 7.73-7.65 (m, 2H), 7.42 (d, J=8.2Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 5.73 (ddt, J=16.3, 10.2,6.1Hz, 1H), 5.05 (dd, J=10.2,1.2Hz, 1H), 4.94 (d, J=J=17.0,1.3Hz, 1H), 4.83 (d, J =6.1Hz, 2H), 3.98 (s, 2H), 3.54 (d, J=12.5Hz, 2H), 3.12 (t, J=5.9Hz, 2H), 3.00 (m, 5H), 2.82 (s, 3H), 2.27 (d, J=12.6Hz, 2H), 1.99 (dd, J=22.9,11.1Hz, 2H), 1.60 (s, 6H)

Embodiment 88

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- ((1,2,3,4- tetrahydroisoquinoline -6- Base) amino) -1,2- dihydro -3H- pyrazolo [3,4-d] pyrimidine -3- ketone (100mg, 0.22mmol) is (as shown in Formulas I -88-a Compound), tetrahydro -4H- pyrans -4- ketone (100mg, 1mmol) and sodium acetate (60mg, 0.44mmol) are added to the methanol of 30ml In.Then sodium cyanoborohydride (110mg, 1.75mmol) is added, 48h is stirred at room temperature.By reaction solution concentrated column { 3mol/L ammonia Methanol: (methylene chloride: ethyl acetate=5:1)=0-15% }, obtain white object product 70mg.Yield: 59%.LC-MS: m/z:(M+H)⁺=542,1H NMR (400MHz, CDCl3:MeOH=3:1) δ 8.85 (s, 1H), 7.93 (t, J=7.9Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.58 (s, 1H), 7.54 (d, J=7.7Hz, 1H), 7.35 (d, J=8.3Hz, 1H), 7.04 (d, J=8.4Hz, 1H), 5.69 (dq, J=10.3,6.1Hz, 1H), 5.05 (d, J=10.2Hz, 1H), 4.92 (d, J= 17.1Hz, 1H), 4.81 (d, J=5.9Hz, 2H), 4.16-4.03 (m, 2H), 3.81 (s, 2H), 3.47 (t, J=11.5Hz, 2H), 2.92 (d, J=4.4Hz, 4H), 2.72 (dd, J=15.4,7.3Hz, 1H), 1.93 (d, J=11.6Hz, 2H), 1.72 (qd, J=12.3,4.4Hz, 2H), 1.60 (s, 6H)

Embodiment 103

Step 1:

By N- (5- oxygen -5-, 6-, 7-, 8- naphthane -2- base) acetamide (59mmol) (chemical combination as shown in Formulas I -103-a Object) it is dissolved in toluene (200mL), it is placed in tube sealing, glyoxylic acid ethyl ester (118mmol) is added into reaction solution, p-methyl benzenesulfonic acid Reaction solution is heated to 120 DEG C by (5.9mmol) and magnesium sulfate (395mmol), and reaction solution stirs 16 hours.Reaction solution is filtered, Filtrate is evaporated to obtain crude product, and crude product column chromatographic purifying (petrol ether/ethyl acetate=100/0-50/50) obtains target compound ethyl (E) -2 (- 2 (1H)-methylene of 6- acetylaminohydroxyphenylarsonic acid 1- oxo -3,4- dihydronaphthalene) acetic acid esters (9.5g, 56%), yellow solid. LC-MS:m/z:[M+1]⁺=288.

Step 2:

By ethyl (E) -2 (- 2 (1H)-methylene of 6- acetylaminohydroxyphenylarsonic acid 1- oxo -3,4- dihydronaphthalene) acetic acid esters (31mmol) (such as Formulas I -103-b compound represented) is dissolved in methanol (100mL), and Pd/C (900mg) and the concentrated sulfuric acid are added into reaction solution (1.0mL) stirs reaction solution 18 hours in hydrogen.With saturated sodium carbonate solution by reaction solution tune pH=9, filtering is removed Reaction solution is evaporated by Pd/C, is layered with water and ethyl acetate, organic phase saturated common salt water washing, and anhydrous sodium sulfate is dry, mistake Filter, is evaporated, and reaction solution is evaporated to obtain crude product by crude product, and crude product is washed with ethyl acetate, filtering, column chromatographic purifying (petroleum ether/acetic acid Ethyl ester=100/0-50/50) target compound 6- (piperidines -1- methyl) -5-, 6-, 7-, 8- naphthane -2- amine (4.0g, 46.0%), white solid.LC-MS:m/z:[M+1]⁺=276.

Step 3:

By 6- (piperidines -1- methyl) -5-, 6-, 7-, 8- naphthane -2- amine (such as Formulas I -103-c compound represented) (15.0mmol) is dissolved in tetrahydrofuran (50mL), and 0 DEG C will be cooled under reaction solution nitrogen protection, and tetrahydrochysene lithium aluminium is added (29mmol) adds rear reaction solution and stirs at room temperature 4 hours.Reaction solution is quenched with saturated ammonium chloride, reaction solution ethyl acetate Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate are dried, filtered, are evaporated, column chromatographic purifying (petrol ether/ethyl acetate =100/0-50/50) target compound N- (6-(2- ethoxy)-5-, 6-, 7-, 8- naphthane-2- base) acetamide (2.70g, 80.0%), white solid.LC-MS:m/z:[M+1]⁺=234.

Step 4:

By N- (6- (2- ethoxy) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (12mmol) (such as Formulas I -103-d institute The compound shown) it is dissolved in methylene chloride (30mL), triethylamine (46mmol) is added into reaction solution, N, N- lutidines -4- Amine (5.8mmol) and paratoluensulfonyl chloride (23mmol), reaction solution stir 16 hours at room temperature.1N hydrochloric acid is added in phase reaction (200mL), methylene chloride extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate are dried, filtered, are evaporated, column chromatographic purifying The target compound 2- (6- acetylaminohydroxyphenylarsonic acid 1,2,3,4- naphthane -2- base) of (petrol ether/ethyl acetate=100/0-30/70) 4- toluenesulfonic acid ethyl ester (2.40g, 54.0%), white solid.LC-MS:m/z:[M+1]⁺=388.

Step 5:

By 2- (1,2,3,4- naphthane -2- base of 6- acetylaminohydroxyphenylarsonic acid) 4- toluenesulfonic acid ethyl ester (1.03mmol) (such as Formulas I - 103-e compound represented) it is dissolved in methanol (10mL), it is added sodium methoxide (2.07mmol), reaction solution is heated to 50 DEG C, stirring 16 Hour.Reaction solution is evaporated, the target compound N- (6- of column chromatographic purifying (petrol ether/ethyl acetate=100/0-50/50) (2- methoxy ethyl) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (250mg, 97.93%), yellow oil.LC-MS: m/z:[M+1]⁺=248.

Step 6:

By N- (6- (2- methoxy ethyl) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (1.01mmol) (such as Formulas I - 103-f compound represented) it is dissolved in ethyl alcohol (10mL), it is added concentrated hydrochloric acid (10mL), reaction solution is heated to flowing back, stirring 16 is small When.Reaction solution is evaporated, crude product target compound 6- (2- methoxy ethyl) -5-, 6-, 7-, 8- naphthane -2- amine are obtained (160mg, 77.09%), gray solid.LC-MS:m/z:[M+1]⁺=206.

Step 7:

By 2- allyl-1- (6- (2- hydroxy propane-2- base) pyridine-2- base)-6-(methyl mercapto)-1,2- dihydro-3H- pyrroles Simultaneously [3,4-D] pyrimidine -3- ketone (such as formula 1A compound represented) (0.28mmol) is dissolved in toluene (15mL) azoles, and m-chloro peroxide is added Benzoic acid (0.31mmol), reaction solution stir 0.5 hour at room temperature, reaction solution are evaporated, and gained sulfoxide intermediate is dissolved in diformazan 6- (piperidines -1- methyl) -5-, 6-, 7- is added in sulfoxide (10mL), and 8- naphthane -2- amine (0.34mmol) is (such as Formulas I -103-g institute The compound shown) and trifluoroacetic acid (0.5mL), reaction solution is heated to stirring 16 hours at 60 DEG C.Reaction solution unsaturated carbonate Water (50mL) ethyl acetate (50mL), layering, organic phase saturated common salt water washing, anhydrous sodium sulfate is added in sodium solution tune pH=9 It dries, filters, is evaporated, liquid phase preparation purifies to obtain target compound 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- Base) -6- ((6- (2- methoxy ethyl) -5,6,7,8- naphthane -2- base) amino) -1,2- dihydro 3H- pyrazoles [3,4-d] is phonetic Pyridine -3- ketone (32mg, 22.22%), gray solid.LC-MS:m/z:[M+1]⁺=515.1H NMR(400MHz,CDCl3)δ 8.87 (s, 1H), 7.81 (t, J=38.9Hz, 3H), 7.53-7.36 (m, 2H), 7.07 (s, 1H), 5.72 (s, 1H), 5.02 (dd, J=42.8,13.2Hz, 2H), 4.80 (s, 2H), 3.55 (t, J=6.3Hz, 2H), 3.42-3.36 (m, 3H), 2.89 (d, J=21.4Hz, 3H), 2.53-2.39 (m, 1H), 1.96 (d, J=26.2Hz, 4H), 1.75-1.66 (m, 3H), 1.61 (s, 6H).

Embodiment 114

Step 1:

By 6- nitro -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salt (214mg, the 1mmol) (chemical combination as shown in Formulas I -114-a Object), 3- aza-oxo-cyclobutane -1- carboxylic acid tert-butyl ester (190mg, 1.1mmol), acetic acid sodium borohydride (422mg, 2mmol) and N,N-diisopropylethylamine (0.5ml) is added in the methylene chloride of 15ml, is stirred overnight for 70 degree of temperature in tube sealing China and foreign countries.It will reaction The concentrated column of liquid (ethyl acetate: petroleum ether=0-50%), obtains light yellow target product 300mg.Yield: 90%.LC-MS: m/z:[M+1]⁺=334.

Step 2:

By 3- (- 2 (1H)-yl of 6- nitro -3,4- dihydro-isoquinoline) azetidine -1- carboxylic acid tert-butyl ester (300mg, 0.9mmol) (such as Formulas I -114-b compound represented) and 3ml trifluoroacetic acid are added sequentially in 3ml methylene chloride, and room temperature is stirred It mixes overnight.The ammonia methanol of 10ml 7mol/L is added after reaction solution concentration, is then concentrated to give crude product 200mg, is directly used in next Step.Yield: 95%.LC-MS:m/z:[M+1]⁺=234.

Step 3:

By 2- (azetidine -3- base) -6- nitro -1,2,3,4- tetrahydroisoquinoline (180mg, 0.77mmol) (such as formula I-114-c compound represented), 37% formalin (0.2ml) and acetic acid sodium borohydride (340mg, 1.6mmol) is added Into the methanol of 15ml, it is stirred overnight at room temperature.20ml methylene chloride and 2ml methanol is added after reaction solution concentration, with 5ml saturation Sodium carbonate liquor is washed, concentrated column (the ammonia methanol of 7mol/L: methylene chloride=0-20%) after anhydrous sodium sulfate is dry, Obtain 175mg white solid.Yield: 91%.LC-MS:m/z:[M+1]⁺=248.

Step 4:

By 2- (1- methyl azepine -3- base) -6- nitro -1,2,3,4- tetrahydroisoquinoline (170mg, 0.69mmol) (such as formula I-114-d compound represented) and Raney nickel (0.2g) be added in 30ml ethyl alcohol, hydrazine hydrate is then slowly added dropwise into solution 2h is stirred at room temperature after being added dropwise in (0.5ml).Reaction solution filtering and concentrating is obtained into crude product.Yield: 93%.LC-MS:m/z:[M+1 ]⁺=218.

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (140mg, 0.39mmol) (such as formula 1A compound represented) adds azoles in the solution of 15ml toluene Enter metachloroperbenzoic acid (100mg, 0.45mmol), 2h is stirred at room temperature in acquired solution.

2- (1- methyl azepine -3- base) -1,2,3,4- tetrahydroisoquinoline -6- amine will be added after the concentration of above-mentioned reaction solution (90mg, 0.41mmol) (such as Formulas I -114-e compound represented), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide, 60 degree are stirred It mixes for 24 hours.The aqueous sodium carbonate and 15ml water of 10ml saturation are added into above-mentioned reaction solution, (3* three times is extracted with dichloromethane 20ml), merge organic phase, washed respectively with the sodium chloride solution that 20ml water and 20ml are saturated, is concentrated after anhydrous sodium sulfate is dry Crude product is obtained, gained crude product first separates primary { 3M ammonia methanol: (methylene chloride: ethyl acetate=1:1)=0- with thin layer chromatography board 15% }, yellow solid 65mg, yield 31% then is prepared with efficient liquid phase again.LC-MS:m/z:(M+H)⁺=527,¹H NMR(400MHz,CDCl₃) δ 8.84 (s, 1H), 8.42 (s, 1H), 7.92 (t, J=8.1Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.64-7.54 (m, 2H), 7.39 (dd, J=8.2,2.0Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 5.76-5.61 (m, 1H), 5.04 (dd, J=10.2,1.1Hz Hz, 1H), 4.91 (dd, J=17.0,1.2Hz, 1H), 4.82 (d, J=6.2Hz, 2H), 4.42-4.32 (m, 2H), 3.87-3.76 (m, 2H), 3.54 (m, 3H), 2.94 (t, J=5.8Hz, 2H), 2.88 (s, 3H), 2.68 (t, J=5.9Hz, 2H), 1.59 (s, 6H)

Embodiment 115

Step 1:

Bromo- 3,4- dihydronaphthalene -2 (1H) -one (400mg, 1.78mmol) (such as Formulas I -115-a compound represented) of 6- is molten In 18mL methanol, ammonium acetate (1368mg, 17.8mmol) then is added, sodium cyanoborohydride is added after 2h is stirred at room temperature Reaction 16h is stirred at room temperature in (120mg, 1.91mmol).30ml water is added after being concentrated under reduced pressure in reaction solution, and with the hydrochloric acid of 1mol/L PH value is adjusted to acidity, is extracted twice every time with the methylene chloride of 30ml.Water phase is with the sodium hydroxide solution of 1mol/L by pH value It is adjusted to alkali (pH=10-11).Every time three times with the methylene chloride extraction of 40ml.Organic phase is washed with 30ml saturated salt solution It washs, with being concentrated after anhydrous sodium sulfate drying, gained crude product is directly used in next step.Obtain rufous grease (197mg, 0.87mmol), yield 48%.LC-MS:m/z:(M+H)⁺=226.0,228.0.

Step 2:

The bromo- 1,2,3,4- naphthane -2- amine (97mg, 0.43mmol) (such as Formulas I -115-b compound represented) of 6- is molten It in 10ml methylene chloride, is added sodium carbonate (182mg, 1.72mmol), room temperature room temperature is stirred to react 18h.Reaction solution decompression is dense 30ml is added after contracting, is extracted twice every time with the methylene chloride of 30ml.Merge organic layer concentration, gained crude product crosses column purification (ethyl acetate: petroleum ether=0-33%), obtains brown oil (90mg, 0.30mmol), yield 71%.LC-MS:m/z:(M +H)⁺=297.1,299.1.

Step 3:

By 3- (the bromo- 1,2,3,4- naphthane -2- base of 6-) -1,1- dimethyl urea (90mg, 0.30mmol) (such as Formulas I -115- C compound represented), benzophenone imine (60mg, 0.33mmol), sodium tert-butoxide (58mg, 0.60mmol), Pd₂(dba)₃ (14mg, 0.015mmol), BINAP (19mg, 0.03mmol) are added in 10ml toluene, are taken a breath three times in argon gas, are then heated To 100 DEG C of reaction 16h.Reaction solution concentration, gained crude product cross column purification (methanol: methylene chloride=0-10%), obtain brown Grease (76mg, 0.19mmol), yield 63%.LC-MS:m/z:(M+H)⁺=398.3.

Step 4:

By 3- (6- ((diphenyl methylene) amino -1,2,3,4- naphthane -2- base) -1,1- dimethyl urea (76mg, 0.19mmol) (such as Formulas I -115-d compound represented) is dissolved in 10ml methanol, then be added acetic acid sodium trihydrate (78mg, 0.57mmol) with hydroxylamine hydrochloride (29mg, 0.42mmol), it is heated to 60 degree and reacts 6 hours.Reaction solution filtering and concentrating, gained are thick Product crosses column purification (methanol: methylene chloride=0-20%), obtains brown oil (44mg, 0.19mmol), yield 99%. LC-MS:m/z:(M+H)⁺=234.2.

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (70mg, 0.2mmol) (such as formula 1A compound represented) is added azoles in the solution of 15ml toluene Metachloroperbenzoic acid (48mg, 0.22mmol), acquired solution is stirred at room temperature after 1h solvent is evaporated off after obtain 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] is phonetic Pyridine -3- ketone crude product.In above-mentioned acquired solution be added dimethyl sulfoxide 5mL, trifluoroacetic acid 1mL, 3- (6- amino -1,2,3,4- tetra- Hydrogen naphthalene -2- base) -1,1- dimethyl urea (44mg, 0.19mmol) (such as Formulas I -115-e compound represented), 60 degree of stirrings are for 24 hours. It is concentrated under reduced pressure, gained crude product isolates and purifies (7M ammonia methanol: methylene chloride=0-10%) with thin layer chromatography and obtains targeted Close object 31mg, yellow solid, yield 30%.LC-MS:m/z:(M+H)⁺=543.3,¹H NMR(400MHz,DMSO)δ10.21 (s, 1H), 8.88 (s, 1H), 8.03 (t, J=7.9Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.64 (d, J=7.7Hz, 2H), 7.36 (d, J=7.4Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 6.11 (d, J=7.5Hz, 1H), 5.67 (ddd, J= 16.4,10.9,6.1Hz, 1H), 5.00 (d, J=10.5Hz, 1H), 4.82 (d, J=17.5Hz, 1H), 4.70 (d, J= 5.7Hz, 2H), 3.80 (s, 1H), 2.89 (dd, J=16.4,4.6Hz, 2H), 2.81 (s, 6H), 2.69-2.52 (m, 2H), 2.04–1.94(m,1H),1.71–1.56(m,1H),1.47(s,6H)。

Embodiment 116

Step 1:

By the bromo- 1,2,3,4- tetrahydroisoquinoline (740mg, 3.49mmol) (such as Formulas I -114-a compound represented) of 6-, 3- Oxo-pyrrolidine -1- carboxylic acid tert-butyl ester (1g, 5.4mmol), acetic acid sodium borohydride (1.5g, 7.1mmol) and acetic acid (0.2ml) add Enter into the methylene chloride of 35ml, is stirred overnight at room temperature.Organic layer is washed with the saturated sodium carbonate solution of 20ml, anhydrous sodium sulfate Dry concentration, then crosses column purification (methylene chloride: triethylamine=100:1), obtains brown solid 850mg.Yield: 64%.LC- MS:m/z:[M+1]⁺=381.

Step 2:

By 3- (bromo- -2 (the 1H)-yl of 3,4- dihydro-isoquinoline of 6-) pyrrolidines -1- carboxylic acid tert-butyl ester (850mg, 2.2mmol) (such as Formulas I -114-b compound represented) and 5ml trifluoroacetic acid are added sequentially in 5ml methylene chloride, are stirred overnight at room temperature.Instead 50ml methylene chloride and 5ml methanol are added after answering liquid to be concentrated, is washed with the sodium carbonate liquor that 10ml is saturated, anhydrous sodium sulfate is dry After be concentrated to give crude product brown oil 600mg, be directly used in next step.Yield: 95%.LC-MS:m/z:[M+1]⁺=281.

Step 3:

By 6- bromo- 2- (pyrrolidin-3-yl) -1,2,3,4- tetrahydroisoquinoline (600mg, 2.1mmol) (such as Formulas I -114-c Compound represented), 37% formalin (1ml) and acetic acid sodium borohydride (900mg, 4.24mmol) is added to 35ml's In methanol, it is stirred overnight at room temperature.20ml methylene chloride and 2ml methanol is added after reaction solution concentration, the sodium carbonate being saturated with 5ml is molten Liquid is washed, and concentrated column (the ammonia methanol of 7mol/L: methylene chloride=0-15%) after anhydrous sodium sulfate is dry obtains 530mg brown oil.Yield: 84%.LC-MS:m/z:[M+1]⁺=295.

Step 4:

By the bromo- 2- of 6- (1- methylpyrrolidin- 3- yl) -1,2,3,4- tetrahydroisoquinoline (530mg 1.8mmol) (such as Formulas I - 114-d compound represented), benzophenone imine 360mg (2mmol), sodium tert-butoxide 260mg (2.7mmol), Pd₂(dba)₃65mg (0.07mmol), BINAP (115mg, 0.185mmol) are added in 35ml toluene, argon gas ventilation three times, then plus Heat spends night to 110.Reaction solution concentration, gained crude product cross column purification [7M ammonia methanol: (methylene chloride: ethyl acetate=2:1) =0-10%], obtain brown oil 540mg, yield 76%.LC-MS:m/z:[M+1]⁺=396.

Step 5:

By N- (2- (1- methylpyrrolidin- 3- yl) -1,2,3,4- tetrahydroisoquinoline -6- base) -1,1- benzophenone imine (540mg, 1.365mmol) (such as Formulas I -114-e compound represented) is dissolved in 40ml methanol, and sodium acetate 0.56g is then added (6.83mmol) and hydroxylamine hydrochloride (190mg, 2.73mmol) is heated to 60 degree of reactions overnight.Reaction solution filtering and concentrating, gained are thick Product crosses column purification (7M ammonia methanol: methylene chloride=0-15%), obtains brown oil 260mg, yield 82%.LC-MS:m/ z:[M+1]⁺=232.

Step 6:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-d] pyrimidine -3- ketone (155mg, 0.43mmol) (such as formula 1A compound represented) adds azoles in the solution of 15ml toluene Enter metachloroperbenzoic acid (106mg, 0.47mmol), 2h is stirred at room temperature in acquired solution.

2- (1- methylpyrrolidin- 3- yl) -1,2,3,4- tetrahydroisoquinoline -6- amine will be added after the concentration of above-mentioned reaction solution (130mg, 0.56mmol) (such as Formulas I -114-f compound represented), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide, 60 degree are stirred It mixes for 24 hours.The aqueous sodium carbonate and 15ml water of 10ml saturation are added into above-mentioned reaction solution, (3* three times is extracted with dichloromethane 20ml), merge organic phase, washed respectively with the sodium chloride solution that 20ml water and 20ml are saturated, is concentrated after anhydrous sodium sulfate is dry Crude product, gained crude product with thin layer chromatography board separate twice 7M ammonia methanol: (methylene chloride: ethyl acetate=2:1)=1: 9 }, white solid 160mg, yield 68% are obtained.LC-MS:m/z:(M+H)⁺=541,¹H NMR(400MHz,MeOD)δ8.84 (s, 1H), 8.02 (t, J=7.9Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.68 (d, J=7.7Hz, 1H), 7.63 (s, 1H), 7.36 (d, J=8.2Hz, 1H), 7.03 (d, J=8.4Hz, 1H), 5.73 (ddt, J=16.4,10.3,6.1Hz, 1H), 5.05 (dd, J=10.2,1.1Hz, 1H), 4.90-4.94 (d, J=17.0,1.2Hz, 1H), 4.84 (d, J=6.1Hz, 2H), 3.72-3.60 (m, 2H), 3.12 (m, 2H), 2.97-2.83 (m, 4H), 2.74 (m, 1H), 2.55 (dd, J=16.5,9.1Hz, 1H),2.50–2.39(m,4H),2.18(m,1H),1.92(m,1H),1.60(s,6H).

Embodiment 117

Step 1:

By 2- (1,2,3,4- naphthane -2- base of 6- acetylaminohydroxyphenylarsonic acid) 4- toluenesulfonic acid ethyl ester (1.03mmol) (such as Formulas I - 117-a compound represented) it is dissolved in acetonitrile (10mL), morpholine (3.10mmol) and potassium carbonate are added into reaction solution Reaction solution is heated to 50 DEG C by (4.13mmol), and reaction solution stirs 16 hours.Reaction solution is filtered, filtrate is evaporated to obtain crude product, slightly Capo chromatographic purifying (petrol ether/ethyl acetate=100/0-50/50) target compound N- (6- (2- morpholine ethyl) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (230mg, 73.7%), white solid.LC-MS:m/z:[M+1]⁺=303.

Step 2:

By N- (6- (2- morpholine ethyl) -5-, 6-, 7-, 8- naphthane -2- base) acetamide (0.76mmol) (such as Formulas I - 117-b compound represented) it is dissolved in ethyl alcohol (10mL), sodium hydroxide (10mL, 10mol/L) is added into reaction solution, will react Liquid is heated to return stirring 18 hours.Reaction solution water and ethyl acetate layering, organic phase saturated common salt water washing, anhydrous slufuric acid Sodium dries, filters, and is evaporated, and reaction solution is evaporated to obtain crude product target compound 6- (2- morpholine ethyl) -5-, 6-, 7-, 8- tetra- by crude product Hydrogen naphthalene -2- amine (152mg, 76.7%), gray solid.LC-MS:m/z:[M+1]⁺=261.

Step 3:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Simultaneously [3,4-D] pyrimidine -3- ketone (0.28mmol) (such as formula 1A compound represented) is dissolved in toluene (15mL) azoles, and 3- chlorine peroxide is added Benzoic acid (0.31mmol), reaction solution stir 0.5 hour at room temperature, reaction solution are evaporated, and gained sulfoxide intermediate is dissolved in diformazan 6- (2- morpholine ethyl) -5-, 6-, 7-, 8- naphthane -2- amine (such as Formulas I -117-c compound represented) is added in sulfoxide (10mL) Reaction solution is heated to stirring 16 hours at 60 DEG C by (0.31mmol) and trifluoroacetic acid (0.5mL).Reaction solution saturated sodium carbonate Water (50mL) ethyl acetate (50mL) is added in solution tune pH=9, is layered, organic phase saturated common salt water washing, and anhydrous sodium sulfate is dry Dry, filtering is evaporated, and liquid phase preparation purifies to obtain target compound 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- Base) -6- (6- (2- morpholine ethyl) -5-, 6-, 7-, 8- naphthane -2- base) amino -1,2- dihydro -3H- pyrazolo [3,4-D] is phonetic Pyridine -3- ketone (68mg, 42.6%), white solid.LC-MS:m/z:[M+H]⁺=570.1H NMR(400MHz,CDCl3)δ8.87 (s, 1H), 7.93-7.80 (m, 2H), 7.49-7.35 (m, 2H), 7.26 (d, J=2.2Hz, 1H), 7.05 (d, J=8.3Hz, 1H), 5.72 (d, J=6.7Hz, 1H), 5.01 (ddd, J=18.2,13.6,1.0Hz, 2H), 4.78 (d, J=6.2Hz, 2H), 3.80 (s, 2H), 2.85 (dd, J=8.4,4.4Hz, 2H), 2.70-2.39 (m, 4H), 2.00 (d, J=12.2Hz, 1H), 1.83 (s, 1H), 1.64 (d, J=19.4Hz, 4H), 1.54-1.42 (m, 1H)

Embodiment 119

Step 1:

Bromo- 3,4- dihydronaphthalene -2 (1H) -one (200mg, 0.89mmol) (such as Formulas I -119-a compound represented) of 6- is molten In 10mL methylene chloride, be then added benzylamine (0.14ml, 1.33mmol) and Sodium triacetoxyborohydride (753mg, 3.55mmol), reaction 16h is stirred at room temperature.30ml water is added in reaction solution after being concentrated under reduced pressure, extracted every time with the methylene chloride of 30ml Twice.Merge organic layer concentration, gained crude product crosses column purification (ethyl acetate: petroleum ether=0-33%), obtains brown oil Object (140mg, 0.44mmol), yield 50%.LC-MS:m/z:(M+H)⁺=316.0,318.0.

Step 2:

By (the change as shown in Formulas I -119-b of the bromo- 1,2,3,4- naphthane -2- amine (140mg, 0.44mmol) of N- benzyl -6- Close object) it is dissolved in 10ml methanol, acetaldehyde (0.1ml) and sodium cyanoborohydride (140mg, 2.22mmol), Room is then added Temperature is stirred to react 18h.30ml water is added after being concentrated under reduced pressure in reaction solution, is extracted twice every time with the methylene chloride of 30ml.It is associated with The concentration of machine layer, gained crude product crosses column purification (ethyl acetate: petroleum ether=0-33%), obtain brown oil (102mg, 0.30mmol), yield 67%.LC-MS:m/z:(M+H)⁺=344.1,346.1.

Step 3:

By bromo- N- ethyl -1,2,3,4- naphthane -2- amine (102mg, the 0.30mmol) (such as Formulas I -119-c of N- benzyl -6- Compound represented), benzophenone imine (58mg, 0.32mmol), sodium tert-butoxide (56mg, 0.60mmol), Pd₂(dba)₃ (13mg, 0.015mmol), BINAP (18mg, 0.03mmol) are added in 10ml toluene, and argon gas is taken a breath three times, are then heated to 100 DEG C of reaction 16h.Reaction solution concentration, gained crude product cross column purification (methanol: methylene chloride=0-10%), obtain brown oil Shape object (72mg, 0.16mmol), yield 54%.LC-MS:m/z:(M+H)⁺=445.3.

Step 4:

By N- benzyl -6- ((diphenyl methylene) amino)-N- ethyl -1,2,3,4- naphthane -2- amine (72mg, 0.16mmol) (such as Formulas I -119-d compound represented) is dissolved in 10ml methanol, then be added acetic acid sodium trihydrate (66mg, 0.48mmol) with hydroxylamine hydrochloride (25mg, 0.36mmol), it is heated to 60 degree and reacts 6 hours.Reaction solution filtering and concentrating, gained are thick Product crosses column purification (methanol: methylene chloride=0-20%), obtains brown oil (45mg, 0.16mmol), yield 99%. LC-MS:m/z:(M+H)⁺=281.2.

Step 5:

By 2- allyl -1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methyl mercapto) -1,2- dihydro -3H- pyrrole Azoles simultaneously [3,4-d] pyrimidine -3- ketone (53mg, 0.15mmol) (such as formula 1A compound represented) in the solution of 15ml methylene chloride Be added metachloroperbenzoic acid (37mg, 0.16mmol), acquired solution is stirred at room temperature after 1h solvent is evaporated off after obtain 2- allyl- 1- (6- (2- hydroxy propane -2- base) pyridine -2- base) -6- (methylsulfinyl) -1,2- dihydro -3H- pyrazolo [3,4-d] is phonetic The dichloromethane solution of pyridine -3- ketone.DIPEA (0.08ml) is added in above-mentioned acquired solution, N2- benzyl-N2- ethyl -1,2, 3,4- naphthane -2,6- dimethyl amines (such as Formulas I -119-e compound represented) (44mg, 0.19mmol), 60 degree of stirrings are for 24 hours. It is concentrated under reduced pressure, gained crude product isolates and purifies (7M ammonia methanol: methylene chloride=0-10%) with thin layer chromatography and obtains targeted Close object 51mg, yellow solid, yield 58%.LC-MS:m/z:(M+H)⁺=590.4,¹H NMR(400MHz,MeOD)δ8.79(s, 1H), 7.98 (t, J=7.9Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.67 (d, J=7.7Hz, 1H), 7.52 (s, 1H), 7.40 (d, J=7.1Hz, 2H), 7.35-7.20 (m, 4H), 7.02 (d, J=8.3Hz, 1H), 5.80-5.65 (m, 1H), 5.04 (dd, J=10.2,1.1Hz, 1H), 4.92 (dd, J=17.1,1.3Hz, 1H), 4.83 (d, J=6.0Hz, 2H), 3.77 (s, 2H), 3.08 (s, 1H), 2.84 (dt, J=11.9,10.6Hz, 4H), 2.77-2.65 (m, 2H), 2.14 (d, J=10.0Hz, 1H), 1.71 (dd, J=11.9,5.5Hz, 1H), 1.60 (s, 6H), 1.09 (t, J=7.1Hz, 3H).

Referring to above-described embodiment, 1 compound represented of table is prepared, structural characterization is seen below:

1 embodiment list of table

Effect example 1

One, compound is to WEE1 kinases In-vitro Inhibitory Effect

Test method:

Using ELISA method, test-compound is screened on WEE1 kinases when ATP concentration is Km.? The screening of 3 compounds is carried out on WEE1 kinases, to evaluate the kinase inhibiting activity of test-compound.In detection process, by Examination compound initial concentration is selected as 100nM, and each compound selects 6 gradient dilution concentration, and gradient dilution multiple is 4 Times, 2 multiple holes of every concentration are detected, using MK-1775 as standard control.

WEE1 is purchased from CarnaBiosciences, Inc., article No.: 05-177；Dimethyl sulfoxide is purchased from Sigma- Aldrich, article No.: D8418；ATP is purchased from Sigma-Aldrich, article No.: A7699；DTT solution is purchased from Sigma- Aldrich, article No.: 43816；Protein tyrosine kinase (PTK) substrate (poly-Glu-Tyr), is purchased from Sigma-Aldrich, article No.: P4476；P-Tyr (PY99) is purchased from Santa Cruz, article No.: sc-7020；Anti-mouse IgG HRP-linked Antibody is purchased from Santa Cruz, article No.: 7076S；TMB liquid Substrate System is purchased from Sigma-Aldrich, article No.: T0440；Costar Stripwell Microplate No Lid 1×8 Flat Bottom, Certified High Binding is purchased from Sigma-Aldrich, article No.: 42592；96 hole compound plates, Purchased from Thermo Scientific, article No.: 267245.

Testing procedure:

1, it is coated with substrate: 1) taking the substrate storing liquid protein tyrosine kinase (PTK) of proper volume Substrate (poly-Glu-Tyr) dilutes 10 times with PBS, concentration is diluted to 25mg/mL from 250mg/mL.It is added to In height 96 orifice plates of absorption, every 125 μ L of hole.37 DEG C of incubators are placed into be coated with overnight.2) after for 24 hours, 96 orifice plates is taken out, 96 holes are outwelled Liquid in plate is cleaned 3 times with washing buffer, and 37 DEG C of incubation carton upside downs dry 2h.

2, the preparation and transfer of compound: 1) diluted chemical compound: taking the test-compound storing liquid of 10mM, in 96 hole chemical combination In object plate, compound point multistep is diluted with DMSO, obtain for initial concentration 100 × compound, later again with this concentration Conjunction object is first concentration, carries out 4 times of gradient dilutions using DMSO, dilutes 6 concentration altogether；Take the gradient of 2 μ L dilute respectively later It releases liquid to be added in 1 × reaction buffer of 48 μ L, it is spare to be configured to 4 × compound；2) transfer of 4 × compound: match from upper step 4 × compound that 10 μ L are shifted in the 96 hole compound plates set enters in 96 orifice plates of high absorption of drying；Without compound control hole 1 × reaction buffer of 48 μ L is added with the following liquid that 10 μ L are added in ATP- control wells: the DMSO of 2 μ L.

3, the enzyme reaction stage: 1) using 1 × reaction buffer WEE1 kinases, ATP is respectively configured to 2 × enzyme solutions and 4 × ATP solution.Wherein in this screening, WEE1 kinases it is final concentration of: 0.15ng/ μ L, ATP is final concentration of: 12 μM； 2) 2 enzyme solutions of 20 μ L are added into 96 orifice plates of high absorption；3) 4 × ATP solution of 10 μ L is added into 96 orifice plates of high absorption, ATP- control is empty to be added 10 μ L1 × reaction buffer；4) plate is put in HERAEUS Multifuge X1R centrifuge After 2000rpm is centrifuged 20s, it is placed in room temperature reaction 60min.

4, the reaction terminating stage: 1) outwelling the reaction solution in plate, and 200 μ L washing buffer, cleaning 5 is added in every hole Time；It is added primary antibody P-Tyr (PY99) (dilution ratio 1:2000), every 100 μ L of hole, room temperature 30min.2) primary antibody in plate is outwelled, 200 μ L washing buffer are added in every hole, clean 5 times；Secondary antibody Anti-mouse IgG HRP-linked is added Antibody (dilution ratio 1:2000), every 100 μ L of hole, room temperature 30min.3) secondary antibody in plate is outwelled, washing is used Buffer is washed 5 times, and TMB, every 100 μ L of hole is added, and develop the color 10~30min, depending on shade.It is terminated before reading with 1N sulfuric acid Reaction.

5, detection and data processing: 1) on ThermoScientific MultiScan GO read wavelength 450nM at Light absorption, while background is read at 650nM.2) Log (inhibitor) is carried out to data using Graphpad Prism 5.0 Vs.response-Variable slope (four parameters) curve matching, calculates corresponding IC50 (half maximal inhibitory concentration)。

Two, compound is to 205 cell strain In-vitro Inhibitory Effect of COLO

Test method:

Using Luminescence ATP Detection method, detection compound is to p53 deletion cells strain COLO 205 The inhibiting effect of proliferation.The screening of 4 compounds has been carried out on cell strain, it is external to the cell strain to evaluate test-compound The inhibitory activity of proliferation.In detection process, test-compound initial concentration is selected as 10 μM, selects 9 gradient dilution concentration, ladder Spending extension rate is 3 times, and 2 multiple holes of every concentration are detected, using MK-1775 as standard control.

COLO 205, human colon cancer cell are purchased from Chinese Academy of Sciences's cell bank, catalog number (Cat.No.): TCHu102；ATPlite 1step Single Addition Luminescence ATP Detection Assay system is purchased from PerkinElemer, goods Number: 6016739；RPMI 1640 is purchased from GIBCO, article No.: A10491-01；Strep/pen is purchased from GIBCO, article No.: 15240- 062；Fetal calf serum FBS is purchased from GIBCO, article No.: 10099-141；The 96 saturating tissue culture plates in hole black bottom are purchased from Corning, Article No.: 3603；96 hole compound plates are purchased from Thermo Scientific, article No.: 267245.

Testing procedure:

1, cell culture and inoculation: taking the cell normally cultivated, under its exponential growth state, after digestion dispersion, and adjustment Cell density is to 8.8 × 10³Cells/mL, every 90 μ L of hole are inoculated in 96 porocyte culture plates；By microwell plate after the completion of inoculation 37 DEG C are placed in, 5% CO₂Under conditions of cultivate；

2, agent-feeding treatment cell: taking out microwell plate from incubator, and 10 × change is respectively added in each hole into microwell plate Object is closed, 10 μ L are added in every hole, wherein 2 multiple holes of each administration concentration, each compound totally 9 administration concentrations.According to different The initial concentration of cell strain, each compound is different, microwell plate is placed in 37 DEG C after the completion, 5% CO₂Under conditions of train Support 72h；

3, the acquisition of data: microwell plate is taken out from incubator, equilibrium at room temperature 30min.100 rooms μ l are added in every hole ATPlite reaction solution after temperature balance, 1300rpm room temperature shake 2min, microwell plate are placed in HERAEUS later 2000rpm is centrifuged 1min in Multifuge X1R centrifuge；After equilibrium at room temperature 10min, believe in measuring fluorescence on EnVisionTM Number value.

4, it is calculated by external inhibitory activity of the following equation to compound:

Cell proliferation inhibition rate: inhibiting rate (%)=(signal value control-signal value administration)/signal value control × 100%.And according to the inhibiting rate of each concentration, 50% inhibition concentration (50%inhibitory is calculated using LOGIT method Concentration, IC₅₀).Cell survival rate calculates: Cell viability (%)=signal value administration/signal value control × 100%.Log (inhibitor) is carried out to the fluorescence signal value under each concentration using Graphpad Prism 5.0 Vs.response-Variable slope (four parameters) curve matching, calculates corresponding IC₅₀(half maximal inhibitory concentration)。

Three, the 205 cell strain In-vitro Inhibitory Effect of COLO that compound handles 5-FU

Test method:

This report uses Luminescence ATP Detection method, and detection compound lacks the p53 that 5-FU is handled Lose the inhibiting effect that cell strain COLO 205 is proliferated.The screening of 4 compounds is carried out, on cell strain to evaluate tested chemical combination To the inhibitory activity of the cell strain in-vitro multiplication after object and 5-FU combination.In detection process, 5-FU initial concentration is selected as 100 μ M selects 9 gradient dilution concentration, and gradient dilution multiple is 3 times, and 2 multiple holes of every concentration are detected, and test-compound uses The 5-FU synergy of 300nM and two concentration of 100nM respectively at 9 concentration.MK-1775 is as standard control.

COLO 205, human colon cancer cell are purchased from Chinese Academy of Sciences's cell bank, catalog number (Cat.No.): TCHu102；ATPlite 1step Single Addition Luminescence ATP Detection Assay system is purchased from PerkinElemer, goods Number: 6016739；RPMI 1640 is purchased from GIBCO, article No.: A10491-01；Strep/pen is purchased from GIBCO, article No.: 15240- 062；Fetal calf serum FBS is purchased from GIBCO, article No.: 10099-141；The 96 saturating tissue culture plates in hole black bottom are purchased from Corning, Article No.: 3603；96 hole compound plates are purchased from Thermo Scientific, article No.: 267245；

Testing procedure:

2, agent-feeding treatment cell: taking out microwell plate from incubator, and 10 × 5- is respectively added in each hole into microwell plate FU, 10 μ L are added in every hole, wherein 2 multiple holes of each administration concentration, totally 9 administration concentration control additions contain phase to each compound Microwell plate is placed in 37 DEG C after the completion, 5% CO by the culture medium of solvent DMSO in proportion₂Under conditions of cultivate 72h；

3, agent-feeding treatment cell: taking out microwell plate from incubator, the cell of 9 into microwell plate gradient 5-FU processing And 3300nM 1100nM compound (11 × compound) is added in control wells, 10 μ L are added in every hole, after the completion will be micro- Orifice plate is placed in 37 DEG C, 5% CO₂Under conditions of cultivate 72h；

4, the acquisition of data: microwell plate is taken out from incubator, equilibrium at room temperature 30min.100 rooms μ L are added in every hole ATPlite reaction solution after temperature balance, 1300rpm room temperature shake 2min, microwell plate are placed in HERAEUS later 2000rpm is centrifuged 1min in Multifuge X1R centrifuge；After equilibrium at room temperature 10min, believe in measuring fluorescence on EnVisionTM Number value.

5, it is calculated by external inhibitory activity of the following equation to compound:

Four, test result data.

Control sample structure used in test is shown in Table 2.

2 control sample structure of table

See Table 3 for details for test result.

3 WEE1 enzyme inhibition activity of table and cell inhibitory activity test result

Claims

1. a kind of pyrazolone miazines compound shown in formula I, its enantiomter, its diastereoisomer, its interconversion Isomers, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, feature exist In,

Wherein, X is N or CH；

M and n independently is 0,1,2 or 3, and m+n is 2,3 or 4；

Y is N or CH；

R¹For H, halogen, sulfydryl, nitro, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-C (=NR^1-11)R^1-5,-S (=O) R^1-6,-S (=O)₂R^1-7,-S (=NR^1-12)R^1-8,-S (=NR^1-13) (=NR^1-14)R^1-9,-S (=O) (=NR^1-15)R^1-10, not Substitution or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-17Substituted C₂~C₇Alkenyl, unsubstituted or R^1-18Substituted C₂~C₈ Alkynyl, unsubstituted or R^1-19Substituted C₁~C₇Alkane silicon substrate, unsubstituted or R^1-20Substituted C₃~C₇Naphthenic base, unsubstituted or R^1-21 Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is miscellaneous Naphthenic base ", unsubstituted or R^1-22Substituted C₆~C₁₀Aryl, unsubstituted or R^1-23Replace " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", unsubstituted or R^1-24Substituted C₁~ C₇Alkoxy or unsubstituted or R^1-25Substituted C₁~C₇Alkane sulfydryl；

All R^1-1、R^1-2And R^1-3It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2, unsubstituted or R^1-1-3Substituted C₁~C₇Alkane Base, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen With one of phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-1-1、R^1-1-2And R^1-1-3It independently is C₁~C₇Alkyl, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom For one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9And R^1-10It independently is hydroxyl, C₁~C₇The C that alkyl, halogen replace₁~C₇ Alkyl, halogen, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, C₁~C₇Alkoxy, " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is One of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl " or NR^1-4- ¹R^1-4-2；

All R^1-4-1And R^1-4-2It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl "；

All R^1-11、R^1-12、R^1-13、R^1-14And R^1-15It independently is H, cyano, hydroxyl, C₁~C₇Alkoxy, unsubstituted or R¹ ^-11-1Substituted C₁~C₇Alkyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and One of phosphorus is a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-11-1It independently is halogen, hydroxyl, cyano, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇ Naphthenic base, C₁~C₇Heterocyclylalkyl, C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₁~C₇Heteroaryl " or C₁~C₇Alkoxy；

All R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24And R^1-25It independently is halogen, nitro, cyanogen Base, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, unsubstituted or R^1-16-7Substituted C₃~C₇Cycloalkanes Base, unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R^1-16-2、-OR¹ ^-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6And R^1-16-7It independently is hydrogen, hydroxyl, halogen, cyano, C₁~C₇ Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, One of nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is Heterocyclylalkyl ", halogenated " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl ",-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or R^1-16-5-1-1Replace C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus It is one or more, hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, One of sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16-5-1-1It independently is halogen, hydroxyl, cyano, amino, C₁~C₇Alkyl, C₁~C₇Alkoxy, C₁~C₇Alkane mercapto Base, C₁~C₇Alkane silicon substrate, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and One of phosphorus is a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

Z is 0,1 or 2；

All R²It independently is halogen, hydroxyl, cyano, amino, unsubstituted or R^2-1Substituted C₁~C₇Alkyl, unsubstituted or R² ^-2Substituted C₂~C₈Alkenyl, unsubstituted or R^2-3Substituted C₂~C₇Alkynyl, unsubstituted or R^2-4Substituted C₁~C₇Alkane silicon substrate, not Substitution or R^2-5Substituted C₆~C₁₀Aryl, unsubstituted or R^2-6Replace " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus in C one or more, that hetero atom number is 1~4₁~C₇Heteroaryl ", C₃~C₇Naphthenic base or unsubstituted or R^2-7Replace C₁~C₇Alkoxy；

All R^2-1、R^2-2、R^2-3、R^2-4、R^2-5、R^2-6And R^2-7It independently is halogen, nitro, cyano, C₁~C₇Alkyl, C₂~C₇ Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom is one in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Kind is a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom be boron, silicon, oxygen, sulphur, selenium, One of nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇Alkoxy, C₁~C₇Alkane mercapto Base ,-NR^2-1-1R^2-1-2、-OR^2-1-3、-SR^2-1-4Or-(C=O) R^2-1-5；

All R^2-1-1、R^2-1-2、R^2-1-3And R^2-1-4It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~ C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇ Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl "；

All R^2-1-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom For one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀ Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇It is miscellaneous Aryl "；

Alternatively, two R²It is connected on same carbon atom and unsubstituted or R is collectively formed^2-8Substituted C₃~C₇Naphthenic base or not Substitution or R^2-9Substituted C₁~C₇Heterocyclylalkyl；

2. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is, works as R¹For R^1-16Substituted C₁~C₇When alkyl, the R^1-16Number be one or more, when there are multiple R^1-16 When, the R^1-16It is identical or different；

And/or work as R¹For unsubstituted or R^1-16Substituted C₁~C₇When alkyl, the C₁~C₇Alkyl is C₁~C₄Alkyl；

And/or work as R¹For R^1-17Substituted C₂~C₇When alkenyl, the R^1-17Number be one or more, when there are multiple R^1-17When, the R^1-17It is identical or different；

And/or work as R¹For unsubstituted or R^1-17Substituted C₂~C₇When alkenyl, the C₂~C₇Alkenyl is C₂~C₄Alkenyl；

And/or work as R¹For R^1-18Substituted C₂~C₈When alkynyl, the R^1-18Number be one or more, when there are multiple R^1-18When, the R^1-18It is identical or different；

And/or work as R¹For unsubstituted or R^1-18Substituted C₂~C₈When alkynyl, the C₂~C₈Alkynyl is C₂~C₄Alkynyl；

And/or work as R¹For R^1-19Substituted C₁~C₇When alkane silicon substrate, the R^1-19Number be one or more, when exist it is more A R^1-19When, the R^1-19It is identical or different；

And/or work as R¹For R^1-20Substituted C₃~C₇When naphthenic base, the R^1-20Number be one or more, when exist it is more A R^1-20When, the R^1-20It is identical or different；

And/or work as R¹For unsubstituted or R^1-20Substituted C₃~C₇When naphthenic base, the C₃~C₇Naphthenic base is cyclopropyl, ring Butyl, cyclopenta or cyclohexyl；

And/or work as R¹For R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇When Heterocyclylalkyl ", the R^1-21Number be one or more, when there are multiple R^1-21When, institute The R stated^1-21It is identical or different；

And/or work as R¹For unsubstituted or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₃~C₇When Heterocyclylalkyl ", described " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus It is one or more, hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen and/or oxygen, and hetero atom number is 1 ~2 C₃~C₅Heterocyclylalkyl "；

And/or work as R¹For R^1-22Substituted C₆~C₁₀When aryl, the R^1-22Number be one or more, when there are multiple R^1-22When, the R^1-22It is identical or different；

And/or work as R¹For R^1-23Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₁~C₇When heteroaryl ", the R^1-23Number be one or more, when there are multiple R^1-23When, it is described R^1-23It is identical or different；

And/or work as R¹For R^1-24Substituted C₁~C₇When alkoxy, the R^1-24Number be one or more, when exist it is more A R^1-24When, the R^1-24It is identical or different；

And/or work as R¹For R^1-25Substituted C₁~C₇When alkane sulfydryl, the R^1-25Number be one or more, when exist it is more A R^1-25When, the R^1-25It is identical or different；

And/or work as R^1-1、R^1-2Or R^1-3For unsubstituted or R^1-1-3Substituted C₁~C₇When alkyl, the C₁~C₇Alkyl is C₁~ C₄Alkyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₁~C₇When alkyl, the C₁~C₇Alkyl is C₁~C₄ Alkyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl, the halogen Number is one or more, and when there are multiple halogens, the halogen is identical or different；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl, " halogen " It independently is fluorine, chlorine, bromine or iodine；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl, the C₁~C₇ Alkyl is C₁~C₄Alkyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₂~C₇When alkynyl, the C₂~C₇Alkynyl is C₂~C₄ Alkynyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₁~C₇When alkoxy, the C₁~C₇Alkoxy is C₁~C₄Alkoxy；

And/or work as R^1-4-1Or R^1-4-2For C₁~C₇When alkyl, the C₁~C₇Alkyl is C₁~C₄Alkyl；

And/or work as R^1-11、R^1-12、R^1-13、R^1-14Or R^1-15For R^1-11-1Substituted C₁~C₇When alkyl, the R^1-11-1Number For one or more, when there are multiple R^1-11-1When, the R^1-11-1It is identical or different；

And/or work as R^1-11、R^1-12、R^1-13、R^1-14Or R^1-15For unsubstituted or R^1-11-1Substituted C₁~C₇When alkyl, the C₁ ~C₇Alkyl is C₁~C₄Alkyl；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25When for halogen, the halogen For fluorine, chlorine, bromine or iodine；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For C₁~C₇When alkane silicon substrate, institute The C stated₁~C₇Alkane silicon substrate is trimethyl silicon substrate；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For R^1-16-6" the miscellaneous original replaced Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇When Heterocyclylalkyl ", institute The R stated^1-16-6Number be one or more, when there are multiple R^1-16-6When, the R^1-16-6It is identical or different；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane When base ", described " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃ ~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen and/or oxygen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl "；

And/or work as R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6Or R^1-16-7For C₁~C₇When alkyl, the C₁~C₇Alkyl For C₁~C₄Alkyl；

And/or work as R^1-16-5For " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number is 1~ 4 C₃~C₇When Heterocyclylalkyl ", described " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous original The C that subnumber is 1~4₃~C₇Heterocyclylalkyl " is that " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₃~C₇Heterocyclylalkyl, and it is connect by nitrogen-atoms with carbonyl "；

And/or work as R^1-16-5For halogenated, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇When Heterocyclylalkyl ", the number of the halogen is one or more, when there are multiple halogens, institute The halogen stated is identical or different；

And/or work as R^1-16-5For halogenated, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇When Heterocyclylalkyl ", " halogen " independently is fluorine, chlorine or bromine；

And/or work as R^1-16-5For halogenated, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇When Heterocyclylalkyl ", described " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₇Heterocycle Alkyl, and it is connect by nitrogen-atoms with carbonyl "；

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For R^1-16-5-1-1Substituted C₁~C₇When alkyl, The R^1-16-5-1-1Number be one or more, when there are multiple R^1-16-5-1-1When, the R^1-16-5-1-1It is identical or not Together；

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For unsubstituted or R^1-16-5-1-1Substituted C₁~C₇ When alkyl, the C₁~C₇Alkyl is C₁~C₄Alkyl；

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For C₂~C₇When alkynyl, the C₂~C₇Alkynes Base is C₂~C₄Alkynyl.

3. a kind of pyrazolone miazines compound I as claimed in claim 2, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is, works as R¹For R^1-16Substituted C₁~C₇Alkyl and the R^1-16Number when being multiple, it is described it is multiple be 2,3 It is a or 4；

And/or work as R¹For unsubstituted or R^1-16Substituted C₁~C₇When alkyl, the C₁~C₇Alkyl is methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R¹For R^1-17Substituted C₂~C₇Alkenyl and the R^1-17Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R¹For unsubstituted or R^1-17Substituted C₂~C₇When alkenyl, the C₂~C₇Alkenyl is 2- acrylic；

And/or work as R¹For R^1-18Substituted C₂~C₈Alkynyl and the R^1-18Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R¹For unsubstituted or R^1-18Substituted C₂~C₈When alkynyl, the C₂~C₈Alkynyl is 2-propynyl；

And/or work as R¹For R^1-19Substituted C₁~C₇Alkane silicon substrate and the R^1-19Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R¹For R^1-20Substituted C₃~C₇Naphthenic base and the R^1-20Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R¹For unsubstituted or R^1-20Substituted C₃~C₇When naphthenic base, the C₃~C₇Naphthenic base is cyclobutyl；

And/or work as R¹For R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇Heterocyclylalkyl " and the R^1-21Number when being multiple, it is described it is multiple be 2,3 or 4 It is a；

And/or work as R¹For unsubstituted or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₃~C₇When Heterocyclylalkyl ", described " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus It is one or more, hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen, and hetero atom number is 1~2 C₃~C₅Heterocyclylalkyl " or " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl "；

And/or work as R¹For R^1-22Substituted C₆~C₁₀Aryl and the R^1-22Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R¹For R^1-23Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₁~C₇Heteroaryl " and the R^1-23Number when being multiple, it is described it is multiple be 2,3 or 4；

And/or work as R¹For R^1-24Substituted C₁~C₇Alkoxy and the R^1-24Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R¹For R^1-25Substituted C₁~C₇Alkane sulfydryl and the R^1-25Number when being multiple, it is described it is multiple be 2 It is a, 3 or 4；

And/or work as R^1-1、R^1-2Or R^1-3For unsubstituted or R^1-1-3Substituted C₁~C₇When alkyl, the C₁~C₇Alkyl is first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₁~C₇When alkyl, the C₁~C₇Alkyl be methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl and the halogen Number when being multiple, it is described it is multiple be 2,3 or 4；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl, the C₁~C₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₂~C₇When alkynyl, the C₂~C₇Alkynyl is 2- third Alkynyl or 1- propinyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₁~C₇When alkoxy, the C₁~C₇Alkoxy is Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy；

And/or work as R^1-4-1Or R^1-4-2For C₁~C₇When alkyl, the C₁~C₇Alkyl is methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-11、R^1-12、R^1-13、R^1-14Or R^1-15For R^1-11-1Substituted C₁~C₇Alkyl and the R^1-11-1Number When being multiple, it is described it is multiple be 2,3 or 4；

And/or work as R^1-11、R^1-12、R^1-13、R^1-14Or R^1-15For unsubstituted or R^1-11-1Substituted C₁~C₇When alkyl, the C₁ ~C₇Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25When for halogen, the halogen For fluorine；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For R^1-16-6" the miscellaneous original replaced Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " and institute The R stated^1-16-6Number when being multiple, it is described it is multiple be 2,3 or 4；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane When base ", described " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃ ~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl ", " hetero atom is oxygen, miscellaneous original The C that subnumber is 1~2₃~C₅Heterocyclylalkyl " or

And/or work as R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6Or R^1-16-7For C₁~C₇When alkyl, the C₁~C₇Alkyl For methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-16-5For " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number is 1~ 4 C₃~C₇When Heterocyclylalkyl ", described " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous original The C that subnumber is 1~4₃~C₇Heterocyclylalkyl " is

And/or work as R^1-16-5For halogenated, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇Heterocyclylalkyl " and the R^1-16-5Number when being multiple, it is described it is multiple be 2,3 or 4 It is a；

And/or work as R^1-16-5For halogenated, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇When Heterocyclylalkyl ", " halogen " independently is fluorine；

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For R^1-16-5-1-1Substituted C₁~C₇Alkyl and The R^1-16-5-1-1Number when being multiple, it is described it is multiple be 2,3 or 4；

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For unsubstituted or R^1-16-5-1-1Substituted C₁~C₇ When alkyl, the C₁~C₇Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl；

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For C₂~C₇When alkynyl, the C₂~C₇Alkynes Base is 2-propynyl or 1- propinyl.

4. a kind of pyrazolone miazines compound I as claimed in claim 3, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is, works as R¹For unsubstituted or R^1-16Substituted C₁~C₇When alkyl, the C₁~C₇Alkyl is methyl, ethyl, n-propyl Or isopropyl；

And/or work as R¹For unsubstituted or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅It is miscellaneous When naphthenic base ", described " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl " is that " hetero atom is nitrogen, miscellaneous The C that atomicity is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with Y " or " hetero atom is nitrogen, miscellaneous original The C that subnumber is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by carbon atom with Y "；

And/or work as R¹For unsubstituted or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is that " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅It is miscellaneous When naphthenic base ", described " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl " is

And/or work as R^1-1、R^1-2Or R^1-3For unsubstituted or R^1-1-3Substituted C₁~C₇When alkyl, the C₁~C₇Alkyl is first Base, ethyl, n-propyl or isopropyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₁~C₇When alkyl, the C₁~C₇Alkyl is methyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl, the C₁~C₇ Alkyl is methyl；

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10For C₁~C₇When alkoxy, the C₁~C₇Alkoxy is Methoxyl group；

And/or work as R^1-4-1Or R^1-4-2For C₁~C₇When alkyl, the C₁~C₇Alkyl is methyl；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅When Heterocyclylalkyl ", described " hetero atom is nitrogen, miscellaneous original The C that subnumber is 1~2₃~C₅Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with other groups " or " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocycle Alkyl, and Heterocyclylalkyl is connect by carbon atom with other groups "；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl " is that " hetero atom is oxygen, the C that hetero atom number is 1~2₃~C₅When Heterocyclylalkyl ", described " hetero atom is oxygen, miscellaneous original The C that subnumber is 1~2₃~C₅Heterocyclylalkyl " is

And/or work as R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6Or R^1-16-7For C₁~C₇When alkyl, the C₁~C₇Alkyl For methyl；

And/or work as R^1-16-5For halogenated, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom The C that number is 1~4₃~C₇When Heterocyclylalkyl ", described " halogenated hetero atom is one in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus Kind is a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is

And/or work as R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4Or R^1-16-5-5For unsubstituted or R^1-16-5-1-1Substituted C₁~C₇ When alkyl, the C₁~C₇Alkyl is methyl or ethyl.

5. a kind of pyrazolone miazines compound I as claimed in claim 4, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is, works as R¹For unsubstituted or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₃~C₇Heterocyclylalkyl ", " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocycle alkane Base ", " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl " is that " hetero atom is nitrogen, and hetero atom number is 1~2 A C₃~C₅When Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with Y ", described " hetero atom is nitrogen, and hetero atom number is 1~2 C₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by nitrogen-atoms with Y " be

And/or work as R¹For unsubstituted or R^1-21Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or more Kind, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", " hetero atom be one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or C a variety of, that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅It is miscellaneous Naphthenic base ", " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl " is that " hetero atom is nitrogen, and hetero atom number is 1 ~2 C₃~C₅When Heterocyclylalkyl, and Heterocyclylalkyl is connect by carbon atom with Y ", described " hetero atom is nitrogen, hetero atom The C that number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl is connect by carbon atom with Y " be

And/or work as R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9Or R^1-10The C replaced for halogen₁~C₇When alkyl, the halogen is taken The C in generation₁~C₇Alkyl is trifluoromethyl；

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl ", " hetero atom is nitrogen, hetero atom number is 1~ 2 C₃~C₅Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl It is connect by nitrogen-atoms with other groups " when, " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and it is miscellaneous Naphthenic base is connect by nitrogen-atoms with other groups " be

And/or work as R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24Or R^1-25For unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle Alkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl ", " hetero atom is nitrogen, hetero atom number is 1~ 2 C₃~C₅Heterocyclylalkyl " is that " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and Heterocyclylalkyl It is connect by carbon atom with other groups " when, " hetero atom is nitrogen, the C that hetero atom number is 1~2₃~C₅Heterocyclylalkyl, and it is miscellaneous Naphthenic base is connect by carbon atom with other groups " be

6. a kind of pyrazolone miazines compound I as claimed in claim 5, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is, R¹For following any groups: hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, 2- hydroxyethyl, 2- methoxyl group second Base, 2- methylaminoethyl, 2- dimethyl aminoethyl, cyano methyl, cyano, acetyl group, 2- acrylic, 2-propynyl, two Methylamino, 2- fluoro ethyl, 2,2,2- trifluoroethyl, methoxy acyl group, methylsulfonyl, 2,2,2- trifluoroacetyl group, cyclobutyl, cyclopropyl Ylmethyl, cyclopropyl, diethylamino, diη-propyl amino, dimethylaminomethyl, methoxyl group, hydroxyl, carboxymethyl,

7. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is, X CH；

And/or m and n independently are 0,1,2 or 3, and m+n is 2 or 3；

And/or Y N；

And/or R¹For H, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁ ~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₈Alkynyl, C₃~C₇Naphthenic base or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

And/or all R^1-1、R^1-2And R^1-3It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or R^1-1-3Replace C₁~C₇Alkyl；All R^1-1-1、R^1-1-2And R^1-1-3It independently is C₁~C₇Alkyl or C₆~C₁₀Aryl；

And/or all R^1-4And R^1-7It independently is C₁~C₇The C that alkyl, halogen replace₁~C₇Alkyl, C₂~C₇Alkynyl, C₁~ C₇Alkoxy or NR^1-4-1R^1-4-2；All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

And/or all R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, unsubstituted or R^1-16-7Substituted C₃~ C₇Naphthenic base, unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous original The C that subnumber is 1~4₃~C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；It is all R^1-16-1、R^1-16-2、R^1-16-3、R^1-16-4、R^1-16-6And R^1-16-7It independently is hydrogen or C₁~C₇Alkyl；All R^1-16-5Independently For hydroxyl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is miscellaneous Naphthenic base ", halogenated " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ",-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；All R^1-16-5-1、R^1-16-5-2、 R^1-16-5-3、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁~C₇Alkyl, C₂~C₇Alkynyl or C₃~C₇ Naphthenic base；

And/or z 0.

8. a kind of pyrazolone miazines compound I as claimed in claim 7, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is that m and n independently are 0,1,2 or 3, and m+n is 3；

And/or Y N, and R¹In the atom that is connected with Y be not N；

And/or R¹For-NR^1-1R^1-2、R^1-16Substituted C₁~C₇Alkyl or unsubstituted or R^1-21Replace " hetero atom be boron, One of silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

And/or all R^1-1、R^1-2And R^1-3It independently is hydrogen ,-C (=O) NR^1-1-1R^1-1-2Or unsubstituted or C₆~C₁₀Aryl Substituted C₁~C₇Alkyl；All R^1-1-1And R^1-1-2It independently is C₁~C₇Alkyl；

And/or all R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, C₃~C₇Naphthenic base, unsubstituted or R¹ ^-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~ C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；All R^1-16-1、R^1-16-2、R¹ ^-16-3、R^1-16-4And R^1-16-6It independently is hydrogen or C₁~C₇Alkyl；All R^1-16-5Independently be hydroxyl, " hetero atom be boron, One of silicon, oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", halogenated " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ",-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；All R^1-16-5-1、R^1-16-5-2、R^1-16-5-3、R^1-16-5-4With R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁~C₇Alkyl, C₂~C₇Alkynyl or C₃~C₇Naphthenic base.

9. a kind of pyrazolone miazines compound I as claimed in claim 8, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, it is special Sign is that m and n independently are 1 or 2, and m+n is 3；

And/or all R^1-1、R^1-2And R^1-3It independently is hydrogen or unsubstituted or C₆~C₁₀The C that aryl replaces₁~C₇Alkyl；

And/or all R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, C₃~C₇Naphthenic base, unsubstituted or R¹ ^-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~ C₇Heterocyclylalkyl " ,-NR^1-16-1R^1-16-2、-SR^1-16-4Or-(C=O) R^1-16-5；All R^1-16-1、R^1-16-2、R^1-16-4And R^1-16-6 It independently is hydrogen or C₁~C₇Alkyl；All R^1-16-5Independently be hydroxyl, " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus One of or it is a variety of, hetero atom number is 1~4 C₃~C₇Heterocyclylalkyl ",Or-NR^1-16-5-1R¹ ^-16-5-2；All R^1-16-5-1、R^1-16-5-2、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁~C₇Alkyl, C₂~C₇Alkynyl or C₃~C₇Naphthenic base.

10. a kind of pyrazolone miazines compound I as claimed in claim 9, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, " m 2, n 1 " or " m 1, n 2 "；

And/or all R^1-1And R^1-2It independently is hydrogen or unsubstituted or C₆~C₁₀The C that aryl replaces₁~C₇Alkyl；

And/or all R^1-16And R^1-21It independently is C₁~C₇Alkyl, unsubstituted or R^1-16-6Replace " hetero atom be boron, silicon, One of oxygen, sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " or-(C=O) R^1-16-5； All R^1-16-6It independently is C₁~C₇Alkyl；All R^1-16-5It independently isAll R^1-16-5-4With R^1-16-5-5It independently is C₁~C₇Alkyl.

11. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, X is CH；

" m 1, n 2 " or " m 2, n 1 "；

Y is N or CH；

R¹For H, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-S (=O)₂R^1-7, unsubstituted or R^1-16Substituted C₁~C₇Alkane Base, C₂~C₇Alkenyl, C₂~C₈Alkynyl, C₃~C₇Naphthenic base or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, oxygen, One of sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

All R^1-4And R^1-7It independently is C₁~C₇The C that alkyl, halogen replace₁~C₇Alkyl, C₂~C₇Alkynyl, C₁~C₇Alcoxyl Base or NR^1-4-1R^1-4-2；

All R^1-4-1And R^1-4-2It independently is C₁~C₇Alkyl；

All R^1-16And R^1-21It independently is halogen, cyano, C₁~C₇Alkyl, C₃~C₇Naphthenic base, unsubstituted or R^1-16-6Replace " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base " ,-NR^1-16-1R^1-16-2、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-5It independently is that hydroxyl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous original The C that subnumber is 1~4₃~C₇Heterocyclylalkyl ",Or-NR^1-16-5-1R^1-16-5-2；

All R^1-16-5-1、R^1-16-5-2、R^1-16-5-4And R^1-16-5-5It independently is hydrogen, unsubstituted or hydroxyl generation C₁~C₇Alkyl, C₂ ~C₇Alkynyl or C₃~C₇Naphthenic base；

Z is 0.

12. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, X is CH；

M is 2, n 1；

Y is N or CH；

R¹For-NR^1-1R^1-2、R^1-16Substituted C₁~C₇Alkyl or unsubstituted or R^1-21Replace " hetero atom be boron, silicon, oxygen, One of sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl "；

All R^1-16And R^1-21It independently is C₁~C₇Alkyl, unsubstituted or R^1-16-6Replace " hetero atom be boron, silicon, oxygen, sulphur, One of selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl " or-(C=O) R^1-16-5；

All R^1-16-6It independently is C₁~C₇Alkyl；All R^1-16-5It independently isAll R¹ ^-16-5-4And R^1-16-5-5It independently is C₁~C₇Alkyl；

Z is 0.

13. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, X is N or CH；

M and n independently is 0,1,2 or 3, and m+n is 2,3 or 4；

Y is N or CH；

All R^1-1、R^1-2And R^1-3It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl "；

All R^1-16、R^1-17、R^1-18、R^1-19、R^1-20、R^1-21、R^1-22、R^1-23、R^1-24And R^1-25It independently is halogen, nitro, cyanogen Base, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₁~C₇Alkane silicon substrate, C₃~C₇Naphthenic base, " hetero atom be boron, silicon, oxygen, One of sulphur, selenium, nitrogen and phosphorus are a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl ", C₁~C₇ Alkoxy, C₁~C₇Alkane sulfydryl ,-NR^1-16-1R^1-16-2、-OR^1-16-3、-SR^1-16-4Or-(C=O) R^1-16-5；

All R^1-16-1、R^1-16-2、R^1-16-3And R^1-16-4It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃ ~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~ C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number For 1~4 C₁~C₇Heteroaryl "；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇It is Heterocyclylalkyl ", halogenated " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocycle alkane Base ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 C₁~C₇Heteroaryl " ,-NR^1-16-5-1R^1-16-5-2Or-OR^1-16-5-3；

All R^1-16-5-1、R^1-16-5-2And R^1-16-5-3It independently is hydrogen, unsubstituted or R^1-16-5-1-1Substituted C₁~C₇Alkyl, C₂ ~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus in It is one or more, hetero atom number is 1~4 C₁~C₇Heteroaryl "；

Z is 0,1 or 2；

14. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, X is N or CH；

M and n independently is 0,1,2 or 3, and m+n is 2,3 or 4；

Y is N or CH；

R¹For H, halogen, sulfydryl, nitro, cyano ,-NR^1-1R^1-2、-OR^1-3,-C (=O) R^1-4,-C (=NR^1-11)R^1-5,-S (=O) R^1-6,-S (=O)₂R^1-7,-S (=NR^1-12)R^1-8,-S (=NR^1-13) (=NR^1-14)R^1-9,-S (=O) (=NR^1-15)R^1-10、R¹ ^-16C substituted or unsubstituted₁~C₇Alkyl, R^1-17C substituted or unsubstituted₂~C₇Alkenyl, R^1-18C substituted or unsubstituted₂~C₈Alkynyl, R^1-19C substituted or unsubstituted₁~C₇Alkane silicon substrate, R^1-20C substituted or unsubstituted₃~C₇Naphthenic base, R^1-21It is substituted or unsubstituted " miscellaneous Atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", R^1-22C substituted or unsubstituted₆~C₁₀Aryl, R^1-23It is substituted or unsubstituted that " hetero atom is in boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus C one or more, that hetero atom number is 1~4₁~C₇Heteroaryl ", R^1-24C substituted or unsubstituted₁~C₇Alkoxy or R^1-25C substituted or unsubstituted₁~C₇Alkane sulfydryl；

R^1-1、R^1-2And R^1-3It independently is hydrogen, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " hetero atom For one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~C₁₀ Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇It is miscellaneous Aryl "；

R^1-4、R^1-5、R^1-6、R^1-7、R^1-8、R^1-9And R^1-10It independently is hydroxyl, C₁~C₇Alkyl, halogen, C₂~C₇Alkenyl, C₂~C₇ Alkynyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, and hetero atom number is 1~4 A C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, miscellaneous The C that atomicity is 1~4₁~C₇Heteroaryl " or NR^1-4-1R^1-4-2；

R^1-11、R^1-12、R^1-13、R^1-14And R^1-15It independently is H, cyano, hydroxyl, C₁~C₇Alkoxy, R^1-11-1It is substituted or unsubstituted C₁~C₇Alkyl, C₃~C₇Naphthenic base, " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, hetero atom number For 1~4 C₃~C₇Heterocyclylalkyl ", C₆~C₁₀Aryl or " hetero atom be boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus in one Kind is a variety of, the C that hetero atom number is 1~4₁~C₇Heteroaryl "；

All R^1-16-5It independently is hydroxyl, C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl, C₃~C₇Naphthenic base, " miscellaneous original Son is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₃~C₇Heterocyclylalkyl ", C₆~ C₁₀Aryl or " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, the C that hetero atom number is 1~4₁~C₇ Heteroaryl "；

Z is 0,1 or 2；

All R²It independently is halogen, hydroxyl, cyano, amino, R^2-1C substituted or unsubstituted₁~C₇Alkyl, R^2-2Replace or not Replace C₂~C₈Alkenyl, R^2-3C substituted or unsubstituted₂~C₇Alkynyl, R^2-4C substituted or unsubstituted₁~C₇Alkane silicon substrate, R^2-5Replace or Unsubstituted C₆~C₁₀Aryl, R^2-6Substituted or unsubstituted " hetero atom is one of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus or a variety of, The C that hetero atom number is 1~4₁~C₇Heteroaryl " or R^2-7C substituted or unsubstituted₁~C₇Alkoxy；

Alternatively, two R²It is connected on same carbon atom and R is collectively formed^2-8C substituted or unsubstituted₃~C₇Naphthenic base or R^2-9 C substituted or unsubstituted₁~C₇Heterocyclylalkyl；

15. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, X is CH；

" m 2, n 0 ", " m 1, n 1 " or " m 2, n 1 "；

Y is N；

R¹For H, cyano ,-NR^1-1R^1-2,-C (=O) R^1-4、R^1-16C substituted or unsubstituted₁~C₇Alkyl, C₂~C₇Alkenyl or C₂~ C₇Alkynyl；

R^1-1And R^1-2It independently is C₁~C₇Alkyl；

R^1-4It independently is C₁~C₇Alkyl or C₂~C₇Alkynyl；

All R^1-16It independently is cyano ,-NR^1-16-1R^1-16-2Or-OR^1-16-3；

Z is 0.

16. a kind of pyrazolone miazines compound I as described in claim 1, its enantiomter, its diastereo-isomerism Body, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug, It is characterized in that, the compound I is following any compound:

17. a kind of preparation method of the compound I as described in any one of claim 1~16, which is characterized in that it is as follows Either method:

Method one:

It includes the following steps: that compound 1A is aoxidized, and obtains compound 1B, compound 1D is obtained after substitution, deprotection obtains Compound 1E；

Wherein, PG is amino protecting group；

Method two:

It includes the following steps: that compound 1A is aoxidized, and obtains compound 1B, and compound 2B is obtained after reacting with 2A；

Method three:

Work as R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-17Substituted C₂~C₇Alkenyl, unsubstituted or R^1-18 Substituted C₂~C₈Alkynyl or unsubstituted or R^1-20Substituted C₃~C₇When naphthenic base comprising following step: in organic solvent In, in the presence of a reducing agent, by compound 1E and R¹- CHO carries out reductive amination process, obtains compound I；

Wherein, Y N, the R^1’-CH₂It is equal to R¹；

Method four:

Work as R¹For unsubstituted or R^1-16Substituted C₁~C₇Alkyl, unsubstituted or R^1-17Substituted C₂~C₇Alkenyl, unsubstituted or R^1-18 Substituted C₂~C₈Alkynyl, unsubstituted or R^1-20Substituted C₃~C₇When naphthenic base, cyano or acetyl group comprising following step: In organic solvent, in the presence of base, by compound 1E and R¹-X¹Substitution reaction is carried out, compound I is obtained；

Wherein, the X¹For halogen；Y is N；

Method five:

Work as R¹For-C (=O) R^1-4, and R^1-4For C₁~C₇Alkyl, C₂~C₇Alkenyl, C₂~C₇Alkynyl or C₃~C₇When naphthenic base, Include the following steps: in organic solvent, in the presence of condensing agent, by compound 1E, withCondensation reaction is carried out, Obtain compound I；

Wherein, Y N.

18. one kind is such as formula 1C, 1D or 2A compound represented:

Wherein, PG, m, n, z, Y, R¹And R²Definition as described in any one of claim 1~17.

19. a kind of compound I as described in any one of claim 1~16, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug are being made Application in standby kinase inhibitor.

20. a kind of compound I as described in any one of claim 1~16, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug are being made Application in standby drug, the drug is for treating and/or preventing disease related with WEE1 kinases.

21. a kind of compound I as described in any one of claim 1~16, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug are being made Application in standby drug, the drug is for treatment and/or pre- anti-cancer.

22. a kind of pharmaceutical composition, it includes compound I, its enantiomerisms as described in any one of claim 1~16 Body, its diastereoisomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolism produce Object or its prodrug, and, pharmaceutic adjuvant.

23. a kind of combination, it includes as described in any one of claim 1~16 compound I, its enantiomter, its is non- Enantiomter, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its medicine Object precursor, and, anticancer drug.

24. the application of one kind combination as claimed in claim 23 in medicine preparation, the drug is for treating and/or in advance Anti-cancer.

25. a kind of compound I as described in any one of claim 1~16, its enantiomter, its diastereoisomer, Its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug are being made Application in standby drug, the drug are treated and/or are prevented for " and anti-cancer agent in combination as claimed in claim 23 " Cancer.

26. a kind of application of anticancer drug as claimed in claim 23 in medicine preparation, the drug is for " and joint Compound I, its enantiomter, its diastereoisomer, its tautomerism as described in any one of claim 1~16 Body, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its prodrug " treatment and/or prevention Cancer.

27. a kind of pharmaceutical composition, it includes combination as claimed in claim 23 and pharmaceutic adjuvants.

28. a kind of Combined drug box, it includes pharmaceutical composition As and pharmaceutical composition B；

The pharmaceutical composition A include compound I as described in any one of claim 1~16, its enantiomter, its Diastereoisomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolite or its Prodrug, and, pharmaceutic adjuvant；

The pharmaceutical composition B includes anticancer drug and pharmaceutic adjuvant as claimed in claim 23.