WO2019096322A1

WO2019096322A1 - Pyrazolone-pyrimidine compound, preparation method therefor and application thereof

Info

Publication number: WO2019096322A1
Application number: PCT/CN2018/116352
Authority: WO
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: 上海医药集团股份有限公司
Priority date: 2017-11-20
Filing date: 2018-11-20
Publication date: 2019-05-23
Also published as: CN109810111A; CN109810111B

Abstract

Disclosed are a pyrazolone-pyrimidine compound, a preparation method therefor and an application thereof. The present invention provides a pyrazolone-pyrimidine compound as represented by formula (I), and an enantiomer, a diastereomer, a tautomer, a crystalline form, a pharmaceutically-acceptable salt, a solvate, a metabolite, or a prodrug thereof. The compound has a high inhibiting activity for WEE1 kinase.

Description

Pyrazolone pyrimidine compound, preparation method and application thereof

This application claims priority from Chinese Patent Application No. CN201711159964.0, filed on Nov. 20, 2017. The present application claims priority from Chinese Patent Application No. CN201810968776.0, filed on Aug. 23, 2018. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The invention relates to a pyrazolone pyrimidine compound, a preparation method thereof and application thereof.

Background technique

The cell cycle is closely related to the DNA damage repair process. The cell cycle refers to the whole process that cell division undergoes, and is divided into two phases: interphase and mitotic phase (M). The cell cycle checkpoint is a key point in regulating the cell cycle. The main function is to ensure that each event in the cycle can be completed in time and in order, and the cell state is adjusted to suit the external environment. The main test points of the cells are: 1) G ₁ /S checkpoint: called R (restriction) point in mammals, control cells from the stationary G ₁ phase into the DNA synthesis phase; 2) S phase checkpoint: DNA replication Whether it is completed; 3) G ₂ /M checkpoint: is the control point that regulates the cell into the splitting phase; 4) the middle-late checkpoint: also known as the spindle assembly checkpoint, if the centromere is not properly connected to the spindle , it will cause the interruption of the cell cycle. If there are abnormalities in some processes in the cell division cycle, such as DNA damage, the checkpoint will sense it in time and initiate repair. P53 protein is an important protein regulating G ₁ checkpoint. When DNA is damaged, it prevents cells from entering S phase and activates DNA repair mechanism, which is essential for maintaining the integrity of cell genome. However, due to the presence of P53 mutations in tumor cells, the G1 checkpoint is defective, so the cell division cycle regulation in P53 mutant cells depends on the G ₂ /M checkpoint. WEE1 kinase is a cell cycle regulatory protein that regulates the phosphorylation status of cyclin-dependent kinase 1 (CDK1), thereby regulating the activity of CDK1 and cyclinB complexes. Regulation of the cell cycle and an important regulatory role for DNA damage checkpoints. WEE1 is a key gene for G ₂ /M phase arrest and plays an important role in monitoring. Overexpression in some cancers, inhibition or down-regulation of WEE1 kinase can trigger mitotic catastrophe, so WEE1 kinase inhibitors are key in anticancer therapy. The role has become a hot spot for research and development of anticancer agents.

Some small molecule WEE1 kinase inhibitors are disclosed in international patent applications WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, WO2004007499, etc., but there is currently no small molecule WEE1 kinase inhibitor listed, and there is a need to develop new anticancer activity in the field. A highly safe WEE1 kinase inhibitor.

Summary of the invention

The technical problem to be solved by the present invention is that the existing compound has poor inhibitory activity against WEE1 kinase, and therefore, the present invention provides a pyrazolone pyrimidine compound, a preparation method thereof and application thereof, and the compound inhibits WEE1 kinase The activity is better.

The present invention provides a pyrazolone pyrimidine compound of the formula I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable form thereof. Accepted salt, solvate thereof, metabolite thereof or prodrug thereof;

Where X is N or CH;

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

Y is N or CH;

R ¹ is H, halogen, fluorenyl, nitro, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -C(=NR ^1-11 R ¹ ⁵ , -S(=O)R ^1-6 , -S(=O) ₂ R ^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 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl { , the number of R ^1-16 is one or more [for example, 2, 3 or 4], when there are a plurality of R ^1-16 , the R ^{1-16 is the} same or different; a C ₁ -C ₇ alkyl group such as a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, For example, methyl, ethyl, n-propyl or isopropyl}, unsubstituted or R ^1-17 substituted C ₂ -C ₇ alkenyl {wherein the number of R ^1-17 is one or more [eg 2 , 3 or 4], when a plurality of R ^1-17 are present, the R ^{1-17 is the} same or different; wherein the "C ₂ -C ₇ alkenyl" is, for example, C ₂ - C ₄ An alkenyl group, for example, a 2-propenyl group, an unsubstituted or a R ^1-18 substituted C ₂ -C ₈ alkynyl group {wherein the number of R ^1-18 is one or more [eg 2, 3 or 4 Wherein R ^{1-18 is the} same or different when a plurality of R ^1-18 are present; wherein the "C ₂ -C ₇ alkynyl group" is, for example, a C ₂ -C ₄ alkynyl group, for example 2 a propynyl group, an unsubstituted or a R ^1-19 substituted C ₁ -C ₇ alkyl group {wherein the number of R ^1-19 is one or more [eg 2, 3 or 4], When a plurality of R ^1-19 are present, the R ^{1-19 is the} same or different}, unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl {wherein the number of R ^1-20 is One or more [eg 2, 3 or 4], when a plurality of R ^1-20 are present, said R ^{1-20 are the} same or different; said "C ₃ -C ₇ cycloalkyl" For example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and, for example, cyclobutyl}, unsubstituted or R ^1-21 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. One or more, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms" {wherein the number of R ^1-21 is one or more [for example, 2, 3 or 4 ^Wherein , when a plurality of R ^1-21 are present, said R ^{1-21 is the} same or different; said "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus Kind, C ₃ ~ C ₇ heterocycloalkyl alkyl group having 1 to 4 atoms of "example" is a heteroatom or an oxygen atom, the number of nitrogen and / or hetero atoms of 1 or 2 of C ₃ ~ C ₅ heterocycloalkyl ", and For example, "a nitrogen hetero atom, hetero atom number of 1 to 2 is C ₃ ~ C ₅ heterocycloalkyl" or "hetero atom is oxygen, the number of hetero atoms of 1 or 2 of C ₃ ~ C ₅ heterocycloalkyl base". The "heteroatom is nitrogen, the number of hetero atoms of 1 or 2 of C ₃ ~ C ₅ heterocycloalkyl" e.g. "hetero atom is nitrogen, the number of hetero atoms of 1 or 2 hetero C ₃ ~ C ₅ a cycloalkyl group, and a heterocycloalkyl group is bonded to Y through a nitrogen atom" or "a hetero atom is a nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is passed through a carbon atom. Connect with Y". The "hetero atom is nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a nitrogen atom", for example

The "hetero atom is nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a carbon atom", for example

The "hetero atom is oxygen, and the C ₃ - C ₅ heterocycloalkyl group having 1 to 2 hetero atoms" is, for example,

}, unsubstituted or R ^1-22 substituted C ₆ -C ₁₀ aryl {wherein the number of R ^1-22 is one or more [eg 2, 3 or 4], when there are multiple R ^{1 to} ²² , the R ^{1-22 is the} same or different}, unsubstituted or R ^1-23 substituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms" {wherein the number of R ^1-23 is one or more [for example, 2, 3 or 4], when there are a plurality of When R ^1-23 , the R ^{1-23 is the} same or different}, unsubstituted or R ^1-24 substituted C ₁ -C ₇ alkoxy {wherein the number of R ^1-24 is one or more [e.g., 2, 3 or 4], when a plurality of R ^1-24 are present, the R ^{1-24 is the} same or different}, or the unsubstituted or R ^1-25 substituted C ₁ - C ₇ Alkyl group {wherein the number of R ^1-25 is one or more [for example, 2, 3 or 4], and when there are a plurality of R ^1-25 , the R ^{1-25 is the} same or different} ;

All R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, -C(=O)NR ^1-1-1 R ^1-1-2 , unsubstituted or substituted by R ^1-1-3 a C ₁ -C ₇ alkyl group (for example, a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, Further, for example, methyl, ethyl, n-propyl or isopropyl}, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ cycloalkyl, "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group or a "hetero atom" , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₁ -C ₇ heteroaryl having 1 to 4 hetero atoms";

All R ^1-1-1 , R ^1-1-2 and R ^{1-1-3 are} independently C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group or a "hetero atom" , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₁ -C ₇ heteroaryl having 1 to 4 hetero atoms";

All R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 and R ^{1-10 are} independently hydroxy, C ₁ -C ₇ alkyl {eg C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further methyl, halo substituted C ₁ to C ₇ alkyl {wherein the number of halogens is one or more [for example, 2, 3 or 4], and when a plurality of halogens are present, the halogens are the same or different; "Independently, it is fluorine, chlorine, bromine or iodine; the "C ₁ -C ₇ alkyl group" is, for example, a C ₁ -C ₄ alkyl group, and further, for example, methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; said "halogen-substituted C ₁ -C ₇ alkyl" such as trifluoromethyl}, halogen, C ₂ -C ₇ ene a C ₂ -C ₇ alkynyl group (for example, a C ₂ -C ₄ alkynyl group, for example, a 2-propynyl group or a 1-propynyl group), a C ₃ -C ₇ cycloalkyl group, a C ₁ -C ₇ alkoxy group groups {e.g. C ₁ ~ C ₄ alkoxy group, and for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert Alkoxy, such as methoxy} and "one or more hetero atoms, number of heteroatoms boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus in the range of 1 to 4 hetero C ₃ ~ C ₇ a cycloalkyl group, a C ₆ -C ₁₀ aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C ₁ to have 1 to 4 hetero atoms. C ₇ heteroaryl", or, NR ^1-4-1 R ^1-4-2 ;

All R ^1-4-1 and R ^{1-4-2 are} independently hydrogen, C ₁ -C ₇ alkyl {eg C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, iso a propyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group, a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ to C ₁₀ An aryl group or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

All R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 and R ^{1-15 are} independently H, cyano, hydroxy, C ₁ -C ₇ alkoxy, unsubstituted or R ^{1 1-11-1} substituted C ₁ -C ₇ alkyl {wherein the number of R ^1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R ^1-11 are present ^{When -1} , the R ^{1-11-1 is the} same or different; the "C ₁ -C ₇ alkyl" is, for example, a C ₁ -C ₄ alkyl group, and further, for example, a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl}, C ₃ -C ₇ cycloalkyl, "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus Or a plurality of C ₃ -C ₇ heterocycloalkyl groups having a hetero atom number of 1 to 4, a C ₆ -C ₁₀ aryl group, or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

All R ^{1-11-1 are} independently halogen, hydroxy, cyano, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkane, C ₃ -C ₇ naphthenic a C ₁ -C ₇ heterocycloalkyl group, a C ₆ -C ₁₀ aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ～4 C ₁ -C ₇ heteroaryl" or C ₁ -C ₇ alkoxy;

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 ^1-24 and R ^{1- 25 is} independently halogen {e.g., fluorine, chlorine, bromine or iodine, for example, fluorine}, nitro, cyano, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkylsilyl {e.g. trimethylsilyl}, unsubstituted or R ^1-16-7 substituted C ₃ -C ₇ cycloalkyl, unsubstituted or R ^1- ^16-6 substituted "hetero The atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms" {where R ^1-16- The number of ⁶ is one or more [for example, 2, 3 or 4], and when there are a plurality of R ^1-16-6 , the R ^{1-16-6 are the} same or different; The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms. For example, "the hetero atom is nitrogen and / or oxygen hetero atoms, the number 1 or 2 of C ₃ ~ C ₅ heterocycloalkyl ", and such as" hetero atom is nitrogen, the number of hetero atoms, C ₃ ~ C ₅ heterocycloalkyl group of 1 to 2 "," C _{3 where the} hetero atom is oxygen and the number of hetero atoms is 1 or 2 ~C ₅ heterocycloalkyl" or

The "heteroatom is nitrogen, the number of hetero atoms of 1 or 2 of C ₃ ~ C ₅ heterocycloalkyl" e.g. "hetero atom is nitrogen, the number of hetero atoms of 1 or 2 hetero C ₃ ~ C ₅ a cycloalkyl group, and a heterocycloalkyl group is bonded to another group [for example, C ₁ -C ₇ alkyl group] through a nitrogen atom or a C ₃ -C ₅ hetero atom having a hetero atom of nitrogen and having 1 to 2 hetero atoms. A cycloalkyl group, and a heterocycloalkyl group is bonded to another group [for example, C ₁ -C ₇ alkyl group] through a carbon atom. The "hetero atom is nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a nitrogen atom", for example

The "hetero atom is nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a carbon atom", for example

}, C ₆ -C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₁ -C ₇ heteroatoms having 1 to 4 heteroatoms Aryl", C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkanoyl, -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 Or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 , R ^1-16-4 , R ^1-16-6 and R ^{1-16-7 are} independently hydrogen, hydroxy, Halogen, cyano, C ₁ -C ₇ alkyl {eg C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl, for example, methyl}, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

All R ^{1-16-5 are} independently a hydroxyl group, a C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms" {eg "heteroatoms are boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom, and The atom is one or more of oxygen, sulfur and nitrogen, a C ₃ -C ₇ heterocycloalkyl group having 1 to 2 hetero atoms, and which is bonded to the carbonyl group through a nitrogen atom, for example

}, halogenated "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ -C ₇ heterocycloalkyl having 1 to 4 heteroatoms" { Wherein the "halogen" is independently fluorine, chlorine or bromine; the number of said halogens is one or more [for example, 2, 3 or 4], when a plurality of halogens are present, The halogens are the same or different; the "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the C ₃ -C ₇ heterocyclic ring having 1 to 4 hetero atoms. The alkyl group "for example, "a hetero atom is nitrogen, a C ₃ -C ₇ heterocycloalkyl group having 1 to 2 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom". The "halogenated hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms" E.g

}, C ₆ -C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₁ -C ₇ heteroatoms having 1 to 4 heteroatoms Aryl",

-NR ^1-16-5-1 R ^1-16-5-2 or -OR ^1-16-5-3 ;

All R ^1-16-5-1 , R ^1-16-5-2 , R ^1-16-5-3 , R ^1-16-5-4 and R ^{1-16-5-5 are} independently hydrogen , ^R 1-16-5-1- ¹ unsubstituted or substituted with C ₁ ~ C ₇ alkyl group {wherein ^R 1-16-5-1-1 number of one or more [e.g., 2, 3 Or 4], when a plurality of R ^1-16-5-1-1 are present, the R ^{1-16-5-1-1 is the} same or different; the "C ₁ -C ₇ alkyl group" For example "C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, again such as methyl or ethyl} a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group (for example, a C ₂ -C ₄ alkynyl group, for example, a 2-propynyl group or a 1-propynyl group), a C ₃ -C ₇ cycloalkyl group, "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ to C ₁₀ An aryl group or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

All R ^{1-16-5-1-1 are} independently halogen, hydroxy, cyano, amino, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkanoyl, C ₁ to C ₇ alkylsilyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

z is 0, 1 or 2;

All R ^{2 are} independently halogen, hydroxy, cyano, amino, unsubstituted or R ^2-1 substituted C ₁ -C ₇ alkyl {wherein the number of R ^2-1 is one or more [eg 2 , 3 or 4], when a plurality of R ^2-1 are present, the R ^{2-1 is the} same or different}, unsubstituted or R ^2-2 substituted C ₂ -C ₈ alkenyl {where The number of R ^2-2 is one or more [for example, 2, 3 or 4], and when a plurality of R ^2-2 are present, the R ^{2-2 is the} same or different}, unsubstituted or R ^2-3 substituted C ₂ -C ₇ alkynyl {wherein the number of R ^2-3 is one or more [for example, 2, 3 or 4], when a plurality of R ^2-3 are present, R ^{2-3 is the} same or different}, unsubstituted or R ^2-4 substituted C ₁ -C ₇ alkyl group {wherein the number of R ^2-4 is one or more [for example, 2, 3 Or 4], when a plurality of R ^2-4 are present, the R ^{2-4 is the} same or different}, unsubstituted or R ^2-5 substituted C ₆ -C ₁₀ aryl {where R ^2-5 The number is one or more [for example, 2, 3 or 4], when a plurality of R ^2-5 are present, the R ^{2-5 is the} same or different}, unsubstituted or substituted by R ^2-6 "The heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen. One or more of the number of phosphorus heteroatoms is 1 to 4 of C ₁ ~ C ₇ heteroaryl "{wherein, R ^2-6 is the number of one or more [e.g. 2, 3 or 4], when a plurality of R ^2-6 are present, the R ^{2-6 is the} same or different}, a C ₃ -C ₇ cycloalkyl group, or an unsubstituted or R ^2-7 substituted C ₁ -C ₇ alkoxy {wherein the number of R ^2-7 is one or more [eg 2, 3 or 4], when a plurality of R ^2-7 are present, the R ^{2-7 is the} same or different};

{When z is 2, both R ² are hydroxyl groups and are attached to the same carbon atom, which means that two R ² together with the carbon atom to which they are attached form a carbonyl group}

All of R ^2-1 , R ^2-2 , R ^2-3 , R ^2-4 , R ^2-5 , R ^2-6 and R ^{2-7 are} independently halogen, nitro, cyano, C ₁ ～ C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C ₁ -C ₇ heteroaryl having 1 to 4 hetero atoms", C ₁ -C ₇ alkoxy group, C ₁ -C ₇ Alkyl fluorenyl, -NR ^2-1-1 R ^2-1-2 , -OR ^2-1-3 , -SR ^2-1-4 or -(C=O)R ^2-1-5 ;

All R ^2-1-1 , R ^2-1-2 , R ^2-1-3 and R ^{2-1-4 are} independently hydrogen, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C ₃ -C ₇ heterocycloalkyl", C ₆ -C ₁₀ aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C ₁ -C ₇ heteroaryl groups";

All R ^{2-1-5 are} independently a hydroxyl group, a C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ -C ₁₀ aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

Alternatively, two R ² linkages together form an unsubstituted or R ^2-8 substituted C ₃ -C ₇ cycloalkyl group on the same carbon atom {wherein the number of R ^2-8 is one or more [eg 2 , 3 or 4], when a plurality of R ^2-8 are present, the R ^{2-8 is the} same or different}, or the unsubstituted or R ^2-9 substituted C ₁ -C ₇ heterocycloalkyl Wherein the number of R ^2-9 is one or more [eg 2, 3 or 4], and when a plurality of R ^2-9 are present, the R ^{2-9 is the} same or different; "C ₁ -C ₇ heterocycloalkyl" such as "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ of a heteroatom number of 1 to 4" C ₇ heterocycloalkyl"};

All R ^2-8 and R ^{2-9 are} independently halogen, cyano, fluorenyl, hydroxy, amino, C ₁ -C ₇ alkoxy or C ₁ -C ₇ alkanoyl.

In one embodiment, the compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate The definition of each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):

X is CH.

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

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

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

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

Y is N.

Y is N, and the atom connected to Y in R ¹ is not N.

Y is CH.

R ¹ is H, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -S(=O) ₂ R ^1-7 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₇ cycloalkyl, or unsubstituted or R ^1-21 substituted "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms."

R ¹ is -NR ^1-1 R ^1-2 , R ^1-16 substituted C ₁ -C ₇ alkyl, or unsubstituted or R ^1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms.

All R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, -C(=O)NR ^1-1-1 R ^1-1-2 , or unsubstituted or R ^{1-1- 3-} substituted C ₁ -C ₇ alkyl;

All of R ^1-1-1 , R ^1-1-2 and R ^{1-1-3 are} independently a C ₁ -C ₇ alkyl group or a C ₆ -C ₁₀ aryl group.

All R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, -C(=O)NR ^1-1-1 R ^1-1-2 , or unsubstituted or C ₆ -C ₁₀ An aryl substituted C ₁ -C ₇ alkyl group;

All R ^1-1-1 and R ^{1-1-2 are} independently C ₁ -C ₇ alkyl.

All of R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, or an unsubstituted or C ₆ -C ₁₀ aryl-substituted C ₁ -C ₇ alkyl group.

All R ^1-1 and R ^{1-2 are} independently hydrogen, -C(=O)NR ^1-1-1 R ^1-1-2 , or unsubstituted or C ₆ -C ₁₀ aryl substituted C ₁ to C ₇ alkyl; all R ^1-1-1 and R ^{1-1-2 are} independently C ₁ -C ₇ alkyl.

All R ^1-1 and R ^{1-2 are} independently hydrogen, or an unsubstituted or C ₆ -C ₁₀ aryl-substituted C ₁ -C ₇ alkyl group.

All R ^1-4 and R ^{1-7 are} independently C ₁ -C ₇ alkyl, halogen-substituted C ₁ -C ₇ alkyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, Or, NR ^1-4-1 R ^1-4-2 ;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl.

All R ^1-16 and R ^{1-21 are} independently halogen, cyano, C ₁ -C ₇ alkyl, unsubstituted or R ^1-16-7 substituted C ₃ -C ₇ cycloalkyl, unsubstituted or The R ^1-16-6 substituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ -C ₇ heterocycloalkane having 1 to 4 hetero atoms. "," NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -(C=O)R ^1-16- ⁵ ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 , R ^1-16-4 , R ^1-16-6 and R ^{1-16-7 are} independently hydrogen or C ₁ ～C ₇ alkyl;

All of R ^{1-16-5 are} independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C ₃ of a heteroatom number of 1 to 4" C ₇ heterocycloalkyl", halogenated "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ - C ₇ having 1 to 4 hetero atoms Heterocycloalkyl",

-NR ^1-16- ^5-1 R ^1-16-5-2 or -OR ^1-16-5-3 ;

All R ^1-16-5-1 , R ^1-16-5-2 , R ^1-16-5-3 , R ^1-16-5-4 and R ^{1-16-5-5 are} independently hydrogen An unsubstituted or hydroxy C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkynyl group, or a C ₃ -C ₇ cycloalkyl group.

All R ^1-16 and R ^{1-21 are} independently halogen, cyano, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, unsubstituted or R ¹ ^16-6 substituted "heteroatom" Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 , R ^1-16-4 and R ^{1-16-6 are} independently hydrogen or C ₁ -C ₇ alkyl;

-NR ^1-16- ^5-1 R ^1-16-5-2 or -OR ^1-16-5-3 ;

All R ^1-16 and R ^{1-21 are} independently halogen, cyano, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, unsubstituted or R ¹ ^16-6 substituted "heteroatom" Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", -NR ^1-16-1 R ^1-16-2 , -SR ^1-16-4 or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-4 and R ^{1-16-6 are} independently hydrogen or C ₁ -C ₇ alkyl;

All of R ^{1-16-5 are} independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C ₃ of a heteroatom number of 1 to 4" C ₇ heterocycloalkyl",

Or -NR ^1-16-5-1 R ^1-16-5-2 ;

All R ^1-16-5-1 , R ^1-16-5-2 , R ^1-16-5-4 and R ^{1-16-5-5 are} independently hydrogen, unsubstituted or hydroxy C ₁ a C ₇ alkyl group, a C ₂ -C ₇ alkynyl group, or a C ₃ -C ₇ cycloalkyl group.

All R ^1-16 and R ^{1-21 are} independently C ₁ -C ₇ alkyl, unsubstituted or R ^1-16-6 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms", -OR ^1-16-3 or -(C=O)R ^1-16-5 ;

All R ^1-16-3 and R ^{1-16-6 are} independently C ₁ -C ₇ alkyl; all R ^{1-16-5 are} independently

All R ^1-16-5-4 and R ^{1-16-5-5 are} independently C ₁ -C ₇ alkyl.

All R ^1-16 and R ^{1-21 are} independently C ₁ -C ₇ alkyl, unsubstituted or R ^1-16-6 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, a C ₃ -C ₇ heterocycloalkyl group having a hetero atom number of 1 to 4" or -(C=O)R ^1- ^16-5 ;

All R ^{1-16-6 are} independently C ₁ -C ₇ alkyl; all R ^{1-16-5 are} independently

All R ^1-16-5-4 and R ^{1-16-5-5 are} independently C ₁ -C ₇ alkyl.

R ¹ is any of the following groups: hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-methylaminoethyl, 2-Dimethylaminoethyl, cyanomethyl, cyano, acetyl, 2-propenyl, 2-propynyl, dimethylamino, 2-fluoroethyl, 2,2,2-trifluoro Ethyl, methoxyl, methylsulfonyl, 2,2,2-trifluoroacetyl, cyclobutyl, cyclopropylmethyl, cyclopropyl, diethylamino, di-n-propylamino, dimethyl Aminomethyl, methoxy, hydroxy, carboxymethyl,

z is 0.

X is CH;

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

Y is N or CH;

R ¹ is H, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -S(=O) ₂ R ^1-7 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₇ cycloalkyl, or unsubstituted or R ^1-21 substituted "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms";

All R ^1-1-1 , R ^1-1-2 and R ^{1-1-3 are} independently C ₁ -C ₇ alkyl or C ₆ -C ₁₀ aryl;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl;

-NR ^1-16- ^5-1 R ^1-16-5-2 or -OR ^1-16-5-3 ;

All R ^1-16-5-1 , R ^1-16-5-2 , R ^1-16-5-3 , R ^1-16-5-4 and R ^{1-16-5-5 are} independently hydrogen An unsubstituted or hydroxy C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkynyl group, or a C ₃ -C ₇ cycloalkyl group;

z is 0.

X is CH;

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

Y is N or CH;

All R ^1-1-1 and R ^{1-1-2 are} independently C ₁ -C ₇ alkyl;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl;

-NR ^1-16- ^5-1 R ^1-16-5-2 or -OR ^1-16-5-3 ;

z is 0.

X is CH;

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

Y is N or CH;

All of R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, or an unsubstituted or C ₆ -C ₁₀ aryl substituted C ₁ -C ₇ alkyl group;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl;

Or -NR ^1-16-5-1 R ^1-16-5-2 ;

All R ^1-16-5-1 , R ^1-16-5-2 , R ^1-16-5-4 and R ^{1-16-5-5 are} independently hydrogen, unsubstituted or hydroxy C ₁ -C ₇ alkyl, C ₂ -C ₇ alkynyl, or C ₃ -C ₇ cycloalkyl;

z is 0.

X is CH;

m is 2 and n is 1;

Y is N or CH;

R ¹ is -NR ^1-1 R ^1-2 , R ^1-16 substituted C ₁ -C ₇ alkyl, or unsubstituted or R ^1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms";

All R ^1-1 and R ^{1-2 are} independently hydrogen, -C(=O)NR ^1-1-1 R ^1-1-2 , or unsubstituted or R ^1-1-3 substituted C ₁ ～C ₇ alkyl; all R ^1-1-1 , R ^1-1-2 and R ^{1-1-3 are} independently C ₁ -C ₇ alkyl or C ₆ -C ₁₀ aryl;

All R ^1-16-5-4 and R ^{1-16-5-5 are} independently C ₁ -C ₇ alkyl;

z is 0.

X is CH;

m is 2 and n is 1;

Y is N or CH;

All R ^1-1 and R ^{1-2 are} independently hydrogen, -C(=O)NR ^1-1-1 R ^1-1-2 , or unsubstituted or C ₆ -C ₁₀ aryl substituted C ₁ to C ₇ alkyl; all R ^1-1-1 and R ^{1-1-2 are} independently C ₁ -C ₇ alkyl;

All R ^1-16-5-4 and R ^{1-16-5-5 are} independently C ₁ -C ₇ alkyl;

z is 0.

X is CH;

m is 2 and n is 1;

Y is N or CH;

All of R ^1-1 and R ^{1-2 are} independently hydrogen, or unsubstituted or C ₆ -C ₁₀ aryl substituted C ₁ -C ₇ alkyl;

All R ^1-16-5-4 and R ^{1-16-5-5 are} independently C ₁ -C ₇ alkyl;

z is 0.

Where X is N or CH;

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

Y is N or CH;

R ¹ is H, halogen, fluorenyl, nitro, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -C(=NR ^1-11 R ¹ ⁵ , -S(=O)R ^1-6 , -S(=O) ₂ R ^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 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl { , the number of R ^1-16 is one or more [for example, 2, 3 or 4], when there are a plurality of R ^1-16 , the R ^{1-16 is the} same or different; a C ₁ -C ₇ alkyl group such as a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, For example, methyl, ethyl, n-propyl or isopropyl}, unsubstituted or R ^1-17 substituted C ₂ -C ₇ alkenyl {wherein the number of R ^1-17 is one or more [eg 2 , 3 or 4], when a plurality of R ^1-17 are present, the R ^{1-17 is the} same or different; wherein the "C ₂ -C ₇ alkenyl" is, for example, C ₂ - C ₄ An alkenyl group, for example, a 2-propenyl group, an unsubstituted or a R ^1-18 substituted C ₂ -C ₈ alkynyl group {wherein the number of R ^1-18 is one or more [eg 2, 3 or 4 Wherein R ^{1-18 is the} same or different when a plurality of R ^1-18 are present; wherein the "C ₂ -C ₇ alkynyl group" is, for example, a C ₂ -C ₄ alkynyl group, for example 2 a propynyl group, an unsubstituted or a R ^1-19 substituted C ₁ -C ₇ alkyl group {wherein the number of R ^1-19 is one or more [eg 2, 3 or 4], When a plurality of R ^1-19 are present, the R ^{1-19 is the} same or different}, unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl {wherein the number of R ^1-20 is One or more [eg 2, 3 or 4], when a plurality of R ^1-20 are present, said R ^{1-20 are the} same or different; said "C ₃ -C ₇ cycloalkyl" For example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and, for example, cyclobutyl}, unsubstituted or R ^1-21 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. One or more, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms" {wherein the number of R ^1-21 is one or more [for example, 2, 3 or 4 , when R ^1-21 is present, the R ^{1-21 is the} same or different; the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. Kind, Atoms of 1 to 4 C ₃ ~ C ₇ heterocycloalkyl "e.g." hetero atom is nitrogen, the number of hetero atoms of 1 or 2 of C ₃ ~ C ₅ heterocycloalkyl ", and for example," heteroatom Is nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a nitrogen atom", for example

}, unsubstituted or R ^1-22 substituted C ₆ -C ₁₀ aryl {wherein the number of R ^1-22 is one or more [eg 2, 3 or 4], when there are multiple R ^1-22 , the R ^{1-22 is the} same or different}, unsubstituted or R ^1-23 substituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms" {wherein the number of R ^1-23 is one or more [for example, 2, 3 or 4], when there are a plurality of When R ^1-23 , the R ^{1-23 is the} same or different}, unsubstituted or R ^1-24 substituted C ₁ -C ₇ alkoxy {wherein the number of R ^1-24 is one or more [e.g., 2, 3 or 4], when a plurality of R ^1-24 are present, the R ^{1-24 is the} same or different}, or the unsubstituted or R ^1-25 substituted C ₁ - C ₇ Alkyl group {wherein the number of R ^1-25 is one or more [for example, 2, 3 or 4], and when there are a plurality of R ^1-25 , the R ^{1-25 is the} same or different} ;

All R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, C ₁ -C ₇ alkyl {for example C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or isopropyl}, C ₂ -C ₇ alkenyl, C ₂ -C ₇ Alkynyl group, C ₃ -C ₇ cycloalkyl group, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ to C having 1 to 4 hetero atoms ₇ heterocycloalkyl", C ₆ -C ₁₀ aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C having 1 to 4 hetero atoms ₁ to C ₇ heteroaryl";

All R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 and R ^{1-10 are} independently hydroxy, C ₁ -C ₇ alkyl {eg C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further methyl, halo substituted C ₁ to C ₇ alkyl {wherein the number of halogens is one or more [for example, 2, 3 or 4], and when a plurality of halogens are present, the halogens are the same or different; _{a 1} -C ₇ alkyl group such as a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example Methyl; said "halogen-substituted C ₁ -C ₇ alkyl" such as trifluoromethyl}, halogen, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl {eg C ₂ -C ₄ alkyne Further, for example, 2-propynyl or 1-propynyl}, C ₃ -C ₇ cycloalkyl, C ₁ -C ₇ alkoxy {for example C ₁ -C ₄ alkoxy, for example methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy}, "heteroatoms are boron, silicon , one or more of oxygen, sulfur, selenium, nitrogen and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₁ -C ₇ heteroaryl having 1 to 4 hetero atoms", or NR ^1-4-1 R ^{1 -4-2} ;

All R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 and R ^{1-15 are} independently H, cyano, hydroxy, C ₁ -C ₇ alkoxy, unsubstituted or R ^{1 1-11-1} substituted C ₁ -C ₇ alkyl {wherein the number of R ^1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R ^1-11 are present ^{When -1} , the R ^{1-11-1 is the} same or different}, the C ₃ -C ₇ cycloalkyl group, "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. , a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms, a C ₆ -C ₁₀ aryl group, or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. One or more, C ₁ -C ₇ heteroaryl having 1 to 4 hetero atoms";

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 ^1-24 and R ^{1- 25 is} independently halogen {e.g., fluorine, chlorine, bromine or iodine, for example, fluorine}, nitro, cyano, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, a C ₁ -C ₇ alkyl group (for example, trimethylsilyl), a C ₃ -C ₇ cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms" (for example, "a C ₃ -C ₅ heterocycloalkyl group having a hetero atom is nitrogen and having 1 to 2 hetero atoms", for example, "The hetero atom is nitrogen, a C ₃ -C ₅ heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group such as a C ₁ -C ₇ alkyl group through a nitrogen atom", Also for example

}, C ₆ -C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₁ -C ₇ heteroatoms having 1 to 4 heteroatoms Aryl", C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkanoyl, -NR ^1-16-1 R ^1-16-2 , -OR ^1- ^16-3 , -SR ^1-16-4 Or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 and R ^{1-16-4 are} independently hydrogen, C ₁ -C ₇ alkyl {eg C ₁ -C ₄ alkyl Further, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl}, C ₂ -C ₇ alkenyl, C ₂ - C ₇ alkynyl, C ₃ -C ₇ cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ having 1 to 4 hetero atoms -C ₇ heterocycloalkyl", C ₆ -C ₁₀ aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C ₁ -C ₇ heteroaryl";

}, halogenated "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ -C ₇ heterocycloalkyl having 1 to 4 heteroatoms" { Wherein the number of said halogens is one or more [for example, 2, 3 or 4], and when a plurality of halogens are present, said halogens are the same or different; said "halogen" is independently Fluorine, chlorine or bromine; the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ -C ₇ heterocyclic ring having 1 to 4 hetero atoms An alkyl group, for example, "a hetero atom is nitrogen, a C ₃ -C ₇ heterocycloalkyl group having 1 to 2 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom"; the "halogenated hetero atom is boron" , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms"

}, C ₆ -C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₁ -C ₇ heteroatoms having 1 to 4 heteroatoms aryl ^{^",} -NR 1-16-5-1 R 1-16-5- ² or ^-OR 1-16-5-3;

All R ^1-16-5-1 , R ^1-16-5-2 and R ^{1-16-5-3 are} independently hydrogen, unsubstituted or R ^1-16-5-1-1 substituted C ₁ ～C ₇ alkyl {wherein the number of R ^1-16-5-1-1 is one or more [for example, 2, 3 or 4], when there are a plurality of R ^{1-16-5-1 When -1} , the R ^{1-16-5-1-1 is the} same or different; the "C ₁ -C ₇ alkyl" is, for example, a C ₁ -C ₄ alkyl group, for example, a methyl group, an ethyl group, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl}, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl {for example a C ₂ -C ₄ alkynyl group, for example, a 2-propynyl group or a 1-propynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. One or more, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms, C ₆ -C ₁₀ aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

z is 0, 1 or 2;

Alternatively, two R ² linkages together form an unsubstituted or R ^2-8 substituted C ₃ -C ₇ cycloalkyl group on the same carbon atom {wherein the number of R ^2-8 is one or more [eg 2 , 3 or 4], when a plurality of R ^2-8 are present, the R ^{2-8 is the} same or different}, or the unsubstituted or R ^2-9 substituted C ₁ -C ₇ heterocycloalkyl Wherein the number of R ^2-9 is one or more [eg 2, 3 or 4], and when a plurality of R ^2-9 are present, the R ^{2-9 is the} same or different};

X is CH.

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

m and n are independently 0, 1, 2 or 3, and m+n is 3 {for example, m is 2, n is 1}.

Y is N.

Y is CH.

R ¹ is H, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -S(=O) ₂ R ^1-7 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, heteroatoms The number is 1 to 4 C ₃ to C ₇ heterocycloalkyl groups.

R ¹ is hydrogen, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -S(=O) ₂ R ^1-7 , unsubstituted or R ^{1- 16-} substituted C ₁ -C ₇ alkyl group, C ₃ -C ₇ cycloalkyl group or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1. ~4 C ₃ -C ₇ heterocycloalkyl groups".

R ¹ is unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl, or unsubstituted or R ^1-21 substituted" The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ to C ₇ heterocycloalkyl group having 1 to 4 hetero atoms.

R ¹ is -NR ^1-1 R ^1-2 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, or unsubstituted or R ^1-21 substituted "hetero atom is boron, silicon, oxygen , one or more of sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms";

All R ^1-1 and R ^{1-2 are} independently hydrogen or C ₁ -C ₇ alkyl;

All R ^{1-16 are} independently C ₃ -C ₇ cycloalkyl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4 C ₁ -C ₇ heterocycloalkyl", -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -(C=O)R ^1-16-5 .

R ¹ is an unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl group, or an unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl group;

All R ^1-16 and R ^{1-20 are} independently C ₃ -C ₇ cycloalkyl.

R ¹ is unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, -NR ^1-1 R ^1-2 , or "heteroatoms are among boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more kinds of C ₃ -C ₇ heterocycloalkyl groups having 1 to 4 hetero atoms.

All R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen or C ₁ -C ₇ alkyl.

All R ^1-1 and R ^{1-2 are} independently hydrogen or C ₁ -C ₇ alkyl.

All R ^1-4 and R ^{1-7 are} independently C ₁ -C ₇ alkyl, halogen-substituted C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, C ₂ -C ₇ alkynyl or NR ^1-4-1 R ^1-4-2 ;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl.

All R ^1-4 and R ^{1-7 are} independently C ₁ -C ₇ alkyl, halogen-substituted C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy or NR ^1-4-1 R ^{1 -4-2} ;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl.

All R ^{1-16 are} independently halogen, cyano, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, "hetero The atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms", -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 and R ^{1-16-4 are} independently hydrogen or C ₁ -C ₇ alkyl;

All R ^{1-16-5 are} independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ to C ₇ having 1 to 4 hetero atoms. Heterocycloalkyl" or -NR ^1-16-5-1 R ^1-16-5-2 ;

All R ^1-16-5-1 and R ^{1-16-5-2 are} independently hydrogen, unsubstituted or R ^1-16-5-1-1 substituted C ₁ -C ₇ alkyl, C ₂ ～ C ₇ alkynyl or C ₃ -C ₇ cycloalkyl;

All R ^{1-16-5-1-1 are} independently hydroxy.

All R ^{1-16 are} independently halogen, C ₁ -C ₇ alkylsilyl, C ₃ -C ₇ cycloalkyl, "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus Or a plurality of C ₁ -C ₇ heterocycloalkyl groups having 1 to 4 hetero atoms", -NR ^1-16-1 R ^1-16-2 or -(C=O)R ^1-16-5 ;

All R ^1-16-1 and R ^{1-16-2 are} independently C ₁ -C ₇ alkyl;

All R ^{1-16-5 are} independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ to C ₇ having 1 to 4 hetero atoms. Heterocycloalkyl", or -NR ^1-16-5-1 R ^1-16-5-2 ;

All R ^{1-16-5-1-1 are} independently hydroxy.

All R ^{1-16 are} independently C ₃ -C ₇ cycloalkyl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4 C ₁ -C ₇ heterocycloalkyl", -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -(C=O)R ^1-16-5 ;

All of R ^1-16-5-1 and R ^{1-16-5-2 are} independently hydrogen, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkynyl or C ₃ -C ₇ cycloalkyl.

z is 0.

X is CH;

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

Y is N or CH;

R ¹ is H, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -S(=O) ₂ R ^1-7 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, heteroatoms a number of 1 to 4 C ₃ -C ₇ heterocycloalkyl";

All R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen or C ₁ -C ₇ alkyl;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl;

All R ^{1-16-5-1-1 are} independently a hydroxyl group;

z is 0.

X is CH;

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

Y is N or CH;

R ¹ is hydrogen, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -S(=O) ₂ R ^1-7 , unsubstituted or R ^{1- 16-} substituted C ₁ -C ₇ alkyl group, C ₃ -C ₇ cycloalkyl group or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1. ~4 C ₃ -C ₇ heterocycloalkyl";

All R ^1-4 and R ^{1-7 are} independently C ₁ -C ₇ alkyl, halogen-substituted C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, or NR ^1-4-1 R ^1-4-2 ;

All R ^1-4-1 and R ^{1-4-2 are} independently C ₁ -C ₇ alkyl;

All R ^1-16-1 and R ^{1-16-2 are} independently hydrogen or C ₁ -C ₇ alkyl;

All R ^{1-16-5-1-1 are} independently a hydroxyl group;

z is 0.

X is CH;

m and n are independently 0, 1, 2 or 3, and m+n is 3 {for example, m is 2, n is 1};

Y is N;

R ¹ is unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl or unsubstituted or R ^1-21 substituted "hetero" The atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ to C ₇ heterocycloalkyl having 1 to 4 hetero atoms;

All R ^1-16 , R ^1-20 and R ^{1-21 are} independently halogen, nitro, cyano, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl , C ₁ -C ₇ alkylsilyl, C ₃ -C ₇ cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 - 4 C ₃ -C ₇ heterocycloalkyl", C ₆ -C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms 1 to 4 C ₁ -C ₇ heteroaryl", C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkanoyl, -NR ^1-16-1 R ^1-16-2 , -OR ^{1 -16-3} , -SR ^1-16-4 or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 and R ^{1-16-4 are} independently hydrogen, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C ₃ -C ₇ heterocycloalkyl", C ₆ -C ₁₀ aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C ₁ -C ₇ heteroaryl groups";

All R ^{1-16-5 are} independently a hydroxyl group, a C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms, and halogenated "heteroatoms are boron," One or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ -C ₁₀ aryl, "hetero atom" Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₁ -C ₇ heteroaryl having 1 to 4 hetero atoms", -NR ^1-16-5-1 R ^1-16-5-2 or -OR ^1-16-5-3 ;

All R ^1-16-5-1 , R ^1-16-5-2 and R ^{1-16-5-3 are} independently hydrogen, unsubstituted or R ^1-16-5-1-1 substituted C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ cycloalkyl, "heteroatom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms, C ₆ -C ₁₀ aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and One or more of phosphorus, a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

z is 0.

X is CH;

Y is CH;

All R ^1-1 and R ^{1-2 are} independently hydrogen or C ₁ -C ₇ alkyl;

All R ^{1-16 are} independently C ₃ -C ₇ cycloalkyl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4 C ₃ -C ₇ heterocycloalkyl", -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -(C=O)R ^1-16-5 ;

All R ^{1-21 are} independently halogen, nitro, cyano, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkyl, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C ₃ -C ₇ heterocyclic ring having 1 to 4 hetero atoms. "Alkyl", C ₆ -C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₁ -C having 1 to 4 hetero atoms ₇ heteroaryl ", C ₁ ~ C ₇ alkoxy, C ₁ ~ C ₇ ^{^{^{alkylmercapto, -NR 1-16-1 R 1-16-2, -OR 1-16-3}}} , -SR 1-16 ^-4 or -(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;

R ¹ may be H, cyano, nitro, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4 , -C(=NR ^1-11 )R ^1-5 , -S( =O)R ^1-6 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, unsubstituted or R ^1-17 substituted C ₂ -C ₇ alkenyl, unsubstituted or R ^1-18 substituted C ₂ -C ₇ alkynyl, unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl, or unsubstituted or R ^1-21 substituted "heteroatoms are boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms";

All R ^1-1 and R ^1-2 may independently be hydrogen, C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl;

All R ^1-4 , R ^1-5 and R ^{1-6 are} independently C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkyne a group, a C ₁ -C ₇ alkoxy group, or NR ^1-4-1 R ^1-4-2 ;

All R ^1-4-1 and R ^{1-4-2 are} independently hydrogen, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ ring An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms";

R ^1-11 is H;

All R ^1-16 , R ^1-17 , R ^1-18 , R ^1-20 and R ^{1-21 are} independently cyano, -NR ^1-16-1 R ^1-16-2 , -OR ^{1- 16-3} , -SR ^1-16-4 , C ₃ -C ₇ cycloalkyl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C ₃ -C ₇ heterocycloalkyl" or -(C=O)R ^1-16-5 ;

All R ^1-16-1 , R ^1-16-2 , R ^1-16-3 and R ^{1-16-4 are} independently hydrogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₇ alkyl ;

All R ^{1-16-5 are} independently a hydroxyl group, a C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ -C ₁₀ aryl, " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms", -NR ^{1-16-5 -1} R ^1-16-5-2 or OR ^1-16-5-3 ;

z can be 0.

X can be CH;

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

Y can be N;

R ¹ may be H, cyano, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4 , R ^1-16 substituted or unsubstituted C ₁ -C ₇ alkyl, C ₂ -C _a alkenyl group, or a C ₂ -C ₇ alkynyl group, an R ^1-20 substituted or unsubstituted C ₃ -C ₇ cycloalkyl group;

R ^1-1 and R ^1-2 may independently be a C ₁ -C ₇ alkyl group;

R ^{1-4 is} independently C ₁ -C ₇ alkyl or C ₂ -C ₇ alkynyl;

All R ^{1-16 are} independently cyano, -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 or C ₃ -C ₇ cycloalkyl;

All R ^1-16-1 , R ^1-16-2 and R ^{1-16-3 are} independently hydrogen or C ₁ -C ₇ alkyl;

z can be 0.

X can be CH;

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

Y can be C;

R ¹ may be H, cyano, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4 , unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, C ₂ ～ a C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, an unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl group, or an unsubstituted or R ^1-21 substituted "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, and C ₃ to C ₇ heterocycloalkyl having 1 to 4 hetero atoms;

R ^1-1 and R ^1-2 may independently be a C ₁ -C ₇ alkyl group;

R ^{1-4 is} independently C ₁ -C ₇ alkyl or C ₂ -C ₇ alkynyl;

All R ^{1-16 are} independently cyano, -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , or , heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms;

z can be 0.

Where X is N or CH;

Y is N or CH;

R ¹ is H, halogen, fluorenyl, nitro, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -C(=NR ^1-11 R ¹ ⁵ , -S(=O)R ^1-6 , -S(=O) ₂ R ^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 , R ^1-16 substituted or unsubstituted C ₁ -C ₇ alkyl {where The number of R ^1-16 is one or more [for example, 2, 3 or 4], and when there are a plurality of R ^1-16 , the R ^{1-16 is the} same or different; the "C" _{a 1} -C ₇ alkyl group such as a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example Methyl, ethyl, n-propyl or isopropyl}, R ^1-17 substituted or unsubstituted C ₂ -C ₇ alkenyl { wherein the number of R ^1-17 is one or more [eg 2, 3 or 4], when a plurality of R ^1-17 are present, the R ^{1-17 is the} same or different; wherein the "C ₂ -C ₇ alkenyl" is, for example, C ₂ -C ₄ alkenyl Further, for example, 2-propenyl}, R ^1-18 substituted or unsubstituted C ₂ -C ₈ alkynyl {wherein the number of R ^1-18 is one or more [for example, 2, 3 or 4] , When there are plural R ^1-18, R ^1-18 is the same or different; wherein, the "C ₂ ~ C ₇ alkynyl group", for example, C ₂ ~ C ₄ alkynyl group, 2-propynyl group and e.g. }, R ^1-19 substituted or unsubstituted C ₁ -C ₇ alkyl silicon {wherein the number of R ^1-19 is one or more [eg 2, 3 or 4], when there are multiple R ^{When 1-19} , the R ^{1-19 is the} same or different}, R ^{1-20 is} substituted or unsubstituted C ₃ -C ₇ cycloalkyl {wherein the number of R ^1-20 is one or more [for example] 2, 3 or 4], the time when a plurality of R ^1-20, the R ^1- ²⁰ are the same or different}, R ^1-21 substituted or unsubstituted "hetero atom is boron, silicon, oxygen , one or more of sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms" {wherein the number of R ^1-21 is one or more [eg 2, 3 or 4], when a plurality of R ^1-21 are present, said R ^{1-21 is the} same or different}, R ^{1-22 is} substituted or unsubstituted C ₆ -C ₁₀ aryl { Wherein the number of R ^1-22 is one or more [for example, 2, 3 or 4], and when there are a plurality of R ^1-22 , the R ^{1-22 is the} same or different}, R ¹ a substituted or unsubstituted ^-23 "heteroatom Boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus in one or more of the number of hetero atoms of 1 to 4 C ₁ ~ C ₇ heteroaryl "{wherein the number of R ^1-23 is One or more [eg 2, 3 or 4], when a plurality of R ^1-23 are present, the R ^{1-23 is the} same or different}, R ^{1-24 is} substituted or unsubstituted C ₁ -C ₇ alkoxy {wherein the number of R ^1-24 is one or more [eg 2, 3 or 4], when a plurality of R ^1-24 are present, the R ^{1-24 is the} same or Different}, or, R ^1-25 substituted or unsubstituted C ₁ -C ₇ alkyl fluorenyl { wherein the number of R ^1-25 is one or more [eg 2, 3 or 4], when present When R ^1-25 , the R ^{1-25 is the} same or different};

R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, C ₁ -C ₇ alkyl {for example C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl a base, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl}, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ cycloalkyl," The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms, and C ₆ to C ₁₀ aromatic Or "heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 and R ^{1-10 are} independently hydroxy, C ₁ -C ₇ alkyl {eg C ₁ ～C ₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl}, halogen, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl {eg C ₂ -C ₄ alkynyl, for example 2-propynyl or 1-propynyl}, C ₃ -C ₇ cycloalkyl, "hetero atom is boron , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ -C ₁₀ aryl, "hetero The atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms", or NR ^1-4-1 R ^1-4-2 ;

All R ^1-4-1 and R ^{1-4-2 are} independently hydrogen, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ ring An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms", C ₆ ～C ₁₀ aryl or “hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ —C ₇ heteroaryl group having 1 to 4 hetero atoms”;

R ^1-11 , R ^1-12 , R ^1-13 , R ^1-14 and R ^{1-15 are} independently H, cyano, hydroxy, C ₁ -C ₇ alkoxy, R ^1-11-1 Or unsubstituted C ₁ -C ₇ alkyl {wherein the number of R ^1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R ^1-11-1 are present , R ^{1-11-1 is the} same or different}, C ₃ -C ₇ cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, miscellaneous a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 atoms, a C ₆ -C ₁₀ aryl group, or "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Or a plurality of C ₁ -C ₇ heteroaryl groups having a hetero atom number of 1 to 4";

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 ^1-24 and R ^{1- 25} independently is halogen, nitro, cyano, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkyl, C ₃ -C ₇ a cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms", C ₆ to C ₁₀ aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms" , C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkanoyl, -NR ^1-16-1 R ^1-16-2 , -OR ^1-16-3 , -SR ^1-16-4 or -( C=O)R ^1-16-5 ;

All R ^{1-16-5 are} independently a hydroxyl group, a C ₁ -C ₇ alkyl group, a C ₂ -C ₇ alkenyl group, a C ₂ -C ₇ alkynyl group, a C ₃ -C ₇ cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ -C ₁₀ aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

z is 0, 1 or 2;

All R ^{2 are} independently halogen, hydroxy, cyano, amino, R ^2-1 substituted or unsubstituted C ₁ -C ₇ alkyl {wherein the number of R ^2-1 is one or more [eg 2 , 3 or 4], when a plurality of R ^2-1 are present, the R ^{2-1 is the} same or different}, R ^{2-2 is} substituted or unsubstituted C ₂ -C ₈ alkenyl {where R ² The number of ^-2 is one or more [for example, 2, 3 or 4], when there are a plurality of R ^2-2 , the R ^{2-2 is the} same or different}, R ^{2-3 is} substituted or Unsubstituted C ₂ -C ₇ alkynyl { wherein the number of R ^2-3 is one or more [eg 2, 3 or 4], when a plurality of R ^2-3 are present, the R ^2-3 identical or different}, R ^2-4 substituted or unsubstituted C ₁ -C ₇ alkyl silicon {wherein the number of R ^2-4 is one or more [for example, 2, 3 or 4] When R ^2-4 is present, R ^{2-4 is the} same or different}, R ^{2-5 is} substituted or unsubstituted C ₆ -C ₁₀ aryl { wherein R ^2-5 is one Or more than [eg 2, 3 or 4], when a plurality of R ^2-5 are present, the R ^{2-5 is the} same or different}, R ^{2-6 is} substituted or unsubstituted "the hetero atom is boron , one of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus More, the number of hetero atoms, 1 to 4 of C ₁ ~ C ₇ heteroaryl "{wherein, R ^2-6 is the number of one or more [e.g. 2, 3 or 4], when there is When R ^2-6 , R ^{2-6 is the} same or different}, or R ^{2-7 is} substituted or unsubstituted C ₁ -C ₇ alkoxy {wherein the number of R ^2-7 is one Or a plurality [for example, 2, 3 or 4], when there are a plurality of R ^2-7 , the R ^{2-7 is the} same or different};

Alternatively, two R ² linkages together form the R ^2-8 substituted or unsubstituted C ₃ -C ₇ cycloalkyl group on the same carbon atom {wherein the number of R ^2-8 is one or more [eg 2, 3 or 4], when a plurality of R ^2-8 are present, the R ^{2-8 is the} same or different}, or R ^{2-9 is} substituted or unsubstituted C ₁ -C ₇ heterocycloalkyl { , the number of R ^2-9 is one or more [eg 2, 3 or 4], when there are a plurality of R ^2-9 , the R ^{2-9 is the} same or different};

X can be CH.

m+n can be 2 or 3.

m can be 0 and n can be 2.

m can be 1, and n can be 1.

m can be 2, and n can be 0.

m can be 1, and n can be 2.

m can be 2, and n can be 1.

Y can be N.

R ¹ may be H, cyano, nitro, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4 , -C(=NR ^1-11 )R ^1-5 , -S( =O)R ^1-6 , R ^1-16 substituted or unsubstituted C ₁ -C ₇ alkyl, R ^1-17 substituted or unsubstituted C ₂ -C ₇ alkenyl, R ^1-18 substituted or unsubstituted C ₂ -C ₇ alkynyl, or R ^1-20 substituted or unsubstituted C ₃ -C ₇ cycloalkyl, which may be H, cyano, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4, R ^1- ¹⁶ substituted or unsubstituted C ₁ ~ C ₇ alkyl group, C ₂ ~ C ₇ alkenyl group, or, C ₂ ~ C ₇ alkynyl group.

R ^1-1 and R ^1-2 may independently be hydrogen, a C ₁ -C ₇ alkyl group or a C ₃ -C ₇ cycloalkyl group, or may independently be a C ₁ -C ₇ alkyl group.

R ^1-4 , R ^1-5 and R ^{1-6 are} independently C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ alkenyl or C ₂ -C ₇ alkynyl; Further, it may independently be a C ₁ -C ₇ alkyl group or a C ₂ -C ₇ alkynyl group.

R ^1-11 is H.

All R ^1-16 , R ^1-17 , R ^1-18 and R ^{1-20 are} independently cyano, -NR ^1-16-1 R ^1-16-2 or -OR ^1-16-3 ;

All R ^1-16-1 , R ^1-16-2 and R ^{1-16-3 are} independently hydrogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₇ alkyl; independently hydrogen Or C ₁ -C ₇ alkyl.

z can be 0.

Where X is CH;

Y is N or CH;

R ¹ is H, halogen, fluorenyl, nitro, cyano, -NR ^1-1 R ^1-2 , -OR ^1-3 , -C(=O)R ^1-4 , -C(=NR ^1-11 R ¹ ⁵ , -S(=O)R ^1-6 , -S(=O) ₂ R ^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 , R ^1-16 substituted or unsubstituted C ₁ -C ₇ alkyl {where The number of R ^1-16 is one or more [for example, 2, 3 or 4], and when there are a plurality of R ^1-16 , the R ^{1-16 is the} same or different}, R ^1-17 a substituted or unsubstituted C ₂ -C ₇ alkenyl group {wherein the number of R ^1-17 is one or more [eg 2, 3 or 4], when a plurality of R ^1-17 are present, R ^{1 -} ^{17 is the} same or different}, R ^{1-18 is} substituted or unsubstituted C ₂ -C ₈ alkynyl {wherein the number of R ^1-18 is one or more [for example, 2, 3 or 4 ], when a plurality of R ^1-18 are present, the R ^{1-18 is the} same or different}, R ^{1-19 is} substituted or unsubstituted C ₁ -C ₇ alkyl silicon {wherein, the number of R ^1-19 As one or more [for example, 2, 3 or 4], when a plurality of R ^{1 -} ¹⁹ are present, the R ^{1-19 is the} same or different}, R ^{1-20 is} substituted or unsubstituted C ₃ ～ C ₇ cycloalkyl {where R ^1- The number of ²⁰ is one or more [for example, 2, 3 or 4], when a plurality of R ^1-20 are present, the R ^{1-20 is the} same or different}, R ¹ ^{21 is} substituted or not The substituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 hetero atoms" {where R The number of ^1-21 is one or more [for example, 2, 3 or 4], when a plurality of R ^1-21 are present, the R ^{1-21 is the} same or different}, and R ^{1-22 is} substituted. Or unsubstituted C ₆ -C ₁₀ aryl { wherein the number of R ^1- ²² is one or more [eg 2, 3 or 4], when a plurality of R ^1-22 are present, said R ^{1-22 is the} same or different}, R ^{1-23 is} substituted or unsubstituted "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C ₁ -C ₇ heteroaryl" { wherein R ^1-23 is one or more [eg 2, 3 or 4], when a plurality of R ^1-23 are present, said R ^{1-23 is the} same or different}, R ^{1-24 is} substituted or unsubstituted C ₁ -C ₇ alkoxy {wherein the number of R ^1-24 is one or more [for example, 2, 3 or 4 ], when there are multiple R ^{From 1 to 24} , the R ^{1-24 is the} same or different}, or the R ^{1-25 is} substituted or unsubstituted C ₁ -C ₇ alkenyl (wherein the number of R ^1-25 is one or more [ For example, 2, 3 or 4], when there are a plurality of R ^1-25 , the R ^{1-25 is the} same or different};

R ^1-1 , R ^1-2 and R ^{1-3 are} independently hydrogen, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₇ naphthenic The "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C ₃ -C ₇ heterocycloalkyl having 1 to 4 hetero atoms", C ₆ - a C ₁₀ aryl group or "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms";

R ^1-4 , R ^1-5 , R ^1-6 , R ^1-7 , R ^1-8 , R ^1-9 and R ^{1-10 are} independently hydroxy, C ₁ -C ₇ alkyl, halogen, C ₂ to C ₇ alkenyl group, C ₂ -C ₇ alkynyl group, C ₃ -C ₇ cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C ₃ -C ₇ heterocycloalkyl group having 1 to 4 atoms, a C ₆ -C ₁₀ aryl group, and "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. , a C ₁ -C ₇ heteroaryl group having 1 to 4 hetero atoms, or NR ^1-4-1 R ^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;

R ¹ may be H, cyano, nitro, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4 , -C(=NR ^1-11 )R ^1-5 , -S( =O)R ^1-6 , R ^1-16 substituted or unsubstituted C ₁ -C ₇ alkyl, R ^1-17 substituted or unsubstituted C ₂ -C ₇ alkenyl, R ^1-18 substituted or unsubstituted C ₂ ～C ₇ alkynyl, or R ^1-20 substituted or unsubstituted C ₃ -C ₇ cycloalkyl;

R ^1-1 and R ^1-2 may independently be hydrogen, C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl;

R ^1-4 , R ^1-5 and R ^{1-6 are} independently C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ alkenyl or C ₂ -C ₇ alkynyl;

R ^1-11 is H;

All R ^1-16-1 , R ^1-16-2 and R ^{1-16-3 are} independently hydrogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₇ alkyl;

z can be 0.

X can be CH;

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

Y can be N;

R ¹ may be H, cyano, -NR ^1-1 R ^1-2 , -C(=O)R ^1-4 , R ^1-16 substituted or unsubstituted C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, or, C ₂ -C ₇ alkynyl;

R ^1-1 and R ^1-2 may independently be a C ₁ -C ₇ alkyl group;

R ^{1-4 is} independently C ₁ -C ₇ alkyl or C ₂ -C ₇ alkynyl;

All R ^{1-16 are} independently cyano, -NR ^1-16-1 R ^1-16-2 or -OR ^1-16-3 ;

z can be 0.

In one embodiment, the compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, In its metabolite or its prodrug, the compound I is any of the following compounds:

In general, the compounds of the present invention can be prepared using at least the methods described below, but are not limited to the reagents and solvents in the reaction conditions below.

The invention also provides a preparation method of the above compound I, which is any of the following methods:

method one:

The method comprises the steps of: oxidizing compound 1A to obtain compound 1B, and substituting to obtain compound 1D, and deprotecting to obtain compound 1E;

Where Y is N. The definitions of m, n, z and R ² are the same as previously described; the conditions of each step in the reaction route may be conventional conditions for such reactions in the art.

The PG in the compound represented by the formula 1C may be various conventional amino protecting groups in the art, preferably Boc, for the purpose of

When reacting with compound 1B, some of the reactive groups (such as amino groups) on the reaction are not involved in the reaction;

The conditions for the removal of the protecting group may be conventional removal conditions of various protecting groups in the art, such as conditions of the hydrolysis reaction, conditions of the amine hydrolysis reaction, conditions of the hydrogenation reaction, and the like;

After the reaction of removing the protecting group is finished, preferably, it may further comprise a post-treatment operation; the method and conditions of the post-treatment may be conventional methods and conditions for post-treatment of such reactions in the art. Preferably, the reaction system is washed, dried, filtered, and the solvent is evaporated to dryness, followed by column chromatography, or the reaction system is distilled off, washed, and filtered; or the reaction system is distilled off. Solvent, thin layer chromatography, ie;

Wherein, the conditions of the method for reacting in each step in the reaction route can be carried out according to the conventional conditions of the methods of the reactions in the art;

Method Two:

The method comprises the steps of: oxidizing compound 1A to obtain compound 1B, and reacting with 2A to obtain compound 2B;

Wherein, the definitions of m, n, z, Y, R ¹ and R ² are the same as previously described; the conditions of each step in the reaction route may be the conventional conditions for such reactions in the art.

Method three:

When R ¹ is unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, unsubstituted or R ^1-17 substituted C ₂ -C ₇ alkenyl, unsubstituted or R ^1-18 substituted C ₂ ～ When a C ₈ alkynyl group, or an unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl group, the method for producing the compound of the formula I includes the following steps: in an organic solvent (for example, 1, In the presence of a reducing agent such as sodium triacetoxyborohydride and/or sodium cyanoborohydride in one or more of 2-dichloroethane, dichloromethane, methanol and dioxane The reductive amination reaction of the compound 1E with R ¹ -CHO to obtain the compound I; the conditions of the reductive amination reaction can be the conditions conventional for such reactions in the field;

Wherein Y is N and the R ^{1 '} -CH ₂ - is equivalent to R ¹ . The definitions of m, n, z, R ¹ and R ² are the same as described above; the conditions of each step in the reaction route may be the conventional conditions for such reactions in the art.

Method four:

When R ¹ is unsubstituted or R ^1-16 substituted C ₁ -C ₇ alkyl, unsubstituted or R ^1-17 substituted C ₂ -C ₇ alkenyl, unsubstituted or R ^1-18 substituted C ₂ ～ When a C ₈ alkynyl group, an unsubstituted or R ^1-20 substituted C ₃ -C ₇ cycloalkyl group, a cyano group or an acetyl group, the preparation method of the compound of the formula I includes the following steps: in an organic solvent (for example, one or more of methanol, dichloromethane, acetonitrile and DMF) in the presence of a base such as potassium carbonate, cesium carbonate, N,N-diisopropylethylamine or triethylamine, The compound 1E is subjected to a substitution reaction with R ¹ -X ¹ to obtain a compound I; the conditions of the substitution reaction may be conventional conditions in the reaction of the field; and the X ¹ is a halogen (for example, chlorine or bromine). ;

Where Y is N. The definitions of m, n, z, R ¹ and R ² are the same as described above; the conditions of each step in the reaction route may be the conventional conditions for such reactions in the art.

Method five:

When R ¹ is -C(=O)R ^1-4 , and R ^1-4 is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl or C ₃ -C ₇ In the case of a cycloalkyl group, the process for the preparation of the compound of formula I comprises the steps of: in an organic solvent such as one or more of 1,4-dioxane, dichloromethane and DMF. , in the presence of a condensing agent (such as DMAP and EDCI), compound 1E,

The condensation reaction is carried out to obtain the compound I; the conditions of the condensation reaction can be the conditions conventional for such reactions in the field;

The invention also provides a compound of formula 1C, 1D or 2A:

Wherein, the definitions of PG, m, n, z, Y, R ¹ and R ² are the same as described above.

The present invention also provides a compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvent thereof, as described above Use of a compound, a metabolite thereof or a prodrug thereof for the preparation of a kinase (e.g., WEE1 kinase) inhibitor.

The present invention also provides a compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvent thereof, as described above The use of a compound, a metabolite thereof or a prodrug thereof for the preparation of a medicament for the treatment and/or prevention of a disease associated with WEE1 kinase.

The disease associated with WEE1 kinase, such as cancer. The cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's lymphoma, and also, for example, colon cancer or ovarian cancer.

The present invention also provides a compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvent thereof, as described above The use of a compound, a metabolite thereof or a prodrug thereof for the preparation of a medicament for the treatment and/or prevention of cancer.

The cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's lymphoma, and also, for example, colon cancer or ovarian cancer.

The present invention also provides a pharmaceutical composition comprising the compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable compound thereof as described above Accepted salts, solvates thereof, metabolites thereof or prodrugs thereof, and pharmaceutical excipient(s).

The present invention provides a combination comprising the compound I as described above, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable salt thereof , its solvate, its metabolites or their prodrugs and anticancer drugs.

The anticancer drug can be a conventional anticancer drug in the art, such as an anticancer alkylating agent, an anticancer metabolic antagonist, an anticancer antibiotic, a plant-derived anticancer agent, and an anticancer platinum. Coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L-asparaginase, procarbazine , dacarbazine, hydroxyurea, pentastatin, retinoic acid, afaxet, alfabelin, anastrozole, exemestane, bicalutamide, leuprolide, flutamide, One or more of fulvestrant, pegaptanib sodium, diltiazem 2, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine and goserelin, for example Anticancer metabolic antagonist.

The anticancer alkylating agent can be a conventional anticancer alkylating agent in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfir, busulfan, two One or more of bromomannitol, carbazone, thiotepa, remustine, nimustine, temozolomide, and carmustine.

The anticancer metabolic antagonist can be a conventional anticancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, guanidine, 5-fluorouracil, tegafur, deoxyfluoride One or more of glycosides, carmofur, cytarabine, sodium cytarabine octadecyl phosphate, enesitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium Further, for example, 5-fluorouracil.

The anticancer antibiotic may be a conventional anticancer antibiotic in the field, such as actinomycin D, doxorubicin, daunorubicin, neocarcin, bleomycin, and pilomycin. One or more of mitomycin C, arubicin, pirarubicin, epirubicin, net statin, idarubicin, sirolimus, and valrubicin.

The plant-derived anticancer agent can be a conventional plant-derived anticancer agent in the art, such as vincristine, vinblastine, vindesine, etoposide, sobutazox, docetaxel, One or more of paclitaxel and vinorelbine.

The anti-cancer platinum coordination compound may be one or more of conventional anti-cancer platinum coordination compounds such as cisplatin, carboplatin, nedaplatin and oxaliplatin.

The anticancer camptothecin derivative may be one or more of conventional anticancer camptothecin derivatives in the art, such as irinotecan, topotecan, and camptothecin.

The anticancer tyrosine kinase inhibitor may be a conventional anticancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib and erlotinib. .

The monoclonal antibody may be a monoclonal antibody conventional in the art, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab. .

The interferon may be a conventional interferon in the art, such as one of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, and interferon gamma-nl. Or a variety.

The biological response modifier may be a conventional biological response modifier in the art, such as one or more of Yunzhi polysaccharide, lentinan, cilostam, sapylin, and umbrel.

The components of the combination may be used simultaneously or separately (eg, sequentially); when the components of the combination are used simultaneously, the components of the combination may be uniformly mixed (ie, the components mixture).

The components of the combination may be prepared as a single pharmaceutical composition for simultaneous use, or the components may be separately formed into a single separate pharmaceutical composition (for example, in the form of a kit) of these individual independent pharmaceutical compositions. Can be used simultaneously or separately (for example, sequentially).

The invention also provides the use of the above combinations in the manufacture of a medicament for the prevention and/or treatment of cancer.

In the use according to the invention, the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvent The compound, its metabolite or its prodrug, and the anticancer drug described above may be administered simultaneously or separately (for example, sequentially).

The present invention also provides the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolism The use of the product or a prodrug thereof for the preparation of a medicament for "in combination with an anticancer drug as described above" for the prevention and/or treatment of cancer.

The present invention also provides the above anticancer drug, which is prepared for "and the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmacy The use of an acceptable salt, a solvate thereof, a metabolite thereof, or a prodrug thereof, in a medicament for preventing and/or treating cancer.

The invention also provides a pharmaceutical composition comprising a combination of the above and a pharmaceutical excipient(s).

The pharmaceutical composition may consist of the combination and the pharmaceutical excipient.

The present invention also provides a combination kit comprising a pharmaceutical composition A and a pharmaceutical composition B;

The pharmaceutical composition A includes the above compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvate thereof. , a metabolite thereof or a prodrug thereof, and (one or more) pharmaceutical excipients;

The pharmaceutical composition B includes the above-mentioned anticancer drug and the pharmaceutically acceptable excipient(s).

The combination kit can be composed of the pharmaceutical composition A and the pharmaceutical composition B described.

The pharmaceutical composition A may be the above compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof , its metabolites or their prodrugs, and, pharmaceutical excipients;

The pharmaceutical composition B may be composed of the above-mentioned anticancer drug and medicinal adjuvant.

Each of the pharmaceutical compositions in the combination kit can be used simultaneously or separately (e.g., sequentially).

The above preferred conditions can be arbitrarily combined without departing from the general knowledge of the field, that is, preferred embodiments of the present invention.

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

Unless otherwise stated, the following terms appearing in the specification and claims of the present invention have the following meanings:

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "alkyl" refers to a saturated monovalent hydrocarbon radical straight or branched, having one to twelve carbon atoms (e.g., C ₁ -C ₆ alkyl, and C ₁ -C ₄ alkyl, for example). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-g Base and 1-octyl.

The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one unsaturated position, ie, a carbon-carbon sp ² double bond (eg, a C ₂ -C ₆ alkenyl group, For example, C ₂ -C ₄ alkenyl), and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples thereof include, but are not limited to, vinyl, allyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1 - cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one unsaturated position, ie, a carbon-carbon sp triple bond (eg, a C ₂ -C ₆ alkynyl group, such as C. ₂ -C ₄ alkynyl). Examples thereof include, but are not limited to, ethynyl and propynyl.

The term "alkylsilyl" refers to an alkyl group attached through a silicon bridge; the alkyl group defined above; C ₁ -C ₇ alkyl refers to silicon

Wherein R ^A , R ^B and R ^{C are} independently C ₁ -C ₇ alkyl.

The term "cycloalkyl" means a non-aromatic saturated cyclic hydrocarbon radicals (e.g., C ₃ -C ₆ cycloalkyl) a monovalent three to twenty carbon atoms. Examples of monocyclic carbon ring radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl and cyclic. Dodecyl. The term "cycloalkyl" also includes polycyclic (eg, bicyclic and tricyclic) cycloalkyl structures, and bicyclic carbon rings having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5], [5, 5 , [5,6] or [6,6] systems, or arranged as bridged ring systems such as bis[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]decane.

The term "heterocycloalkyl" refers to a saturated carbocyclic group having from 3 to 12 ring atoms, wherein at least one of the ring atoms is a heteroatom independently selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. The remaining ring atoms are C. The group may be a carbon group or a hetero atom group (ie, it may be C-attached or N-attached as long as it is possible). Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thio Ethoxyalkyl and piperazinyl. The spiro portion and the bridge portion are also included within the scope of this definition. For example, a group derived from tetrahydropyrrole may be tetrahydropyrrole-1-yl (N-attached) or tetrahydropyrrol-3-yl (C-attached). For example, a single ring of 3-7 membered rings (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S and Se, where N, B, P or Se Optionally substituted with one or more oxygen atoms to give a group like NO, BOH, PO, PO ₂ , SeO; N may optionally be quaternized; the S atom may optionally be one or more oxygen atoms Or a nitrogen atom is substituted to obtain a group like SO, SO ₂ , S(=O)(=NR ^a ), S(=NR ^b ) or S(=NR ^c ) ₂ , and at the same time, R ^a , R ^b and R ^{c is} independently cyano, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, "C ₃ -C ₇ heterocycloalkyl group having 1 to 4 atoms", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 - 4 C ₁ -C ₇ heteroaryl", C ₆ -C ₁₀ aryl or C ₁ -C ₇ alkoxy; meanwhile, the -CH ₂ - group may be optionally -C(=O)- , -C(=S)- or -C(=NR ^d )- instead, R ^{d is} independently cyano, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, "hetero atom is boron, One of silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus or a plurality of C ₃ -C ₇ heterocycloalkyl groups having a hetero atom number of 1 to 4", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a hetero atom a number of 1 to 4 C ₁ -C ₇ heteroaryl", a C ₆ -C ₁₀ aryl group or a C ₁ -C ₇ alkoxy group; when the ring is a three-membered ring, only one of the hetero atoms , or, a double ring of 7-10 atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S, where N, S, B or P Optionally substituted with one or more oxygen atoms to give a group like NO, BOH, SO, SO ₂ , PO, PO ₂ , SeO, while the -CH ₂ - group may optionally be -C(= O) - alternative). Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group, that is, a heterocyclic group.

The term "aryl" refers to any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.

The term "heteroaryl" refers to a stable monocyclic or bicyclic ring up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, and nitrogen. And phosphorus heteroatoms. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline. "Heteroaryl" is also understood to include any nitrogen-containing heteroaryl N-oxide derivative. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out separately through an aromatic ring. The heteroaryl-heterocyclic ring, bicyclic heteroaryl ring system can be fused in a fused form. Wherein, N, S, B, P or Se is optionally substituted by one or more oxygen atoms to obtain groups like NO, SO, SO ₂ , BOH, PO, PO ₂ , SeO, and the N atom may be quaternized. . A heteroaryl group can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. Depending on the structure, the heteroaryl group can be a monovalent group or a divalent group, ie a heteroarylene group.

The term "alkoxy" refers to an alkyl group attached through an oxygen bridge; the alkyl group is as defined above.

The term "alkyl fluorenyl" refers to an alkyl group attached through a sulphur bridge; the alkyl group is as defined above.

The term "pharmaceutically acceptable salt" refers to a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with Compound I which retains the biological activity of Compound I. The organic acid may be various organic acids which can be salted in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid. And one or more of propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid and salicylic acid. The inorganic acid may be any of various inorganic acids which are conventionally salt-formable in the art, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base may be various organic bases which can be salted in the art, preferably one or more of pyridines, imidazoles, pyrazines, anthracenes, porphyrins, tertiary amines and anilines. Kind. The tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine. The aniline organic base is preferably N,N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic base may be various inorganic bases which can be salted in the art, preferably alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate. One or more of potassium hydrogencarbonate and sodium hydrogencarbonate. The alkali metal hydride is preferably sodium hydride and/or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide.

The term "solvate" refers to a substance formed by the compound I with a suitable solvent. The solvent is, for example, water or an organic solvent.

The term "component" refers to a component of the combination of the invention, ie, compound I, its enantiomer, its diastereomer, its tautomer, its crystalline form, and its pharmaceutically acceptable a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, or an anticancer drug.

The term "pharmaceutical excipient" refers to those excipients that are widely used in the field of pharmaceutical production. The excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition. The ingredients are effectively absorbed. The pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The term "active ingredient" means the active ingredient in the pharmaceutical composition or combination kit of the present invention, ie, Compound I, its enantiomer, its diastereomer, its tautomer, and its crystal form. A pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof or a prodrug thereof, an anticancer drug, or a combination thereof.

The positive progress of the present invention is that the compound of the present invention has a better inhibitory activity against WEE1 kinase.

Detailed ways

The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

The structures of all compounds of the invention can be identified by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS). ^{The 1} H NMR chemical shift (δ) was recorded in PPM (10 ^-6 ). NMR was performed on a Bruker AVANCE-400 spectrometer.

LC-MS was determined by an Agilent 1200 HPLC/6120 mass spectrometer.

The thin layer silica gel plate is a Liangchen silicon source HSGF254 or a Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.

Example 1

first step:

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthiopyrazolo[3,4-d]pyrimidine-3 - Ketone (270 mg, 0.75 mmol) (as the compound of formula 1A) and 4-chloroperoxybenzoic acid (143 mg, 0.83 mmol) were dissolved in toluene (20 ml), stirred at room temperature for 1 hour, then N,N- Diisopropylethylamine (291 mg, 2.26 mmol) and 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (243 mg, 0.98 mmol) (as shown in formula 2) The compound was further stirred at room temperature for 16 hours, and the reaction mixture was concentrated and purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 100% to 50%) to give the compound t-butyl 6-[ [2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidine-6 Ethyl]amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ethyl ester (270 mg, 0.48 mmol). LC-MS: m/z: (M+H) ⁺ = 558.3, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.63 - 7.47 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.73 (dq, J = 10.2, 6.1 Hz, 1H), 5.08 (d, J = 10.1 Hz, 1H), 4.96 (d, J = 17.0 Hz, 1H), 4.79 (d, J = 6.2 Hz, 2H), 4.59 (s, 2H), 3.70 (d, J = 4.5 Hz, 2H), 2.86 (t, J = 5.5 Hz, 2H), 1.62 (s, 6H), 1.53 (s, 9H).

The second step:

tert-Butyl 6-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3, 4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ethyl ester (250 mg, 0.45 mmol) (as compound of formula I-1-a) Soluble in dichloromethane (10 ml), add hydrochloric acid in dioxane solution (2 ml, 4 M), stir at room temperature for 16 hours, filter, and concentrate the filtrate to give the compound 2-allyl- 1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazole [3,4-D]pyrimidin-3-one (200 mg, 0.44 mmol). LC-MS: m/z: (M+H) ⁺ = 458.2, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 9.48 (s, 2H), 8.96 - 8.90 (m, 1H), 8.08 (t, J = 7.9 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H) , 7.19 (d, J = 8.4 Hz, 1H), 5.69 (qd, J = 11.1, 5.7 Hz, 1H), 5.02 (d, J = 10.4 Hz, 1H), 4.84 (d, J = 17.0 Hz, 1H) , 4.72 (d, J = 5.6 Hz, 2H), 4.23 (s, 4H), 3.39 (d, J = 5.0 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H), 1.49 (s, 6H) .

Example 2

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (as a compound of formula I-1) was dissolved in methanol (5 ml), then an aqueous solution of formaldehyde was added ( 0.1 ml, 40%) and sodium triacetylborohydride (46 mg, 0.22 mmol) were stirred at room temperature for 4 hr. The reaction mixture was concentrated, dissolved with a mixture of dichloromethane and methanol (10/1, 20 ml), and washed twice with saturated sodium hydrogen sulfate. The compound 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[(2-methyl-3,4-dihydro-) 1H-Isoquinolin-6-yl)amino]pyrazolo[3,4-d]pyrimidin-3-one (40 mg, 0.085 mmol). LC-MS: m/z: (M+H) ⁺ = 472.3, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 8.89 (s, 1H), 8.05 (t, J = 7.9 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.66 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.3 Hz, 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 = 5.5 Hz, 2H), 2.62 (t, J = 5.8 Hz, 2H), 2.36 (s, 3H), 1.49 (s, 6H).

Example 5

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (as a compound of formula I-1) was dissolved in dichloromethane (5 ml) and then acetone was added ( 0.1 ml, 40%) and sodium triacetylborohydride (46 mg, 0.22 mmol), warmed to reflux and stirred for 48 h. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 100% to 10%, then dichloromethane / methanol / ammonia methanol solution = 100/10/1.5) to give the compound of formula I-5 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[(2-isopropyl-3,4-dihydro-1H- Isoquinolin-6-yl)amino]pyrazolo[3,4-d]pyrimidin-3-one (30 mg, 0.06 mmol). LC-MS: m / z: (M + H) + = 496.2, 1 H NMR (400MHz, MeOD-d 4) δ8.87 (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, 6.2 Hz, 1H), 5.06 (d, J = 10.1 Hz, 1H), 4.95 (s, 1H), 4.84 (d, J = 6.1 Hz, 2H), 4.26 (s, 2H), 3.58 - 3.49 ( m, 1H), 3.42 (t, J = 5.8 Hz, 2H), 3.16 (t, J = 5.8 Hz, 2H), 1.60 (s, 6H), 1.42 (d, J = 6.6 Hz, 6H).

Example 11

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -Aminoamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (as a compound of formula I-1) was dissolved in dichloromethane (5 ml) and methanol (5 ml). Then, 2-bromoethanol (43 mg, 0.34 mmol) and potassium carbonate (72 mg, 0.52 mmol) were added, and the mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated and purified by silica gel chromatography chromatography chromatography eluting The yield was 41%. LC-MS: m/z: (M+H) ⁺ = 502.3, ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.84 (s, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.85 – 7.79 (m, 1H), 7.70–7.60 (m, 2H), 7.38 (dd, J=8.3, 2.0 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 5.72 (ddt, J=16.3) , 10.2, 6.1 Hz, 1H), 5.05 (dd, J = 10.2, 1.1 Hz, 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).

Example 12

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (compound as shown in formula I-1) was dissolved in N,N-dimethylformamide (5 ml) Then, 2-bromoethyl methyl ether (48 mg, 0.34 mmol) and potassium carbonate (72 mg, 0.52 mmol) were added, and stirred at 75 ° C for 16 hours. The reaction mixture was concentrated and purified by silica gel chromatography chromatography chromatography eluting The yield was 18%. LC-MS: m/z: (M+H) ⁺ = 516.3, ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.84 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz) , 1H), 5.80–5.66 (m, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.95 (d, J = 1.1 Hz, 1H), 4.83 (s, 2H), 3.75 (s, 2H) , 3.68 (t, J = 5.5 Hz, 2H), 3.41 (s, 3H), 2.94 (dd, J = 12.2, 4.8 Hz, 4H), 2.83 (t, J = 5.6 Hz, 2H), 1.60 (s, 6H).

Example 14

first step:

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (110 mg, 0.24 mmol) (as shown in formula I-1) and N-Boc-methylaminoacetaldehyde (83 mg, 0.48 mmol) (The compound of the formula 3) was dissolved in methanol (5 ml), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The compound of formula I-14-a is N-[2-[6-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]- 3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]-N-methyl - tert-Butyl carbamate (150 mg, 0.24 mmol). LC-MS: m/z: (M+H) ⁺ = 615.4.

The second step:

N-[2-[6-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazole [3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]-N-methyl-carbamic acid tert-butyl ester (140 mg, 0.23 mmol) (as the compound of the formula I-14-a) is dissolved in aqueous hydrochloric acid (6 ml, 2M), stirred at room temperature for 16 hours, and then aq. The mixed solution (DCM/CH ₃ OH = 10/1) is extracted, the organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and dried to give the compound of formula I-14 2-allyl-1-[6- (1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[[2-[2-(methylamino)ethyl]-3,4-dihydro-1H-isoquinoline -6-yl]amino]pyrazolo[3,4-d]pyrimidin-3-one (90 mg, 0.17 mmol). LC-MS: m/z: (M+H) ⁺ = 515.3, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.90 (s, 1H), 8.05 (t, J = 7.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.67 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.69 (dq, J = 11.7, 6.1 Hz, 1H), 5.37 (s, 1H), 5.01 (d, J = 10.1 Hz, 1H), 4.84 (d, J = 17.2 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H), 3.54 (s, 2H), 2.83 (t, J = 5.2 Hz, 2H), 2.70 (t, J = 6.0 Hz, 4H), 2.57 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 1.48 (s, 6H).

Example 15

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[[2-[2-(methylamino)ethyl]- 3,4-Dihydro-1H-isoquinolin-6-yl]amino]pyrazolo[3,4-d]pyrimidin-3-one (40 mg, 0.116 mmol) (as a compound of formula I-14) Dissolved in methanol (5 ml), and then added aqueous formaldehyde (0.1 ml, 40%) and sodium triacetoxyborohydride (61 mg, 0.30 mmol), and stirred at room temperature for 4 hours. The reaction mixture was concentrated, EtOAc (EtOAc m.). ₃ OH = 100% to 10%, then DCM / CH ₃ OH / NH ₃ .CH ₃ OH = 100/10/1.5) purified as the compound of formula I-15 2-allyl-6-[[2 -(2-dimethylaminoethyl)-3,4-dihydro-1H-isoquinolin-6-yl]amino]-1-[6-(1-hydroxy-1-methyl-ethyl)- 2-pyridyl]pyrazolo[3,4-d]pyrimidin-3-one (30 mg, 0.057 mmol). LC-MS: m/z: (M+H) ⁺ = 529.2, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 - 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).

Example 21

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (compound as shown in formula I-1) was dissolved in dichloromethane (5 ml) and DMF (1 ml) Then, acetyl chloride (6.8 mg, 0.087 mmol) and triethylamine (17.7 mg, 0.175 mmol) were added, and stirred at room temperature for 16 hours. The reaction solution is concentrated, diluted with water, filtered, and dried to give compound 6-[(2-acetyl-3,4-dihydro-1H-isoquinolin-6-yl)amino group as shown in formula I-21. ]-2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]pyrazolo[3,4-d]pyrimidin-3-one (40 mg, 0.085 mmol). LC-MS: m/z: (M+H) + = 500.3, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 8.90 (s, 1H), 8.11 - 8.02 (m, 1H), 7.82–7.73 (m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 5.74 – 5.62 (m, 1H), 5.35 (s, 1H), 5.01 (dd, J = 10.3, 1.3 Hz, 1H), 4.83 (dd, J = 17.3, 1.3 Hz, 1H), 4.71 (d, J = 7.7 Hz) , 2H), 4.61 (s, 1H), 4.56 (s, 1H), 3.68 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 6.2 Hz, 1H), 2.76 (t, J = 6.5 Hz) , 1H), 2.11 (d, J = 4.5 Hz, 3H), 1.48 (s, 6H).

Example 28

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (30 mg, 0.066 mmol) (as a compound of formula I-1) was dissolved in N,N-dimethylformamide (5 ml) Then, 3-bromopropene (8 mg, 0.66 mmol) and potassium carbonate (14 mg, 0.1 mmol) were added, and stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel chromatography chromatography chromatography eluting The yield was 15%. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.84 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.10 - 5.93 (m, 1H), 5.73 (ddd, J = 17.0, 6.1 , 4.1 Hz, 1H), 5.42 (dd, J = 23.2, 5.8 Hz, 2H), 5.05 (dd, J = 10.2, 1.1 Hz, 1H), 4.98 - 4.92 (m, 1H), 4.84 (d, J = 6.1 Hz, 2H), 3.84 (s, 2H), 3.43 (d, J = 6.8 Hz, 2H), 3.02 (s, 4H), 1.60 (s, 6H). LC-MS: m/z: (M+ H) ⁺ = 498.3.

Example 37

first step:

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthiopyrazolo[3,4-d]pyrimidine-3 - Ketone (such as the compound of formula 1A) (100 mg, 0.28 mmol) and 4-chloroperoxybenzoic acid (53 mg, 0.31 mmol) were dissolved in toluene (20 ml), stirred at room temperature for 1 hour, then 2-amino- 7,8-Dihydro-5H-1,6-naphthyridin-6-carboxylic acid tert-butyl ester (243 mg, 0.98 mmol), warmed to 100 ° C and stirred for 16 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (Petroleum ether / ethyl acetate = 100% to 0%) was purified and then purified by preparative liquid phase to give the compound t-butyl 2-[[2-allyl-1-[6- (1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-7,8-dihydro -5H-1,6-naphthyridine-6-carboxylic acid ethyl ester (28 mg, 0.05 mmol). LC-MS: m/z: (M+H) ⁺ = 559.3.

The second step:

tert-Butyl 2-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3, 4-d]pyrimidin-6-yl]amino]-7,8-dihydro-5H-1,6-naphthyridin-6-carboxylic acid ethyl ester (28 mg, 0.05 mmol) (as in formula I-37- The compound of a) is dissolved in dichloromethane (10 ml), and a solution of hydrochloric acid in dioxane (2 ml, 4M) is added, stirred at room temperature for 16 hours, filtered, and the filtrate is concentrated to dryness to give compound 2 as shown in formula I-6 -allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(5,6,7,8-tetrahydro-1,6-diaza Heterophthalen-2-ylamino)pyrazolo[3,4-d]pyrimidin-3-one (200 mg, 0.44 mmol). ^{1 H NMR (400MHz, MeOD-} d 4) δ9.28 (s, 1H), 8.11 (t, J = 7.0Hz, 2H), 7.82 (d, J = 7.4Hz, 2H), 7.43 (d, J = 8.9 Hz, 1H), 5.76 (dq, J = 11.2, 6.5 Hz, 1H), 5.07 (d, J = 9.5 Hz, 1H), 4.95 (s, 1H), 4.90 (d, J = 8.0 Hz, 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.

Example 44

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (1.8 g, 8 mmol) (as shown in formula I-44-a) and ammonium acetate (6.2 g, 81 mmol) were added to 80 ml In methanol, stir at room temperature for 2 h. Then sodium cyanoborohydride (600 mg, 0.984 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 1 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown liquid of 900 mg was obtained in a yield of 50%. LC-MS: m/z: (M+H) ⁺ = 226.

The second step:

6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine (900 mg, 3.98 mmol) (as a compound of formula I-44-b) was dissolved in 10 ml of 37% formaldehyde and 16 ml of formic acid. Heat to reflux for 4 h. The solvent was evaporated to dryness. EtOAc was evaporated. The obtained crude product was obtained as a brown oil (yield: 800 mg). The yield was 79%. LC-MS: m/z: (M+H) ⁺ = 254.

third step:

6-Bromo-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (600 mg, 2.36 mmol) (as shown in formula I-44-c), diphenyl Methyl ketone (470 mg, 2.594 mmol), sodium tert-butoxide (480 mg, 5 mmol), Pd ₂ (dba) ₃ (70 mg, 0.0765 mmol), BINAP (150 mg, 0.241 mmol) was added to 30 ml of toluene in argon Change the air three times and then heat to 120 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified (jjjjjjj LC-MS: m/z: (M+H) ⁺ = 355.

the fourth step:

6-((Diphenylmethylene)amino)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (such as the compound of formula I-44-d) (600 mg, 1.693 mmol) was dissolved in 30 ml of methanol, then sodium acetate (560 mg, 6.83 mmol) and hydroxylamine hydrochloride (350 mg, 5.04 mmol) were added and heated to 60 ° for 3 hours. The reaction mixture was filtered and concentrated, and then purified, mjjjjjj LC-MS: m/z: (M+H) ⁺ = 191.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (such as the compound of formula 1A) (72 mg, 0.2 mmol) was added to a solution of 15 ml of toluene to give m-chloroperoxybenzoic acid (50 mg, 0.22 mmol). 1h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl A toluene solution of oxazo[3,4-d]pyrimidin-3-one (such as the compound of Formula 1B). To the above solution was added N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-2,6-diamine (such as the compound of formula I-44-e) (40 mg, 0.21 mmol) And 0.5 ml of N,N-diisopropylethylamine, stirred at room temperature overnight, and then allowed to stand at room temperature for 16 days. The organic product was concentrated under reduced pressure. The crude product was purified by chromatography (7M ammonia methanol: methylene chloride = 0-10%). White solid, yield 9%. LC-MS: m/z: (M+H) ⁺ = 500, ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.81 (s, 1H), 8.54 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.73 (ddd, J = 17.0, 6.0, 4.2 Hz, 1H), 5.05 (d, J = 9.2 Hz, 1H), 4.94 (d, 1H), 4.83 (d, J=6.0 Hz, 2H), 3.59 (s, 1H), 3.19 (d, J = 12.3 Hz, 1H), 3.07 - 2.87 (m, 9H), 2.35 (m, 1H), 1.92 (m, 1H), 1.60 (s, 6H).

Example 49

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (20 mg, 0.044 mmol) (as a compound of formula I-1) is dispersed in dichloromethane (5 ml) and then added to the butyne Acid (3.7 mg, 0.44 mmol), EDCI (17 mg, 0.088 mmol), 4-dimethylaminopyridine (1 mg, 0.008 mmol). The reaction mixture was concentrated and purified by silica gel chromatography chromatography chromatography eluting The yield was 26%. LC-MS: m/z: (M+H) ⁺ = 524.3, ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.86 (s, 1H), 8.11 - 7.78 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70 (s, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.21 - 7.08 (m, 1H), 5.74 (ddt, J = 16.3, 10.2, 6.1 Hz, 1H) ), 5.05 (dd, J = 10.2, 1.1 Hz, 1H), 4.94 (d, J = 1.3 Hz, 1H), 4.92 (s, 1H), 4.84 (d, J = 6.1 Hz, 2H), 4.70 (s) , 1H), 4.06 (t, J = 5.9 Hz, 1H), 3.84 (t, J = 6.1 Hz, 1H), 2.92 (dt, J = 24.8, 5.9 Hz, 2H), 2.11 (s, 3H), 1.60 (s, 6H).

Example 54

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (compound as shown in formula I-1) was dissolved in methanol (6 ml), then cyclobutanone was added ( 9.2 mg, 0.131 mmol) and sodium triacetylborohydride (37 mg, 0.175 mmol) were stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the mixture was combined with methylene chloride and methanol (10/1, 20 ml). The title compound (12 mg, 0.023 mmol) was obtained (yield: 27%). LC-MS: m / z: (M + H) + = 512.3, 1 H NMR (400MHz, MeOD) δ8.86 (s, 1H), 8.03 (t, J = 7.9Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.75–7.62 (m, 2H), 7.44 (dd, J=8.3, 1.9 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 5.81–5.65 (m, 1H) ), 5.05 (dd, J = 10.2, 1.1 Hz, 1H), 4.92 (dd, J = 17.1, 1.2 Hz, 1H), 4.83 (s, 2H), 3.80 (s, 2H), 3.29 (d, J = 7.8 Hz, 0H), 2.99 (dt, J = 11.7, 6.1 Hz, 4H), 2.36 - 2.23 (m, 1H), 2.13 (dd, J = 15.4, 6.1 Hz, 1H), 1.92 - 1.80 (m, 1H) ).

Example 55

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-(1,2,3,4-tetrahydroisoquinoline-6 -ylamino)pyrazolo[3,4-D]pyrimidin-3-one (40 mg, 0.087 mmol) (as the compound of formula I-1) was dissolved in methanol (6 ml), then cyclopropanal was added ( 9.2 mg, 0.131 mmol) and sodium triacetylborohydride (37 mg, 0.175 mmol) were stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the mixture was combined with methylene chloride and methanol (10/1, 20 ml). The title compound (14 mg, 0.023 mmol) was obtained (yield: 31%). 1H NMR (400MHz, MeOD) δ 8.85 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.74 (ddt, J = 16.4, 10.3, 6.1 Hz, 1H), 5.05 (dd, J = 10.2, 1.2 Hz, 1H), 4.92 (dd, J = 17.1, 1.3 Hz, 1H), 4.83 (s, 2H), 3.80 (s, 2H), 2.97 (d, J = 4.0 Hz, 4H), 2.55 (d, J) = 6.7 Hz, 2H), 1.70 - 1.49 (m, 6H), 1.04 (dd, J = 13.2, 6.4 Hz, 1H), 0.71 - 0.58 (m, 2H), 0.27 (q, J = 4.7 Hz, 2H) .LC-MS: m/z: (M+H) ⁺ = 512.3.

Example 56

first step:

6-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (100 mg, 0.47 mmol) (as a compound of formula I-55-a) was dissolved in 10 mL of methanol then 1 Ethoxy-1-trimethylsiloxycyclopropane (98 mg, 0.56 mmol) and sodium cyanoborohydride (29 mg, 0.46 mmol) were stirred at 60 ° C for 16 h. After completion of the reaction, the residue was evaporated to dryness crystals crystals crystals ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 7.5 Hz, 2H), 7.21. (d, J = 8.5 Hz, 1H), 3.91 (s, 2H), 3.01 (s, 4H), 1.87 (s, 1H), 0.61 (d, J = 6.0 Hz, 4H). LC-MS: m/z: (M+H) ⁺ = 219.1.

The second step:

2-Cyclopropyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (56 mg, 0.26 mmol) (as shown in formula I-55-b) and palladium on carbon (10 mg) Dissolved in 10 ml of methanol, and stirred under a hydrogen balloon at room temperature for 4 h at room temperature. After completion of the reaction, celite was filtered to give a yellow solid (yield: EtOAc (EtOAc) LC-MS: m/z: (M+H) ⁺ = 189.1.

third step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (86 mg, 0.24 mmol) (as a compound of formula 1A) was added to m-chloroperoxybenzoic acid (65 mg, 0.29 mmol) in 10 ml of methanol. 3h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl A solution of oxazolo[3,4-d]pyrimidin-3-one (such as the compound of formula 1B) in dichloromethane. 2-cyclopropyl-1,2,3,4-tetraisoquinolin-6-amine (48 mg, 0.26 mmol) (as shown in formula I-55-c) and 0.13 ml were added to the solution obtained above. N,N-diisopropylethylamine was stirred at room temperature for 18 h. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc m. LC-MS: m/z: (M+H) ⁺ = 498.3, ¹ H NMR (400 MHz, CDCl ₃ ) 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 = 7.8 Hz, 1H), 7.30 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 5.72 (s, 1H) , 5.07 (d, J = 9.5 Hz, 1H), 4.96 (d, J = 17.8 Hz, 1H), 4.78 (s, 2H), 3.92 (s, 3H), 3.03 (d, J = 36.6 Hz, 4H) , 1.98 (s, 1H), 1.28 (s, 6H), 0.65 (s, 4H).

Example 57

first step:

5-Nitroindole-2-one (280 mg, 1.58 mmol) (as the compound of formula I-57-a) was dissolved in 5 ml of methanol, 2 ml (2M in methanol) dimethylamine was added and stirred at room temperature about 2 After hrs, 298 mg (4.74 mmol) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 16 hours, concentrated, dissolved with 2N aqueous hydrochloric acid, extracted with dichloromethane, and the aqueous layer was adjusted to pH=8 with 2N aqueous sodium hydroxide. After extraction with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound N,N-dimethyl-5-nitroindane-2- as shown in formula I-57-b Amine 60 mg, yield 18%, tan solid. LC-MS: m/z: [M+1] ⁺ = 207.1

The second step:

N,N-Dimethyl-5-nitroindane-2-amine (60 mg, 0.29 mmol) (compound as shown in formula I-57-b) was dissolved in 5 ml of methanol and 50 mg (0.76 mmol) was added. Zinc powder, then added 2 ml of saturated aqueous ammonium chloride solution, stirred at room temperature for about 2 hours, concentrated, added 5 ml of 2N aqueous hydrochloric acid, extracted with dichloromethane, the aqueous layer was adjusted to pH 8 with 2N aqueous ammonium hydroxide, then Extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound N2, N2-dimethylindole-2,5-diamine 50 mg of formula I-57-c, yield 97%, brown solid. LC-MS: m/z: [M+1] ⁺ = 177.2

third step:

2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthiopyrazolo[3,4-d]pyrimidine-3- Ketone (20 mg 0.056 mmol) (compound as shown in Formula 1A) was dissolved in 10 ml of dichloromethane, 10.6 mg (0.062 mmol) of m-chloroperoxybenzoic acid was added, and stirred at room temperature for about 1 hour, then 10 mg (0.056 mmol) was added. N2,N2-dimethylindole-2,5-diamine (such as the compound of formula I-57-c) and 14 mg (0.11 mmol) of DIPEA, stirred at room temperature for 4 days, the reaction solution was washed with water and the organic layer was passed. The aqueous solution was dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, UV, petroleum ether / ethyl acetate = 100% to 40%) to give the compound of formula I-57 2-allyl-6-[[2- (Dimethylamino)indan-5-yl]amino]-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]pyrazolo[3,4-d] Pyrimidine-3-one 15 mg, yield 55%, yellow solid. LC-MS: m/z: [M+1] ⁺ = 486.2, 1H NMR (400 MHz,MeOD) δ 8.85 (s, 1H), 8.46 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H) ), 7.80 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.49 (dd, J = 8.2, 1.8 Hz, 1H), 7.23 (d) , J = 8.2 Hz, 1H), 5.73 (ddt, J = 16.3, 10.2, 6.1 Hz, 1H), 5.05 (dd, J = 10.2, 1.2 Hz, 1H), 4.92 (dd, J = 17.1, 1.3 Hz, 1H), 4.83 (d, J = 6.1 Hz, 2H), 4.03 (p, J = 7.8 Hz, 1H), 3.40 (dt, J = 15.8, 7.8 Hz, 2H), 3.17 (td, J = 15.0, 7.5) Hz, 2H), 2.88 (s, 6H), 1.59 (s, 6H).

Example 58

first step:

6-Nitroindole-1-one (1 g, 5.64 mmol) (as the compound of formula I-58-a) was dissolved in 10 ml of methanol, 2 ml (2M in methanol) dimethylamine was added, and stirred at room temperature about 2 After the hour, 1.06 g (16.9 mmol) of sodium cyanoborohydride was added, the temperature was raised to 100 ° C under microwave conditions and stirred for 1 hour, concentrated, dissolved with 2N aqueous hydrochloric acid, extracted with dichloromethane, and the aqueous layer was hydrogenated with 2N. The sodium aqueous solution was adjusted to pH = 8 and extracted with dichloromethane. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and concentrated to give compound N, N-dimethyl-6- Nitroindan-1-amine 500 mg, yield 43%, brown oil. LC-MS: m/z: [M+1] ⁺ = 207.1.

The second step:

N,N-Dimethyl-6-nitroindane-1-amine (500 mg, 2.42 mmol) (as a compound of formula I-58-b) was dissolved in 30 ml of methanol and 476 mg (7.27 mmol) was added. Zinc powder, then added 5 ml of saturated aqueous ammonium chloride solution, stirred at room temperature for about 2 hours, concentrated, added 5 ml of 2N aqueous hydrochloric acid, extracted with dichloromethane, and the aqueous layer was adjusted to pH 8 with 2N aqueous ammonium hydroxide, then Extracted with dichloromethane, the methylene chloride layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound N1, N1-dimethylindole-1,6-diamine 420 mg of formula I-58-c, yield 100% yellow oil. LC-MS: m/z: [M+1] ⁺ = 177.2

third step:

2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthiopyrazolo[3,4-d]pyrimidine-3- The ketone (60 mg, 0.17 mmol) (as the compound of formula 1A) was dissolved in 20 ml of dichloromethane, 32 mg (0.18 mmol) of m-chloroperoxybenzoic acid was added, and stirred at room temperature for about 1 hour, then N1, N1-di was added. Methyl hydrazine-1,6-diamine (30 mg, 0.17 mmol) (such as the compound of formula I-58-c) and (65 mg, 0.50 mmol) of DIPEA, stirred at room temperature for 4 days, the reaction mixture was washed with water, organic layer Drying over anhydrous sodium sulfate, concentration, purification by high-purity liquid chromatography, purification by thin-layer chromatography (dichloromethane / methanol = 10/1) to give the compound 2-ylpropyl-6 as shown in formula I-58. -[[3-(dimethylamino)indan-5-yl]amino]-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]pyrazolo[3 , 4-d]pyrimidin-3-one 4 mg, 5% yield, yellow solid. </ RTI>^< RTIgt 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, 6.7 Hz, 2H), 1.59 (s, 6H).

Example 59

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (0.7 g, 3 mmol) (as the compound of formula I-59-a) and ammonium acetate (2.4 g, 31 mmol) were added to 20 ml In methanol, stir at room temperature for 2 h. Then sodium cyanoborohydride (230 mg, 3.77 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then 20 ml of water was added, and the pH was adjusted to acid with 1 mol/L hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 2 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown liquid of 300 mg was obtained in a yield of 40%. LC-MS: m/z: (M+H) ⁺ = 226.

The second step:

6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine (300 mg, 1.33 mmol) (as shown in formula I-59-b), 0.65 ml N,N-diisopropyl Amine and tert-butoxycarbonyl tert-butyl carbonate (400 mg, 1.83 mmol) were stirred at room temperature overnight. The solvent was evaporated to dryness crystals crystals crystals crystals crystals The yield was 92%. LC-MS: m/z: (M+Na) ⁺ =348.

third step:

tert-Butyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (600 mg, 2.36 mmol) (as compound of formula I-59-c), diphenyl Ketoimine (270 mg, 1.49 mmol), sodium tert-butoxide (145 mg, 1.51 mmol), Pd ₂ (dba) ₃ (30 mg, 0.033 mmol), BINAP (35 mg, 0.056 mmol) in 20 ml of toluene in argon Change the air three times and then heat to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified (jjjjjjjj LC-MS: m/z: (M+H) ⁺ = 427.

the fourth step:

tert-Butyl (6-((diphenylmethylene)amino)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (170 mg, 0.4 mmol) (as in formula I-59- The compound shown by d was dissolved in 20 ml of methanol, and then sodium acetate (110 mg, 1.34 mmol) and hydroxylamine hydrochloride (60 mg, 0.86 mmol) were added, and the mixture was heated to 60 ° C overnight. The reaction mixture was filtered and concentrated, and then purified, mjjjjjj LC-MS: m/z: (M - 55) ⁺ = 207.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (107 mg, 0.3 mmol) (as a compound of formula 1A) was added to m-chloroperoxybenzoic acid (76 mg, 0.34 mmol) in 15 ml of toluene, and the resulting solution was stirred at room temperature. 1h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl Zoxao[3,4-d]pyrimidin-3-one. This solution was used directly for the next reaction. LC-MS: m/z: (M+H) ⁺ = 374.

To the solution obtained above, tert-butyl (6-amino-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (90 mg, 0.34 mmol) (such as the compound of formula I-59-e) And 1 ml of N,N-diisopropylethylamine, stirred at room temperature overnight. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc: LC-MS: m/z: (M+H) ⁺ = 572.

The sixth step:

(6-((2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazole [3,4] tert-butyl-d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydro-naphthalen-2-yl)carbamic acid (110 mg, 0.19 mmol) (as in formula I- The compound shown by 59-f was dissolved in a mixed solvent of 5 ml of dichloromethane and 2 ml of methanol, and 10 ml of 4 mol/L of dioxane hydrochloride was added thereto, and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, 30 ml of a mixed solvent of methanol and dichloromethane (methanol: methylene chloride = 10:1) and 10 ml of saturated aqueous sodium carbonate solution were stirred at room temperature for 20 min, and the organic layer was dried and concentrated and purified by column. Dichloromethane: ethyl acetate = 2:1) = 0-20%), yielded 40 mg of white solid. LC-MS: m/z: (M+H) ⁺ = 472, 1H NMR (400 MHz, CDCl3:MeOD=2:1) δ 8.85 (d, J = 4.9 Hz, 1H), 7.93 (dd, J = 10.3, 5.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.38 - 7.31 (m, 1H), 7.06 ( d, J = 8.3 Hz, 1H), 5.70 (dq, J = 10.4, 6.0 Hz, 1H), 5.05 (d, J = 10.2 Hz, 1H), 4.93 (d, J = 17.1 Hz, 1H), 4.82 ( d, J = 5.9 Hz, 2H), 3.28 - 3.16 (m, 1H), 3.03 (dd, J = 15.9, 4.6 Hz, 1H), 2.91 (dd, J = 7.7, 4.8 Hz, 2H), 2.60 (dd , J = 15.6, 9.6 Hz, 1H), 2.10 (d, J = 9.5 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.61 (d, J = 4.8 Hz, 6H).

Example 60

2-Allyl-6-[(6-amino-5,6,7,8-tetrahydronaphthyridin-2-yl)amine]-1-[6-(2-hydroxypropyl-2-yl) Pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-one (20 mg, 0.042 mmol) (compound as shown in formula I-59) is dissolved Into methanol (6 ml), a 40% acetaldehyde solution (1 mL) and sodium triacetoxyborohydride (45 mg, 0.212 mmol) were then added and stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the mixture was combined with methylene chloride and methanol (10/1, 20 ml). The title compound (4 mg, 0.008 mmol) was obtained from the title compound (4 mg, m. LC-MS: m/z: (M+H) ⁺ = 528.3, ¹ H NMR (400 MHz, EtOAc) δ 8. s (s, 1H), 8.1 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H) , 5.73 (ddt, J = 16.3, 10.2, 6.1 Hz, 1H), 5.10 - 5.02 (m, 1H), 4.92 (dd, J = 17.1, 1.2 Hz, 1H), 4.82 (s, 2H), 3.14 (d , J = 10.8 Hz, 0H), 2.92 (dt, J = 16.3, 14.4 Hz, 1H), 2.79 (t, J = 12.2 Hz, 5H), 2.17 (d, J = 10.2 Hz, 0H), 1.70 (dd , J = 11.7, 6.5 Hz, 0H), 1.60 (s, 6H), 1.17 (t, J = 7.2 Hz, 6H).

Example 61

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (400 mg, 1.78 mmol) (as compound of formula I-61-a) was dissolved in 18 mL of methanol then added (1368 mg, 17.8) Ethyl ammonium acetate was stirred at room temperature for 2 h, then (120 mg, 1.91 mmol) sodium cyanoborohydride. The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 1 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown oil (as compound of formula I-61-b) (200 mg, 0.84 mmol) was obtained in 50% yield. LC-MS: m/z: (M+H) ⁺ = 226.0, 228.0.

The second step:

6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine (200 mg, 0.84 mmol) (as the compound of formula I-61-b) and sodium cyanoborohydride (280 mg, 4.46 mmol) Dissolved in 10 ml of methanol, added with 0.5 mL of propionaldehyde, and stirred at room temperature for 16 h at room temperature. The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 1 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown oil (190 mg, 0.61 mmol) (as compound of formula I-61-c) was obtained with a yield of 69%. LC-MS: m/z: (M+H) ⁺ = 310.1, 3121.

third step:

6-Bromo-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (190 mg, 0.61 mmol) (as shown in formula I-61-c), diphenyl Methyl ketone (122 mg, 0.67 mmol), sodium tert-butoxide (118 mg, 1.22 mmol), Pd ₂ (dba) ₃ (28 mg, 0.03 mmol), BINAP (38 mg, 0.06 mmol) was added to 10 ml of toluene in argon The gas was ventilated three times and then heated to 100 ° C for 18 h. The reaction mixture was concentrated, and the obtained crude crystal was purified (jjjjjjjjjj . LC-MS: m/z: (M+H) ⁺ = 41.

the fourth step:

6-((Diphenylmethylene)amino)-N,N-dipropyl-1,2,3,4-tetrahydronaphthalen-2-amine (220 mg, 0.54 mmol) (as in formula I-61- The compound shown by d was dissolved in 10 ml of methanol, and then sodium acetate trihydrate (220 mg, 1.62 mmol) and hydroxylamine hydrochloride (82 mg, 1.18 mmol) were added, and the mixture was heated to 60 ° for 5 hours. The reaction mixture was concentrated by EtOAc (EtOAc m.j. %. LC-MS: m / z: (M + H) + = 247.2, 1 H NMR (400MHz, CDCl 3) δ6.91 (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 = 9.7 Hz, 1H), 2.13 - 1.82 (m, 8H), 1.03 (t, J = 7.3 Hz, 6H).

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (72 mg, 0.2 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (50 mg, 0.22 mmol) in 15 ml of toluene. 2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazole And a toluene solution of [3,4-d]pyrimidin-3-one. To the above obtained solution was added N,N-dipropyl-1,2,3,4-tetrahydronaphthalene-2,6-diamine (65 mg, 0.27 mmol) (as the compound of formula I-61-e) It was stirred with 0.1 ml of N,N-diisopropylethylamine at room temperature for 18 h. The organic product was concentrated under reduced pressure and purified (yield: 7M ammonia methanol: methylene chloride = 0-10%). Yellow solid, yield 40%. LC-MS: m/z: (M+H) ⁺ = 556.3, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 7.90 (t, J = 7.8 Hz, 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, 5.0 Hz, 1H), 5.07 (d, J = 10.2 Hz, 1H), 4.96 (d, J = 17.1 Hz, 1H), 4.78 (d, J = 6.2 Hz, 2H), 3.91 (s, 1H), 3.06 (s, 1H), 2.87 (d, J = 30.3 Hz, 4H), 2.57 (s, 4H), 2.13 (s, 2H), 1.61 (s, 6H), 1.57 (s, 4H), 0.94 (t, J = 7.3 Hz, 6H).

Example 62

first step:

6-Amino-1,4-dihydronaphthalene-1(2H)-1 (148.9 mmol) (as the compound of formula I-62-a) was dissolved in dichloromethane (200 mL), and N was added to the reaction mixture. N-diisopropylethylamine (446.7 mmol), the reaction solution was cooled to 0 ° C, acetyl chloride (223.3 mmol) was slowly added to the reaction mixture, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssss (Compound as shown in formula I-62-b) (26.5 g), yield: 87.6%, gray solid. LC-MS: m/z: [M+1] ⁺ = 204.

The second step:

N-(5-oxo-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (25 mmol) (as a compound of formula I-62-b) is dissolved in 1,1- Dimethoxy-N,N-dimethylmethylamine (60 mL) was heated to reflux and stirred for 18 h. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals crystalsssssssssssssssssssssssssssss 6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (as compound of formula I-62-c) (5.8 g, 91%). LC-MS: m/z: [M+1] ⁺ = 259.

third step:

(E)-N-(6-((Dimethylamino)methylene)-5-oxo-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (3.96 mmol) (A compound of the formula I-62-c) was dissolved in methanol (15 mL), palladium carbon (500 mg) and concentrated hydrochloric acid (1 mL) were added, and the reaction mixture was heated to reflux and stirred for 24 hours. The reaction mixture was adjusted to pH = 9 with aq. EtOAc. EtOAc. Target compound 6-((dimethylamino)methyl)-5-,6-,7-,8-tetrahydronaphthalen-2-amine (compounds of formula I-62-d) = 20/1) (150 mg, 19%), yellow oil. LC-MS: m/z: [M+1] ⁺ = 205.

the fourth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-D]pyrimidin-3-one (0.56 mmol) (as the compound of formula 1A) was dissolved in 1,2-dichloroethane (10 mL), and m-chloroperoxybenzoic acid (0.62 mmol) was added. The solution was stirred at room temperature for 0.5 hours, and 6-((dimethylamino)methyl)-5-,6-,7-,8-tetrahydronaphthalen-2-amine (0.56 mmol) was added to the reaction mixture (as in formula I) -62-d compound) and N,N-diisopropylethylamine (1.68 mmol). The reaction mixture was heated to 70 ° C and stirred for 16 hours. The reaction liquid was evaporated to dryness to give a crude product. EtOAc (EtOAc) Hydronaphthalen-2-yl)amino)-1-(3-(2-hydroxypropan-2-yl)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidine- 3-ketone (as compound of formula I-62) (31 mg, 10.8%) as a 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, 2.2 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 5.73 (ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.01 (ddd, J = 18.3, 13.6, 1.2 Hz, 2H), 4.78 (d, J = 6.2 Hz, 2H), 3.91 (s, 1H), 2.96 (dd, J = 16.7, 4.8 Hz, 1H), 2.86 (dd, J = 7.8, 4.3 Hz, 2H), 2.44 (dd, J = 16.2, 10.4 Hz, 1H), 2.31 (s, 8H), 2.01 (s, 2H), 1.61 (s, 6H).

Example 63

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (400 mg, 1.78 mmol) (as a compound of formula I-63-a) was dissolved in 18 mL of methanol then ammonium acetate (1368 mg, After stirring at room temperature for 2 h, sodium cyanoborohydride (120 mg, 1.91 mmol). The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 1 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown oil (as a compound of formula I-63-2) (150 mg, 0.84 mmol) was obtained in a yield of 37%. LC-MS: m/z: (M+H) ⁺ = 226.0, 228.0.

The second step:

6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine (150 mg, 0.67 mmol) (as compound of formula I-63-b) and sodium cyanoborohydride (209 mg, 3.3 mmol) Dissolved in 10 ml of methanol, added 0.5 mL of acetone, and stirred at room temperature for 16 h at room temperature. The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 1 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown oil (170 mg, 0.55 mmol) (as compound of formula I-63-c) was obtained in a yield of 83%. LC-MS: m/z: (M+H) ⁺ = 268.1, 270.1.

third step:

6-Bromo-N-isopropyl-1,2,3,4-tetrahydronaphthalen-2-amine (170 mg, 0.5 mmol) (as shown in formula I-63-c) and Boc ₂ O (137 mg) , 0.55 mmol) was dissolved in 10 ml of dichloromethane, and 0.16 mL of N,N-diisopropylethylamine was added, and the mixture was stirred at room temperature to 40 ° C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc The yield was 76%. LC-MS: m/z: (M+H) ⁺ = 368.1, 370.1.

the fourth step:

(6-Bromo-1,2,3,4-tetrahydronaphthylamine-2-yl)(isopropyl)carbonate tert-butyl ester (176 mg, 0.48 mmol) (as compound of formula I-63-d) , benzophenone imine (94 mg, 0.52 mmol), sodium tert-butoxide (91 mg, 0.95 mmol), Pd ₂ (dba) ₃ (22 mg, 0.02 mmol), BINAP (30 mg, 0.05 mmol) was added to 10 ml of toluene , ventilate three times in argon, then heat to 100 ° C for 18h. The reaction mixture was concentrated, and the obtained crude material was purified (jjjjjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 469.3.

the fifth step:

(6-((Diphenylmethylene)amino)-1,2,3,4-tetrahydronaphthylamine-2-yl)(isopropyl)carbonate tert-butyl ester (180 mg, 0.38 mmol) The compound shown by I-63-e was dissolved in 10 ml of methanol, and then sodium acetate trihydrate (157 mg, 1.15 mmol) and hydroxylamine hydrochloride (82 mg, 0.85 mmol) were added, and the mixture was heated to 60 ° C for 5 hours. The reaction mixture was filtered and concentrated, and then purified,jjjjjjjjjjjjjjjjjjjj . ^{_{1 H NMR (400MHz, CDCl 3}} ) δ6.91 (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 = 11.0 Hz, 1H), 2.18 (dt, J = 44.1, 12.4 Hz, 2H), 1.83 (d, J = 10.1 Hz, 1H), 1.50 ( s, 9H), 1.26 (d, J = 16.4 Hz, 6H). LC-MS: m/z: (M+H) ⁺ = 305.3.

The sixth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (such as the compound of formula 1A) (108 mg, 0.3 mmol) was added to a solution of 15 ml of toluene to m-chloroperoxybenzoic acid (82 mg, 0.47 mmol). 2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazole And a toluene solution of [3,4-d]pyrimidin-3-one (such as the compound of Formula 1B). To the solution obtained above was added (6-amino-1,2,3,4-tetrahydronaphthylamine-2-yl)(isopropyl)carbonate tert-butyl ester (102 mg, 0.33 mmol) (as in formula I-63- The compound shown by g) and 0.16 ml of N,N-diisopropylethylamine were stirred at room temperature for 18 h. Concentration under reduced pressure, the crude product was purified by EtOAc (EtOAc (EtOAc:EtOAc) The yield was 46%. LC-MS: m/z: (M+H) ⁺ = 614.3.

Step 7:

(6-((2-Allyl-1-(6-(2-hydroxyisopropyl-2-yl)pyridin-2-yl)-3-one-2,3-dihydro-1H-pyridyl) Zyrazo[3,4-d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydronaphthylamine-2-yl)(isopropyl)carbonate tert-butyl ester (85 mg, 0.3 mmol) (The compound of the formula I-63-g) was dissolved in 10 ml of dichloromethane, and 0.5 mL of a 4N hydrogen chloride dioxane solution was added thereto, and stirred at room temperature for 4 hours. The organic layer was concentrated under reduced pressure and the obtained crude crystals were evaporated. The aqueous layer was adjusted to pH = 10 with a 2N NaOH solution, and filtered to give the title compound (yield of the compound of formula I-63) (yield of formula I-63) 70 mg as a yellow solid, yield 98%. LC-MS: m/z: (M+H) ⁺ = 514.3, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 7.90 (t, J = 7.8 Hz, 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 = 6.1 Hz, 6H) ).

Example 64

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (0.5 g, 2.22 mmol) (as a compound of formula I-64-a) was added to 15 ml of methanol under ice bath Sodium borohydride (100 mg, 2.65 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The combined organic layers were dried with anhydrous sodium sulfate and evaporated. A colorless liquid of 380 mg was obtained in a yield of 75%. LC-MS: m/z: (M+Na) ⁺ = 249.

The second step:

Powdered potassium hydroxide (470 mg, 8.39 mmol) and 6-bromo-1,2,3,4-tetrahydronaphthalen-2-ol (380 mg, 1.67 mmol) (as shown in formula I-64-b) The compound) was added to 7 ml of anhydrous dimethyl sulfoxide and stirred at room temperature for 15 min. Methyl iodide (700 mg, 4.93 mmol) was then added and stirred at room temperature overnight. 20 ml of a saturated saline solution and 3 times of dichloromethane (3*20 ml) were added to the reaction mixture. The organic layer was washed with water (3×15 ml), and evaporated. The yield was 84%. LC-MS: m/z: (M+Na) ⁺ = 263.

third step:

6-Bromo-2-methoxy-1,2,3,4-tetrahydronaphthalene (340 mg, 1.41 mmol) (as shown in formula I-64-c), benzophenone imine (300 mg) , 1.66 mmol), sodium tert-butoxide (220 mg, 2.29 mmol), Pd ₂ (dba) ₃ (45 mg, 0.05 mmol), BINAP (90 mg, 0.14 mmol) was added to 20 ml of toluene, ventilated three times in argon, then Heat to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude material was purified (jjjjjjj 1H NMR (400MHz, CDCl3) δ 7.77 - 7.71 (m, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.33 - 7.29 (m, 3H) , 7.15 (dd, J = 7.3, 2.2 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.45 (dd, J = 8.0, 2.0 Hz, 1H), 3.60 ( m, 1H), 3.42 (s, 3H), 3.00 (dd, J = 16.3, 4.9 Hz, 1H), 2.78 (dt, J = 16.9, 5.7 Hz, 1H), 2.65 (m, 2H), 2.04 (m) , 1H), 1.80–1.68 (m, 1H).

the fourth step:

N-(6-Methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-benzophenone imine (450 mg, 1.3 mmol) (as in formula I-64- The compound shown by d was dissolved in 20 ml of methanol, and then sodium acetate (340 mg, 4.15 mmol) and hydroxylamine hydrochloride (210 mg, 3 mmol) were added, and the mixture was heated to 60 ° C overnight. The reaction mixture was filtered and concentrated, and then purified, mjjjjjj LC-MS: m/z: (M+H) ⁺ = 178.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (107 mg, 0.3 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (76 mg, 0.34 mmol) in 25 ml of toluene, and the resulting solution was stirred at room temperature. 1h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl Zoxao[3,4-d]pyrimidin-3-one. This solution was used directly for the next reaction. LC-MS: m/z: (M+H) ⁺ = 374.

To the above obtained solution was added 6-methoxy-5,6,7,8-tetrahydronaphthalen-2-amine (55 mg, 0.31 mmol) (as the compound of formula I-64-e) and 1 ml of N, N-Diisopropylethylamine was stirred at room temperature overnight. Concentration under reduced pressure, the obtained crude product was purified by column (methanol: (dichloromethane: ethyl acetate = 2:1) = 1: 15), and then purified by thin layer chromatography. Ethyl acetate = 2:1) = 0-15%)} gave 25 mg as a white solid. LC-MS: m/z: (M+H) ⁺ = 487, 1H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.87 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H) ), 7.78 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.41 - 7.33 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 5.75 - 5.60 (m, 1H), 5.32 (s, 1H), 5.00 (dd, J = 10.3, 1.2 Hz, 1H), 4.83 (dd, J = 17.1, 1.3 Hz, 1H), 4.70 (d, J = 5.9 Hz, 2H), 3.64 (m, 1H), 3.32 (s, 3H), 2.97 (dd, J = 16.4, 4.5 Hz, 1H), 2.88 - 2.59 (m, 3H), 2.08 - 1.96 (m, 1H), 1.83 –1.68 (m, 1H), 1.47 (s, 6H).

Example 65

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (0.6 g, 2.66 mmol) (compound as shown in formula I-64-a) was added to 15 ml of methanol under ice bath Sodium borohydride (110 mg, 2.91 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The combined organic layers were dried with anhydrous sodium sulfate and evaporated. A colorless liquid of 460 mg was obtained in a yield of 75%. LC-MS: m/z: (M-OH) ⁺ = 209.

The second step:

Addition of imidazole (330 mg, 4.85 mmol) and 6-bromo-1,2,3,4-tetrahydronaphthalen-2-ol (440 mg, 1.94 mmol) (compound as shown in formula I-64-b) to 5 ml In N,N-dimethylformamide, tert-butyldimethylsilyl chloride (360 mg, 2.39 mmol) was then added and stirred at room temperature overnight. 30 ml of ethyl acetate was added to the reaction mixture. The organic layer was washed twice with water (2*15 ml), EtOAc (EtOAc) (EtOAc) 540mg. The yield was 81%. 1H NMR (400MHz, CDCl3) δ 7.23 - 7.18 (m, 2H), 6.91 (d, J = 8.0 Hz, 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).

third step:

((6-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (540 mg, 1.58 mmol) (as in Formula I-65-c) The compound shown), benzophenone imine (330 mg, 1.82 mmol), sodium tert-butoxide (240 mg, 2.5 mmol), Pd ₂ (dba) ₃ (45 mg, 0.05 mmol), BINAP (95 mg, 0.15 mmol) Into 20 ml of toluene, argon gas was exchanged three times and then heated to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified (yield: ethyl acetate: petroleum ether = -30%).

the fourth step:

N-[2-[tert-Butyl(dimethyl)silyl]oxytetrahydronaphthalen-6-yl]-1,1-diphenyl-imine (600 mg, 1.36 mmol) (as in formula I) The compound shown by -65-d was dissolved in 30 ml of methanol, then sodium acetate (340 mg, 4.15 mmol) and hydroxylamine hydrochloride (210 mg, 3 mmol) were added and heated to 60 ° for 2 h. The reaction mixture was concentrated by filtration, and then purified, mjjjjj LC-MS: m/z: (M+H) ⁺ = 278.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (120 mg, 0.33 mmol) (as the compound of formula 1A) was added m-chloroperoxybenzoic acid (85 mg, 0.38 mmol) in 25 ml of toluene, and the resulting solution was stirred at room temperature. 1h. To the solution obtained above was added 6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-amine (100 mg, 0.36 mmol) (eg, formula I-64) The compound shown by -e) and 1 ml of N,N-diisopropylethylamine were stirred at room temperature overnight. Concentration under reduced pressure, the obtained crude product was purified by column (methanol: (dichloromethane: ethyl acetate = 2:1) = 1: 15), and then purified by thin layer chromatography. Ethyl acetate = 2:1) = 0-15%)} gave a white solid, 110 mg, yield 55%. LC-MS: m/z: (M+H) ⁺ = 587.

The sixth step:

2-Allyl-6-((6-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)amino)-1-( 6-(2-Hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (100 mg, 0.17 mmol) ( The compound shown in formula I-65-f) and 1 ml of tetra-n-butylammonium fluoride (1 mol/L in THF) were added to 5 ml of tetrahydrofuran and stirred at 35 degrees overnight. The organic product was concentrated under reduced pressure. EtOAc (methanol: EtOAc (EtOAc:EtOAc) LC-MS: m/z: (M+H) ⁺ = 473. 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.86 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H) ), 7.78 (d, J = 7.8 Hz, 1H), 7.64 (dd, J = 7.7, 0.6 Hz, 1H), 7.60 (s, 1H), 7.36 (dd, J = 8.3, 1.9 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 5.67 (ddt, J = 16.2, 10.3, 5.9 Hz, 1H), 5.32 (s, 1H), 5.00 (dd, J = 10.3, 1.3 Hz, 1H), 4.83 ( Dd, J = 17.1, 1.4 Hz, 1H), 4.76 (s, 1H), 4.70 (d, J = 5.9 Hz, 2H), 3.91 (s, 1H), 2.86 (ddd, J = 16.6, 13.7, 5.1 Hz) , 2H), 2.79–2.66 (m, 1H), 2.56 (dd, J = 16.1, 8.1 Hz, 1H), 1.98–1.88 (m, 1H), 1.65 (ddd, J=12.5, 9.0, 3.4 Hz, 1H) ), 1.47 (s, 6H).

Example 66

first step:

6-Acetylamino-1,2,3,4-tetrahydro-1-naphthalenone (2000 mg, 9.8406 mmol) (as shown in formula 1-66-a) was dissolved in toluene (40 mL), then B was added Ethyl aldehyde (2 equiv., 19.681 mmol, 50 mass%) (as shown in formula I-66-b), magnesium sulfate (5 equiv., 49.203 mmol) and p-toluenesulfonic acid (0.1 equiv., 0.98406 mmol) . The reaction was heated to 120 ° C and stirred for 12 hours. After adding 20 ml of water, the mixture was evaporated. The crude product was separated and purified on a normal phase silica gel column (eluent EA/PE = 0% to 60%, 12 CV) to afford the title compound (the compound of formula I-66-c) 2.0 g, yellow solid, yield 61 %. LC-MS: m/z: (M+H) ⁺ = 288.0.

The second step:

Ethyl (E)-2-(6-acetamido-1-oxo-3,4-dihydronaphthalen-2-(1H)-methylene) acetate (2000 mg, 6.961 mmol) (eg The compound of formula I-66-c) was dissolved in ethanol (20 mL), then sulfuric acid solution (1 mL, 70 mass%) and Pd/C (200 mg, 10 mass%) were added. The reaction was stirred at room temperature for 12 hours under a hydrogen atmosphere. Filter and adjust the pH of the filtrate to 7-8 with saturated sodium bicarbonate solution. The solution was extracted with EtOAc (2×20 mL). The crude product was separated and purified on a normal phase silica gel column (eluent EA/PE = 8% to 60%, 12 CV) to afford the title compound (as compound of formula I-66-d) 0.7 g, yellow solid, yield 36 %. 1H NMR (400MHz, MeOD) δ 7.27 (s, 1H), 7.23 (dd, J = 8.2, 2.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 4.11 (t, J = 7.1 Hz) , 2H), 2.87 (d, J = 4.5 Hz, 1H), 2.81 (dd, J = 8.2, 4.3 Hz, 2H), 2.44 (dd, J = 15.8, 10.1 Hz, 1H), 2.38 (d, J = 7.1 Hz, 2H), 2.20 (d, J = 7.8 Hz, 1H), 2.11 (s, 3H), 2.01 - 1.90 (m, 1H), 1.47 (dd, J = 12.8, 10.8 Hz, 1H), 1.29 ( t, J = 5.1 Hz, 3H).

third step:

Ethyl-2-(6-acetamide-1,2,3,4-dihydronaphthalen-2-yl)acetate (700 mg, 2.436 mmol) (as compound of formula I-66-d) Dissolved in ethanol (20 mL) solution, then added sulfuric acid solution (2 mL, 70 mass%). The reaction was heated to reflux and stirred for 12 hours. The mixture was extracted with ethyl acetate (2×2 mL), EtOAc (EtOAc m. 99%. ^{1 H NMR (400MHz, MeOD)} δ6.79 (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, 2.9 Hz, 1H), 1.96–1.86 (m, 1H), 1.49–1.37 (m, 1H), 1.35–1.21 (m, 3H).

the fourth step:

2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthio-pyrazole[3,4-d]pyrimidin-3-one ( 70 mg, 0.1959 mmol) (as the compound of formula 1A) was dissolved in dichloroethane (2 mL) then mCPBA (1.3 equiv., 0.2546 mmol, 77 mass%). The reaction was stirred at room temperature for 2 hours. Thereafter, DIPEA (3 equiv., 0.5876 mmol) and ethyl 2-(6-amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetate were added (as shown in Formula I-66-e). Compound) (3 equiv., 0.5876 mmol,). The reaction was stirred at room temperature for 12 hours. The mixture was extracted with EtOAc (EtOAc) (EtOAc m. The crude product was purified by pre-HPLC (Eluent acetonitrile/water (formic acid 0.1%) = 30% to 60%) to give the title compound (the compound of formula I-66) 25 mg, white solid, yield 23.5% . 1H NMR (400MHz, DMSO) δ 10.19 (s, 1H), 8.87 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 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, 1.3 Hz, 1H), 4.83 (dd, J = 17.1, 1.3 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.80 (dd, J = 16.0, 4.2 Hz, 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 = 7.1 Hz, 3H). LC-MS: m/z: (M+H) ⁺ = 543.

Example 67

2-(6-((2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyridyl) Iso[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetate (520 mg, 0.9583 mmol) (as shown in Formula I-66) The compound was dissolved in a mixed solvent of methanol (5 ml) and tetrahydrofuran (5 ml), and then aqueous lithium hydroxide (1 mol/L, 5 ml) was added. The reaction was stirred for 2 hours while heating to 50 ° 50 ° C. The reaction was quenched with 1N aqueous HCl and pH was adjusted to 6-7, and then a large white solid was precipitated and filtered to give a white solid, which was rinsed twice with petroleum ether (5 ml). The product was further purified by Pre-HPLC (conditions: acetonitrile/water (0.1% formic acid) = 30% to 60% of 12 CV) to afford the title compound (the compound of formula I-67) 400 mg, white solid, yield: 81.1% . 1H NMR (400MHz, DMSO) δ 10.21 (s, 1H), 8.87 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 0H), 7.64 (d) , J = 7.5 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.67 (dd, J = 17.1, 10.3 Hz, 1H), 5.34 (s) , 1H), 5.00 (d, J = 10.2 Hz, 1H), 4.82 (d, J = 17.1 Hz, 1H), 4.70 (d, J = 5.9 Hz, 1H), 2.81 (dd, J = 21.9, 4.6 Hz , 3H), 2.39 (dd, J = 16.6, 10.4 Hz, 1H), 2.29 (d, J = 7.0 Hz, 2H), 2.08 (s, 1H), 1.92 (s, 1H), 1.58 - 1.32 (m, 7H). LC-MS: m/z: (M+H) ⁺ = 515.

Example 68

Ethyl 2-(6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H) -pyrazol[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid (40 mg, 0.07773 mmol) (as shown in Formula I-67) The compound was dissolved in DMF (2 ml), then HATU (1 equiv., 0.07773 mmol) and DIPEA (2 equiv., 0.1555 mmol) were added, and finally ethylamine (2equive., 0.1555 mmol) was added. The reaction was stirred at room temperature for 12 hours. 20 ml of water was added and the mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed twice with brine (20 ml), dried over sodium sulfate, filtered and evaporated. The crude product was further purified by Pre-HPLC (conditions: acetonitrile/water (0.1% formic acid) = 30% to 60% 12 CV) to give the desired compound (as compound of formula I-68) 18 mg as a white solid, yield 41. ). NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.03 (t, J = 7.9 Hz, 0H), 7.85 (t, J = 5.3 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.67 (ddd, J = 23.0, 10.3, 5.9 Hz, 1H), 5.34 (s, 1H), 5.00 (d, J = 10.3 Hz, 1H), 4.90 - 4.76 (m, 1H), 4.70 (d, J = 5.8 Hz, 2H), 3.16–3.04 (m, 2H), 2.74 (dd, J=23.4, 14.8 Hz, 3H), 2.43–2.30 (m, 1H), 2.10 (d, J = 12.8 Hz, 2H), 1.88 (d, J=) 12.7 Hz, 1H), 1.47 (s, 6H), 1.38 (s, 1H), 1.04 (t, J = 7.2 Hz, 3 GH). LC-MS: m/z: (M+H) ⁺ = 542.

Example 69

Using the same compound as ethyl 2-(6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro) -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (such as the compound of formula I-67) In the same manner, 18 mg of the title compound was obtained as white solid. 1H NMR (400MHz, DMSO) δ 10.19 (s, 1H), 8.91 - 8.84 (m, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.35 (d, J = 9.6 Hz, 1H), 6.99 (d, J = 8.3 Hz, 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, 6.1 Hz, 2H), 3.16 (d, J = 5.7 Hz, 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 = 18.7 Hz, 6H), 1.45-1.30 (m, 1H). LC-MS: m/z: (M+H) ⁺ =558.

Example 70

Using the same compound as ethyl 2-(6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro) -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (such as the compound of formula I-67) In the same manner, 20 mg of the title compound (e.g., compound of formula I-70) was obtained as a white solid, yield 46.7%. 1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 3.8 Hz, 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 = 10.3 Hz, 1H), 4.82 (d, J = 18.6 Hz, 1H), 4.70 (d, J = 5.9 Hz, 2H), 2.76 (s) , 3H), 2.69 - 2.61 (m, 1H), 2.32 (d, J = 10.5 Hz, 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, 2.1 Hz, 2H), 0.40 (dd, J = 8.4, 5.8 Hz, 2H). LC-MS: m/z: (M +H) ⁺ =554.

Example 71

Using the same compound as ethyl 2-(6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro) -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (such as the compound of formula I-67) The target compound (as shown in Formula I-71) was obtained in the same manner, 15 mg, white solid, yield: 35.0%. 1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.33 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.1 Hz) , 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.67 (dd, J = 16.9, 10.4 Hz , 1H), 5.33 (s, 1H), 5.00 (d, J = 10.3 Hz, 1H), 4.83 (d, J = 17.1 Hz, 1H), 4.70 (d, J = 5.4 Hz, 2H), 3.89 (d , J = 5.2 Hz, 2H), 3.12 (t, J = 2.5 Hz, 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.

Example 72

Using the same compound as ethyl 2-(6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro) -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (such as the compound of formula I-67) In the same manner, 15 mg of the title compound was obtained as white solid. 1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 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 = 10.4 Hz, 1H), 4.82 (d, J = 17.0 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 4.33 (s, 4H), 3.41 (d, J = 5.8 Hz) , 4H), 2.79 (d, J = 17.1 Hz, 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.

Example 73

Using the same compound as ethyl 2-(6-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro) -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amine-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (such as the compound of formula I-67) In the same manner, a target (e.g., compound of formula I-73) compound 15 mg was obtained as a white solid. 1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.63 (d) , J = 7.6 Hz, 2H), 7.35 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.73 - 5.62 (m, 1H), 5.34 (s, 1H), 5.00 (d, J = 10.7 Hz, 1H), 4.82 (d, J = 16.9 Hz, 1H), 4.70 (d, J = 5.8 Hz, 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 = 32.9 Hz, 3H), 1.47 (s, 6H), 1.45-1.35 (m, 1H). LC-MS: m /z: (M+H) ⁺ =618.

Example 74

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (855 mg, 3.8 mmol) (as shown in formula I-74-a) and (400 mg, 5.6 mmol) pyrrolidine were dissolved in 20 mL Dichloromethane was then added (1.6 g, 7.6 mmol) of sodium borohydride, and the mixture was stirred at 65 ° C overnight. Quenched with 5 ml of water, washed with saturated aqueous sodium sulfate and brine, dried over anhydrous sodium sulfate The solution was freed from solidified ethyl acetate. Filtration gave 1 g of an off-white solid. Yield: 83%. LC-MS: m/z: [M+1] ⁺ = 280.

The second step:

1-(6-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)pyrrolidine hydrochloride (1 g, 3.16 mmol) (as the compound of formula I-74-b), Benzoketimine (620 mg, 3.4 mmol), sodium tert-butoxide (450 mg, 4.69 mmol), Pd ₂ (dba) ₃ (100 mg, 0.11 mmol), BINAP (150 mg, 0.241 mmol) was added to 20 ml of toluene. Argon was ventilated three times and then heated to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified (jjjjjjj LC-MS: m/z: (M+H) ⁺ =381.

third step:

1,1-Diphenyl-N-(6-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)methylimine (1 g, 2.63 mmol) (eg The compound of the formula I-74-c) was dissolved in 30 ml of methanol, then sodium acetate (0.7 g, 8.5 mmol) and hydroxylamine hydrochloride (370 mg, 5.32 mmol) were added, and the mixture was heated to 60 ° C overnight. The reaction mixture was concentrated by filtration and purified to purified crystals crystals crystals LC-MS: m/z: (M+H) ⁺ = 217.

the fourth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (120 mg, 0.336 mmol) (as the compound of formula 1A) was added to a solution of 15 ml of toluene to give m-chloroperoxybenzoic acid (82 mg, 0.367 mmol). 2h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl Zoxao[3,4-d]pyrimidin-3-one. This solution was used directly for the next reaction.

Add 6-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-amine (100 mg, 0.46 mmol) in 10 ml of dichloromethane (as shown in formula I-74-d) The compound and 0.5 ml of N,N-diisopropylethylamine were stirred until the solution was clarified, and then added to the toluene solution obtained above, and stirred at room temperature for 40 h. Concentration under reduced pressure, the crude product was separated and purified by thin layer chromatography (7M ammonia methanol: (dichloromethane: ethyl acetate = 5:1) = 1:12) 16 mg, yield 7%. LC-MS: m/z: (M+H) ⁺ = 526, ¹ H NMR (400 MHz, MeOH) δ 8.85 (s, 1H), 8.40 (s, 2H), 8.14 (s, 1H), 7.92 ( t, J = 7.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.54 - 7.32 (m, 3H), 7.08 (d, J = 7.9 Hz, 1H), 5.81 - 5.62 (m, 1H) ), 5.07 (d, J = 10.0 Hz, 1H), 4.95 (d, J = 16.9 Hz, 1H), 4.77 (d, J = 5.5 Hz, 2H), 3.37 (m, 5H), 3.19 (d, J) = 7.6 Hz, 2H), 2.95 (m, 2H), 2.37 (s, 1H), 2.13 (s, 5H), 1.62 (s, 6H).

Example 75

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (900 mg, 4 mmol) (as the compound of formula I-75-a), azetidine hydrochloride (750 mg, 8 mmol) and 20 ml of water was added to 60 mL of methanol, then (1.31 g, 16 mmol) of sodium acetate was added, and the mixture was stirred at room temperature under nitrogen for 1 h.

(1.5 g, 16 mmol) of acetic acid and (500 mg, 8.2 mmol) of sodium cyanoborohydride were added to the above mixture and stirred at room temperature under nitrogen overnight. After concentration under reduced pressure, 20 ml of saturated aqueous sodium carbonate solution was added, and extracted with dichloromethane (3×30 ml). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Methyl chloride: EA = 2:1) = 0-15%}, yielded a brown oil, 700mg yield: 65%. LC-MS: m/z: [M+1] ⁺ =266.

The second step:

1-(6-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)azetidine (0.7 g, 2.63 mmol) (as a compound of formula I-75-b), Benzophenone imine (530 mg, 2.92 mmol), sodium tert-butoxide (410 mg, 4.27 mmol), Pd ₂ (dba) ₃ (80 mg, 0.087 mmol), BINAP (165 mg, 0.265 mmol) was added to 35 ml of toluene. The gas was ventilated three times with argon and then heated to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 367.

third step:

1,1-Diphenyl-N-(6-(azetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)methylimine (1 g, 2.53 mmol) (A compound such as the formula I-75-c) was dissolved in 40 ml of methanol, then sodium acetate (0.61 g, 7.44 mmol) and hydroxylamine hydrochloride (340 mg, 4.89 mmol) were added, and the mixture was heated to 60 ° C overnight. The reaction mixture was concentrated by filtration and purified to purified crystals crystals crystals LC-MS: m/z: (M+H) ⁺ = 203.

the fourth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (150 mg, 0.42 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (110 mg, 0.49 mmol) in 25 ml of toluene, and the resulting solution was stirred at room temperature. 2h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl Zoxao[3,4-d]pyrimidin-3-one.

After concentrating the above reaction solution, 6-(azetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-amine (100 mg, 0.49 mmol) was added (as in formula I-75-d). The compound shown), 0.2 ml of trifluoroacetic acid and 5 ml of dimethyl sulfoxide, was stirred at 60 degrees for 24 h.

To the above reaction solution, 10 ml of a saturated aqueous solution of sodium carbonate and 25 ml of water were added, and the mixture was extracted three times with dichloromethane (3*20 ml), and the organic phases were combined and washed with 20 ml of water and 20 ml of saturated sodium chloride solution, anhydrous sodium sulfate After drying, the crude product was concentrated to give a crude material (yield: 3M ammonia methanol: (dichloromethane: ethyl acetate = 1:1) = 0-15%}, The yield was 39%. LC-MS: m/z: (M+H) ⁺ = 512, 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 7.89 (t) , J = 7.9 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 8.3, 2.1 Hz , 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.71 (ddt, J = 16.4, 10.2, 6.2 Hz, 1H), 5.05 (dd, J = 10.2, 1.1 Hz, 1H), 4.94 (dd, J = 17.1, 1.2 Hz, 1H), 4.76 (d, J = 6.2 Hz, 2H), 4.01 (t, J = 7.8 Hz, 4H), 3.19 - 3.06 (m, 1H), 3.06 - 2.75 (m, 4H) ), 2.48 (p, J = 7.5 Hz, 2H), 2.13 (d, J = 10.0 Hz, 1H), 1.93 - 1.75 (m, 1H), 1.61 (s, 6H).

Example 76

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (1 g, 4.44 mmol) (as compound of formula I-76-a), piperidine (760 mg, 8.93 mmol) and p-toluene Sulfonic acid (90 mg, 0.52 mmol) was added to 40 mL of toluene, and a water separator was placed on the reaction flask, and stirred at 155 ° C overnight.

The solvent toluene in the reaction was distilled off under reduced pressure, and then 40 ml of methanol was added, and sodium borohydride (0.85 g, 23 mmol) was slowly added to the ice bath, and the ice bath was removed and stirred for 2 h. The organic layer was washed twice with 1 ml/L hydrochloric acid twice (2*20 ml), and the combined acidic solution was alkalized with 5 mol/L sodium hydroxide. The organic phase was dried over anhydrous sodium sulfate (MgSO4). LC-MS: m/z: [M+1] ⁺ = 294.

The second step:

1-(6-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine (0.9 g, 3.06 mmol) (as a compound of formula I-76-b), diphenyl Ketoimine (620mg, 3.42mmol), sodium tert-butoxide (470mg, 4.89mmol), Pd ₂ (dba) ₃ (90mg, 0.1mmol), BINAP (190mg, 0.3mmol) added to 35ml of toluene with argon Change the air three times and then heat to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified (jjjjjjjj LC-MS: m/z: (M+H) ⁺ = 395.

third step:

1,1-Diphenyl-N-(6-(piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)imine (1 g, 2.53 mmol) (eg The compound of the formula I-76-c) was dissolved in 40 ml of methanol, then sodium acetate (1 g, 12.2 mmol) and hydroxylamine hydrochloride (360 mg, 5.18 mmol) were added, and the mixture was heated to 60 ° C overnight. The reaction mixture was concentrated by filtration, and the obtained crude product was purified (jjjjjjj LC-MS: m/z: (M+H) ⁺ = 231.

the fourth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (179 mg, 0.5 mmol) (as the compound of formula 1A) was added m-chloroperoxybenzoic acid (122 mg, 0.546 mmol) in a solution of 35 ml of toluene, and the resulting solution was stirred at room temperature. 2h gave 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyridyl Zoxao[3,4-d]pyrimidin-3-one.

After concentrating the above reaction solution, 6-(piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-amine (130 mg, 0.564 mmol) was added (as shown in Formula I-76-d). Compound), 0.2 ml of trifluoroacetic acid and 5 ml of dimethyl sulfoxide, stirred at 60 degrees for 24 h. To the above reaction solution, 10 ml of a saturated aqueous solution of sodium carbonate and 25 ml of water were added, and the mixture was extracted three times with dichloromethane (3*20 ml), and the organic phases were combined and washed with 20 ml of water and 20 ml of saturated sodium chloride solution, anhydrous sodium sulfate After drying, it was concentrated to give a crude material. The obtained crude product was purified by column (3M ammonia methanol: (dichloromethane: ethyl acetate = 1:1) = 0-15%}. The yield was 41%. LC-MS: m/z: (M+H) ⁺ = 540, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.56 (s, 1H), 7.96 (s, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.71 (ddt, J = 16.4, 10.2, 6.2 Hz, 1H), 5.11 - 5.02 (dd, J = 10.2, 1.1 Hz, 1H), 4.94 (dd, J = 17.1, 1.1 Hz, 1H), 4.77 (d, J = 6.1 Hz, 2H), 3.54 (m, 1H), 3.04 (m, 8H), 2.41 (d, J = 11.9 Hz, 1H) ), 1.99 (s, 4H), 1.87 (m, 1H), 1.63 (d, 8H).

Example 82

first step:

(E)-N-(6-((Dimethylamino)methylene)-5-oxo-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (4.6 mmol (The compound of the formula I-82-a) was dissolved in ethanol (20 mL), and piperidine (14 mmol) was added to the reaction mixture, the reaction mixture was heated to reflux, and the reaction mixture was stirred for 16 hours. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystalsssssssssssssssssssssssss 6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (950 mg, 69%). 1H NMR (400MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J = 29.8 Hz, 2H), 7.16 (d, J = 8.3 Hz, 1H) ), 3.47 (s, 4H), 2.90-2.76 (m, 4H), 2.21 (s, 3H), 1.67 (s, 6H).

The second step:

(E)-N-(5-oxo-6-(piperidin-1-methylene)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (3.18 mmol) (as the compound of formula I-82-b) is dissolved in anhydrous methanol (20 mL), Pd/C (300 mg) and concentrated sulfuric acid (0.5 mL) are added to the reaction mixture, and the reaction solution is heated to hydrogen. It was refluxed and stirred for 18 hours. The reaction mixture was adjusted to pH = 9 with a saturated aqueous solution of sodium carbonate, and then filtered to remove Pd / C. The mixture was evaporated to dryness. The crude product was evaporated to dryness crystals crystals crystals crystals crystals Methyl)-5-,6-,7-,8-tetrahydronaphthalen-2-amine (250 mg, 32.1%), yellow oil. LC-MS: m/z: [M+1] ⁺ = 245.

third step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-D]pyrimidin-3-one (0.56 mmol) (as the compound of formula 1A) was dissolved in toluene (15 mL), m-chloroperoxybenzoic acid (0.62 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hour. The reaction solution was evaporated to dryness, and the obtained sulfone intermediate was dissolved in dimethyl sulfoxide (10 mL), and 6-(piperidin-1-methyl)-5-,6-,7-, 8-tetrahydronaphthalene- 2-Amine (0.67 mmol) (as a compound of formula I-82-c) and trifluoroacetic acid (0.5 mL), and the mixture was stirred at 60 ° C for 16 hours. The reaction mixture was adjusted to pH=9 with EtOAc (EtOAc)EtOAc. The target compound 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((6-(piperidine)) is dichloromethane/methanol = 20/1) -1-methyl)-5,6,7,8-tetrahydronaphthalen-2-yl)amino)-1,2-dihydro 3H-pyrazole [3,4-d]pyrimidin-3-one (182.4 Mg, 58.9%), gray solid. </ RTI>^< RTIgt -7.35 (m, 1H), 7.24 (dd, J = 8.2, 2.1 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 5.72 (dd, J = 17.0, 10.3 Hz, 1H), 5.06 ( Dd, J = 10.2, 1.0 Hz, 1H), 4.95 (dd, J = 17.1, 1.1 Hz, 1H), 4.78 (d, J = 6.2 Hz, 2H), 3.99 (s, 1H), 2.90 (d, J) = 4.6 Hz, 1H), 2.84 (dd, J = 8.0, 4.2 Hz, 2H), 2.43 (dd, J = 15.5, 10.4 Hz, 4H), 2.32 (d, J = 6.9 Hz, 2H), 2.09-1.98 (m, 3H), 1.68-1.58 (m, 10H), 1.53-1.40 (m, 3H).

Example 87

first step:

6-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (215 mg, 1 mmol) (as shown in formula I-87-a) and N,N-diisopropyl B The amine (0.2 ml) was added to 15 ml of dichloromethane and stirred until clear. Then 1-methyl-piperidin-4-one (170 mg, 1.5 mmol), sodium borohydride (422 mg, 2 mmol) and 0.3 mL of acetic acid were added and stirred at room temperature for 40 h. The reaction liquid was concentrated to a column (3 mol/L ammonia methanol: (dichloromethane: ethyl acetate = 5:1) = 0 to 15%) to afford 185 mg of brown desired product. Yield: 67%. LC-MS: m/z: [M+1] ⁺ = 276.

The second step:

2-(1-Methylpiperidin-4-yl)-6-nitro-1,2,3,4-tetrahydroisoquine (180 mg, 0.65 mmol) as shown in formula I-87-b The compound and Raney nickel (0.2 g) were added to 30 ml of ethanol, and then hydrazine hydrate (0.5 ml) was slowly added dropwise to the solution, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated by filtration to give a crude material (150 g). Yield: 93%. LC-MS: m/z: [M+1] ⁺ =246.

third step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (such as the compound of formula 1A) (160 mg, 0.45 mmol) was added to a solution of 15 ml of toluene to m-chloroperoxybenzoic acid (110 mg, 0.49 mmol), and the resulting solution was stirred at room temperature. 2h.

After concentrating the above reaction solution, 2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine (150 mg, 0.61 mmol) was added (as in formula I- The compound shown in 87-c), 0.2 ml of trifluoroacetic acid and 5 ml of dimethyl sulfoxide were stirred at 60 degrees for 24 hours. To the above reaction solution, 10 ml of a saturated aqueous solution of sodium carbonate and 15 ml of water were added, and extracted three times with dichloromethane (3*20 ml), and the organic phases were combined and washed with 20 ml of water and 20 ml of saturated sodium chloride solution, anhydrous sodium sulfate After drying, it is concentrated to give a crude product. The obtained crude product is separated by a thin layer chromatography plate (3M ammonia methanol: (dichloromethane: ethyl acetate = 1:1) = 1:10), and then prepared by high-performance liquid phase. The yellow solid was 110 mg in a yield of 44%. LC-MS: m/z: (M+H) ⁺ = 555, ¹ H NMR (400 MHz, EtOAc) δ 8.84 (s, 1H), 8.37 (s, 2H), 8.02 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.73 ( Ddt, J = 16.3, 10.2, 6.1 Hz, 1H), 5.05 (dd, J = 10.2, 1.2 Hz, 1H), 4.94 (d, J = J = 17.0, 1.3 Hz, 1H), 4.83 (d, J = 6.1 Hz, 2H), 3.98 (s, 2H), 3.54 (d, J = 12.5 Hz, 2H), 3.12 (t, J = 5.9 Hz, 2H), 3.00 (m, 5H), 2.82 (s, 3H) , 2.27 (d, J = 12.6 Hz, 2H), 1.99 (dd, J = 22.9, 11.1 Hz, 2H), 1.60 (s, 6H).

Example 88

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((1,2,3,4-tetrahydroisoquinolin-6-yl) Amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (100 mg, 0.22 mmol) (as compound of formula I-88-a), tetrahydrogen -4H-pyran-4-one (100 mg, 1 mmol) and sodium acetate (60 mg, 0.44 mmol) were added to 30 ml of methanol. Then sodium cyanoborohydride (110 mg, 1.75 mmol) was added and stirred at room temperature for 48 h. The reaction liquid was concentrated to a column (3 mol/L ammonia methanol: (dichloromethane: ethyl acetate = 5:1) = 0-15%) to afford 70 mg of the desired product. Yield: 59%. LC-MS: m/z: (M+H) ⁺ = 542, 1H NMR (400 MHz, CDCl3: MeOH = 3:1) δ 8.85 (s, 1H), 7.93 (t, J = 7.9 Hz, 1H) , 7.79 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.69 (dq, J = 10.3, 6.1 Hz, 1H), 5.05 (d, J = 10.2 Hz, 1H), 4.92 (d, J = 17.1 Hz, 1H), 4.81 (d, J = 5.9 Hz, 2H), 4.16 - 4.03 (m, 2H), 3.81 (s, 2H), 3.47 (t, J = 11.5 Hz, 2H), 2.92 (d, J = 4.4 Hz, 4H), 2.72 (dd, J = 15.4, 7.3 Hz, 1H), 1.93 (d, J = 11.6 Hz, 2H), 1.72 (qd, J = 12.3, 4.4 Hz, 2H), 1.60 (s, 6H).

Example 103

first step:

N-(5-oxo-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (59 mmol) (as a compound of formula I-103-a) was dissolved in toluene (200 mL) , placed in a sealed tube, and added ethyl glyoxylate (118 mmol), p-toluenesulfonic acid (5.9 mmol) and magnesium sulfate (395 mmol) to the reaction mixture, and the reaction mixture was heated to 120 ° C, and the reaction solution was stirred for 16 hours. . The reaction liquid was filtered, and the filtrate was evaporated to dryness to purified crystals. Oxo-3,4-dihydronaphthalene-2(1H)-methylene) acetate (9.5 g, 56%), yellow solid. LC-MS: m/z: [M+1] ⁺ = 288.

The second step:

Ethyl(E)-2(6-acetamido-1-oxo-3,4-dihydronaphthalene-2(1H)-methylene)acetate (31 mmol) (as in formula I-103-b) The compound shown) was dissolved in methanol (100 mL), and Pd/C (900 mg) and concentrated sulfuric acid (1.0 mL) were added to the reaction mixture, and the reaction mixture was stirred under hydrogen for 18 hours. The reaction mixture was adjusted to pH = 9 with a saturated aqueous solution of sodium carbonate, and then filtered to remove Pd / C. The mixture was evaporated to dryness. The crude product was evaporated to dryness crystals crystals crystals crystals crystals Methyl)-5-,6-,7-,8-tetrahydronaphthalen-2-amine (4.0 g, 46.0%), white solid. LC-MS: m/z: [M+1] ⁺ = 276.

third step:

Dissolving 6-(piperidin-1-methyl)-5-,6-,7-,8-tetrahydronaphthalen-2-amine (such as the compound of formula I-103-c) (15.0 mmol) Tetrahydrofuran (50 mL), the reaction solution was cooled to 0 ° C under nitrogen, and then evaporated and evaporated. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. 0-50/50) The target compound N-(6-(2-hydroxyethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (2.70 g, 80.0%) , white solid. LC-MS: m/z: [M+1] ⁺ = 234.

the fourth step:

N-(6-(2-Hydroxyethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (12 mmol) (as shown in formula I-103-d) Dissolved in dichloromethane (30 mL), and added triethylamine (46 mmol), N,N-dimethylpyridin-4-amine (5.8 mmol) and p-toluenesulfonyl chloride (23 mmol) to the reaction mixture. Stir under 16 hours. 1N Hydrochloric acid (200 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj The title compound was methyl 2-(6-acetylamino-1,2,3,4-tetrahydronaphthalen-2-yl) 4-methylbenzenesulfonate (2.40 g, 54.0%). LC-MS: m/z: [M+1] ⁺ = 388.

the fifth step:

Ethyl 2-(6-acetylamino-1,2,3,4-tetrahydronaphthalen-2-yl) 4-methylbenzenesulfonate (1.03 mmol) (as compound of formula I-103-e) Dissolved in methanol (10 mL), added sodium methoxide (2.07 mmol), and the mixture was heated to 50 ° C and stirred for 16 hours. The reaction mixture was evaporated to dryness and purified eluted elut elut elut elut elut elut elut elut 7-, 8-tetrahydronaphthalen-2-yl)acetamide (250 mg, 97.93%), yellow oil. LC-MS: m/z: [M+1] ⁺ = 248.

The sixth step:

N-(6-(2-Methoxyethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (1.01 mmol) (as in Formula I-103-f) The compound shown was dissolved in ethanol (10 mL), concentrated hydrochloric acid (10 mL) was added, and the mixture was warmed to reflux and stirred for 16 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal LC-MS: m/z: [M+1] ⁺ = 206.

Step 7:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-D]pyrimidin-3-one (such as the compound of formula 1A) (0.28 mmol) was dissolved in toluene (15 mL), m-chloroperoxybenzoic acid (0.31 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hour. The reaction solution was evaporated to dryness, and the obtained sulfone intermediate was dissolved in dimethyl sulfoxide (10 mL), and 6-(piperidin-1-methyl)-5-,6-,7-, 8-tetrahydronaphthalene- 2-Amine (0.34 mmol) (as the compound of formula I-103-g) and trifluoroacetic acid (0.5 mL), and the reaction mixture was heated to 60 ° C and stirred for 16 hours. The reaction mixture was adjusted to pH=9 with a saturated aqueous solution of sodium carbonate. Water (50 mL) ethyl acetate (50 mL). The target compound 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((6-(2-methoxyethyl)-5,6, 7,8-tetrahydronaphthalen-2-yl)amino)-1,2-dihydro 3H-pyrazo[3,4-d]pyrimidin-3-one (32 mg, 22.22%), m. </ ^RTI ><RTIgt , 2H), 7.07 (s, 1H), 5.72 (s, 1H), 5.02 (dd, J = 42.8, 13.2 Hz, 2H), 4.80 (s, 2H), 3.55 (t, J = 6.3 Hz, 2H) , 3.42-3.36 (m, 3H), 2.89 (d, J = 21.4 Hz, 3H), 2.53-2.39 (m, 1H), 1.96 (d, J = 26.2 Hz, 4H), 1.75-1.66 (m, 3H) ), 1.61 (s, 6H).

Example 114

first step:

6-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (214 mg, 1 mmol) (as shown in formula I-114-a), 3-oxoazetidine 1-carboxylic acid tert-butyl ester (190 mg, 1.1 mmol), sodium borohydride (422 mg, 2 mmol) and N,N-diisopropylethylamine (0.5 ml) were added to 15 ml of dichloromethane. The external temperature in the tube was stirred at 70 ° overnight. The reaction solution was concentrated to dryness (yield ethyl acetate: petroleum ether = 0-50%) Yield: 90%. LC-MS: m/z: [M+1] ⁺ = 334.

The second step:

3-(6-Nitro-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-carboxylic acid tert-butyl ester (300 mg, 0.9 mmol) (as in formula I- The compound shown by 114-b) and 3 ml of trifluoroacetic acid were sequentially added to 3 ml of dichloromethane, and stirred at room temperature overnight. After the reaction mixture was concentrated, 10 ml of 7 mol/L of ammonia methanol was added, and then concentrated to give a crude product (200 mg), which was directly used for the next step. Yield: 95%. LC-MS: m/z: [M+1] ⁺ = 234.

third step:

2-(Azetidin-3-yl)-6-nitro-1,2,3,4-tetrahydroisoquinoline (180 mg, 0.77 mmol) (as shown in formula I-114-c) Compound), 37% aqueous formaldehyde solution (0.2 ml) and sodium borohydride (340 mg, 1.6 mmol) were added to 15 ml of methanol and stirred at room temperature overnight. After the reaction mixture was concentrated, 20 ml of dichloromethane and 2 ml of methanol were added, and the mixture was washed with 5 ml of saturated sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated, and then concentrated (7 mol/L ammonia methanol: dichloromethane = 0-20%). This gave 175 mg of a white solid. Yield: 91%. LC-MS: m/z: [M+1] ⁺ = 248.

the fourth step:

2-(1-Methylaza-3-yl)-6-nitro-1,2,3,4-tetrahydroisoquinoline (170 mg, 0.69 mmol) (as shown in formula I-114-d) The compound and Raney nickel (0.2 g) were added to 30 ml of ethanol, and then hydrazine hydrate (0.5 ml) was slowly added dropwise to the solution, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated by filtration to give a crude material. Yield: 93%. LC-MS: m/z: [M+1] ⁺ = 218.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (140 mg, 0.39 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (100 mg, 0.45 mmol) in a solution of 15 ml of toluene, and the resulting solution was stirred at room temperature. 2h.

After concentrating the above reaction solution, 2-(1-methylaza-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine (90 mg, 0.41 mmol) was added (as in formula I- The compound shown by 114-e), 0.2 ml of trifluoroacetic acid and 5 ml of dimethyl sulfoxide were stirred at 60 degrees for 24 hours. To the above reaction solution, 10 ml of a saturated aqueous solution of sodium carbonate and 15 ml of water were added, and extracted three times with dichloromethane (3*20 ml), and the organic phases were combined and washed with 20 ml of water and 20 ml of saturated sodium chloride solution, anhydrous sodium sulfate After drying, it is concentrated to give a crude product. The obtained crude product is separated by a thin layer chromatography plate (3M ammonia methanol: (dichloromethane: ethyl acetate = 1:1) = 0-15%), and then prepared by high-performance liquid phase. A yellow solid of 65 mg was obtained in a yield of 31%. LC-MS: m/z: (M+H) ⁺ = 527, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.42 (s, 1H), 7.92 (t, J = 8.1 Hz , 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H) , 5.76 - 5.61 (m, 1H), 5.04 (dd, J = 10.2, 1.1 Hz Hz, 1H), 4.91 (dd, J = 17.0, 1.2 Hz, 1H), 4.82 (d, J = 6.2 Hz, 2H) , 4.42–4.32 (m, 2H), 3.87–3.76 (m, 2H), 3.54 (m, 3H), 2.94 (t, J = 5.8 Hz, 2H), 2.88 (s, 3H), 2.68 (t, J =5.9 Hz, 2H), 1.59 (s, 6H).

Example 115

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (400 mg, 1.78 mmol) (as a compound of formula I-115-a) was dissolved in 18 mL of methanol then ammonium acetate (1368 mg) After stirring at room temperature for 2 h, sodium cyanoborohydride (120 mg, 1.91 mmol). The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time. The aqueous phase was adjusted to a base (pH = 10-11) with a 1 mol/L sodium hydroxide solution. It was extracted three times with 40 ml of dichloromethane each time. The organic phase was washed with 30 ml of brine, dried over anhydrous sodium sulfate and evaporated. A reddish brown oil (197 mg, 0.87 mmol) was obtained in a yield of 48%. LC-MS: m/z: (M+H) ⁺ = 226.0, 228.0.

The second step:

6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine (97 mg, 0.43 mmol) (as a compound of formula I-115-b) was dissolved in 10 ml of dichloromethane and sodium carbonate was added. (182 mg, 1.72 mmol), stirred at room temperature for 18 h. The reaction solution was concentrated under reduced pressure, and then water (30 ml) The combined organic layers were concentrated, EtOAcjjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 297.1, 299.1.

third step:

3-(6-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-1,1-dimethylurea (90 mg, 0.30 mmol) (as shown in formula I-115-c) Compound), benzophenone imine (60 mg, 0.33 mmol), sodium tert-butoxide (58 mg, 0.60 mmol), Pd ₂ (dba) ₃ (14 mg, 0.015 mmol), BINAP (19 mg, 0.03 mmol) added to 10 ml In toluene, argon gas was exchanged three times, and then heated to 100 ° C for 16 h. The reaction mixture was concentrated. EtOAc mjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 398.3.

the fourth step:

3-(6-((Diphenylmethylene)amino-1,2,3,4-tetrahydronaphthalen-2-yl)-1,1-dimethylurea (76 mg, 0.19 mmol) The compound shown by I-115-d was dissolved in 10 ml of methanol, and then sodium acetate trihydrate (78 mg, 0.57 mmol) and hydroxylamine hydrochloride (29 mg, 0.42 mmol) were added, and the mixture was heated to 60 ° C for 6 hours. Concentration, the obtained crude product was purified (jjjjjjjjjjjj ⁺ = 234.2.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (70 mg, 0.2 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (48 mg, 0.22 mmol) in a solution of 15 ml of toluene, and the resulting solution was stirred at room temperature. After 1 h, the solvent was evaporated to give 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-di Hydrogen-3H-pyrazolo[3,4-d]pyrimidin-3-one crude. To the above solution was added 5 mL of dimethyl sulfoxide, 1 mL of trifluoroacetic acid, 3-(6-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-1,1-dimethylurea ( 44 mg, 0.19 mmol) (as a compound of formula I-115-e), stirred at 60 ° for 24 h. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc: m. LC-MS: m / z: (M + H) + = 543.3, 1 H NMR (400MHz, DMSO) δ10.21 (s, 1H), 8.88 (s, 1H), 8.03 (t, J = 7.9Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.36 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H) , 6.11 (d, J = 7.5 Hz, 1H), 5.67 (ddd, J = 16.4, 10.9, 6.1 Hz, 1H), 5.00 (d, J = 10.5 Hz, 1H), 4.82 (d, J = 17.5 Hz, 1H), 4.70 (d, J = 5.7 Hz, 2H), 3.80 (s, 1H), 2.89 (dd, J = 16.4, 4.6 Hz, 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).

Example 116

first step:

6-Bromo-1,2,3,4-tetrahydroisoquinoline (740 mg, 3.49 mmol) (as shown in formula I-114-a), 3-oxopyrrolidine-1-carboxylic acid Butyl ester (1 g, 5.4 mmol), sodium borohydride (1.5 g, 7.1 mmol) and acetic acid (0.2 ml) were added to 35 ml of dichloromethane and stirred at room temperature overnight. The organic layer was washed with EtOAc (EtOAc m. Yield: 64%. LC-MS: m/z: [M+1] ⁺ =381.

The second step:

3-(6-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (850 mg, 2.2 mmol) (as in formula I-114-b) The compound shown and 5 ml of trifluoroacetic acid were sequentially added to 5 ml of dichloromethane and stirred at room temperature overnight. After the reaction mixture was concentrated, 50 ml of dichloromethane and 5 ml of methanol was added, and the mixture was washed with 10 ml of saturated sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated Yield: 95%. LC-MS: m/z: [M+1] ⁺ = 281.

third step:

6-Bromo-2-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (600 mg, 2.1 mmol) (as compound of formula I-114-c), 37 Aqueous aqueous formaldehyde (1 ml) and sodium borohydride (900 mg, 4.24 mmol) were added to 35 ml of methanol and stirred at room temperature overnight. After the reaction mixture was concentrated, 20 ml of dichloromethane and 2 ml of methanol were added, and the mixture was washed with 5 ml of saturated sodium carbonate solution, dried over anhydrous sodium sulfate, and then concentrated and concentrated (7 mol/L ammonia methanol: dichloromethane = 0-15%). Yield 530 mg of a brown oil. Yield: 84%. LC-MS: m/z: [M+1] ⁺ = 295.

the fourth step:

6-Bromo-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (530 mg 1.8 mmol) (as shown in formula I-114-d) ), benzophenone imine 360 mg (2 mmol), sodium tert-butoxide 260 mg (2.7 mmol), Pd ₂ (dba) ₃ 65 mg (0.07 mmol), BINAP (115 mg, 0.185 mmol) added to 35 ml of toluene in argon The gas was ventilated three times and then heated to 110 degrees overnight. The reaction mixture was concentrated, and the obtained crude product was purified (jjjjjjjjjjj LC-MS: m/z: [M+1] ⁺ = 396.

the fifth step:

N-(2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,1-benzophenone imine (540 mg 1,3655 mmol) (as the compound of formula I-114-e) was dissolved in 40 ml of methanol, then 0.56 g (6.83 mmol) of sodium acetate and hydroxylamine hydrochloride (190 mg, 2.73 mmol) were added and heated to 60 ° C overnight. The reaction mixture was concentrated by chromatography. EtOAcjjjjjjj LC-MS: m/z: [M+1] ⁺ = 232.

The sixth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (155 mg, 0.43 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (106 mg, 0.47 mmol) in 15 ml of toluene, and the resulting solution was stirred at room temperature. 2h.

After concentrating the above reaction solution, 2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine (130 mg, 0.56 mmol) was added (as in formula I- Compound shown by 114-f), 0.2 ml of trifluoroacetic acid and 5 ml of dimethyl sulfoxide, stirred at 60 ° for 24 h. To the above reaction solution, 10 ml of a saturated aqueous solution of sodium carbonate and 15 ml of water were added, and extracted three times with dichloromethane (3*20 ml), and the organic phases were combined and washed with 20 ml of water and 20 ml of saturated sodium chloride solution, anhydrous sodium sulfate After drying, it was concentrated to give a crude material. mjjjjjjjjjjjjjjjjjjj %. LC-MS: m/z: (M+H) ⁺ = 541,1H NMR (400 MHz,MeOD) δ 8.84 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.73 (ddt, J = 16.4, 10.3, 6.1 Hz, 1H), 5.05 (dd, J = 10.2, 1.1 Hz, 1H), 4.90 - 4.94 (d, J = 17.0, 1.2 Hz, 1H), 4.84 (d , J = 6.1 Hz, 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, 9.1 Hz, 1H), 2.50–2.39 (m, 4H), 2.18 (m, 1H), 1.92 (m, 1H), 1.60 (s, 6H).

Example 117

first step:

Ethyl 2-(6-acetamido-1,2,3,4-tetrahydronaphthalen-2-yl) 4-methylbenzenesulfonate (1.03 mmol) (as shown in formula I-117-a) The solution was dissolved in acetonitrile (10 mL), and morpholine (3.10 mmol) and potassium carbonate (4.13 mmol) were added to the reaction mixture, and the reaction mixture was heated to 50 ° C, and the mixture was stirred for 16 hours. The reaction liquid was filtered, and the filtrate was evaporated to dryness to purified crystals. -,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (230 mg, 73.7%), white solid. LC-MS: m/z: [M+1] ⁺ =303.

The second step:

N-(6-(2-morpholinoethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (0.76 mmol) (as shown in formula I-117-b) The compound was dissolved in ethanol (10 mL), sodium hydroxide (10 mL, 10 mol/L) was added to the reaction mixture, and the mixture was stirred and refluxed for 18 hours. The reaction mixture was separated with water and ethyl acetate. EtOAc (EtOAc m. -,6-,7-,8-tetrahydronaphthalen-2-amine (152 mg, 76.7%), gray solid. LC-MS: m/z: [M+1] ⁺ = 261.

third step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-D]pyrimidin-3-one (0.28 mmol) (as the compound of formula 1A) was dissolved in toluene (15 mL), 3-chloroperoxybenzoic acid (0.31 mmol) was added, and the reaction mixture was stirred at room temperature. The reaction solution was evaporated to dryness, and the obtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10 mL), and 6-(2-morpholinethyl)-5-,6-,7-, 8-tetrahydronaphthalene- 2-Amine (such as the compound of formula I-117-c) (0.31 mmol) and trifluoroacetic acid (0.5 mL), and the mixture was stirred and stirred at 60 ° C for 16 hours. The reaction mixture was adjusted to pH=9 with a saturated aqueous solution of sodium carbonate. Water (50 mL) ethyl acetate (50 mL). The target compound 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(6-(2-morpholinylethyl)-5-,6-, 7-,8-Tetraquinol-2-yl)amino-1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-one (68 mg, 42.6%), white solid. LC-MS: m/z: [M+H] ⁺ = 570. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.93-7.80 (m, 2H), 7.49-7.35 (m, 2H) , 7.26 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 5.72 (d, J = 6.7 Hz, 1H), 5.01 (ddd, J = 18.2, 13.6, 1.0 Hz, 2H), 4.78 (d, J = 6.2 Hz, 2H), 3.80 (s, 2H), 2.85 (dd, J = 8.4, 4.4 Hz, 2H), 2.70-2.39 (m, 4H), 2.00 (d, J =12.2 Hz, 1H), 1.83 (s, 1H), 1.64 (d, J = 19.4 Hz, 4H), 1.54-1.42 (m, 1H).

Example 119

first step:

6-Bromo-3,4-dihydronaphthalene-2(1H)-one (200 mg, 0.89 mmol) (compound as shown in formula I-119-a) was dissolved in 10 mL of dichloromethane, then benzylamine was added (0.14 ml, 1.33 mmol) and sodium triacetylborohydride (753 mg, 3.55 mmol). The reaction solution was concentrated under reduced pressure, and then water (30 ml) The combined organic layers were concentrated, EtOAcjjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 316.0, 318.0.

The second step:

N-Benzyl-6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (140 mg, 0.44 mmol) (as a compound of formula I-119-b) was dissolved in 10 ml of methanol. Then, acetaldehyde (0.1 ml) and sodium cyanoborohydride (140 mg, 2.22 mmol) were added, and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated under reduced pressure, and then water (30 ml) The combined organic layers were concentrated, EtOAcjjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 344.1, 346.1.

third step:

N-Benzyl-6-bromo-N-ethyl-1,2,3,4-tetrahydronaphthalen-2-amine (102 mg, 0.30 mmol) (as compound of formula I-119-c), Benzophenone imine (58 mg, 0.32 mmol), sodium tert-butoxide (56 mg, 0.60 mmol), Pd ₂ (dba) ₃ (13 mg, 0.015 mmol), BINAP (18 mg, 0.03 mmol) was added to 10 ml of toluene. Argon was ventilated three times and then heated to 100 ° C for 16 h. The reaction mixture was concentrated and purified mjjjjjjjjjj LC-MS: m/z: (M+H) ⁺ = 445.3.

the fourth step:

N-Benzyl-6-((diphenylmethylene)amino)-N-ethyl-1,2,3,4-tetrahydronaphthalen-2-amine (72 mg, 0.16 mmol) (as in formula I- The compound shown by 119-d was dissolved in 10 ml of methanol, and then sodium acetate trihydrate (66 mg, 0.48 mmol) and hydroxylamine hydrochloride (25 mg, 0.36 mmol) were added, and the mixture was heated to 60 ° for 6 hours. The reaction mixture was concentrated with EtOAc EtOAc m. LC-MS: m/z: (M+H) ⁺ = 2821.

the fifth step:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]pyrimidin-3-one (53 mg, 0.15 mmol) (as a compound of formula 1A) was added m-chloroperoxybenzoic acid (37 mg, 0.16 mmol) in 15 ml of dichloromethane. After stirring at room temperature for 1 h, the solvent was evaporated to give 2- allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2 a solution of dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one in dichloromethane. To the above solution was added DIPEA (0.08 ml), N2-benzyl-N2-ethyl-1,2,3,4-tetrahydronaphthalene-2,6-dimethylamine (as in Formula I-119-e The compound shown) (44 mg, 0.19 mmol) was stirred at 60 ° for 24 h. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc m. LC-MS: m / z: (M + H) + = 590.4, 1 H NMR (400MHz, MeOD) δ8.79 (s, 1H), 7.98 (t, J = 7.9Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 7.1 Hz, 2H), 7.35 - 7.20 (m, 4H), 7.02 ( d, J = 8.3 Hz, 1H), 5.80 - 5.65 (m, 1H), 5.04 (dd, J = 10.2, 1.1 Hz, 1H), 4.92 (dd, J = 17.1, 1.3 Hz, 1H), 4.83 (d , J = 6.0 Hz, 2H), 3.77 (s, 2H), 3.08 (s, 1H), 2.84 (dt, J = 11.9, 10.6 Hz, 4H), 2.77 - 2.65 (m, 2H), 2.14 (d, J = 10.0 Hz, 1H), 1.71 (dd, J = 11.9, 5.5 Hz, 1H), 1.60 (s, 6H), 1.09 (t, J = 7.1 Hz, 3H).

Referring to the above examples, the compounds shown in Table 1 were prepared and their structural characterizations are as follows:

Table 1 List of examples

Effect Example 1

I. Inhibition of WEE1 kinase by compounds in vitro

Test Methods:

Test compounds were screened on WEE1 kinase at an ATP concentration of Km using an ELISA method. Three compounds were screened on the WEE1 kinase to evaluate the kinase inhibitory activity of the test compound. During the test, the initial concentration of the test compound was selected to be 100 nM, and each compound was selected to have 6 gradient dilution concentrations, and the gradient dilution factor was 4 times. Two replicate wells per concentration were used for detection, and MK-1775 was used as a standard control.

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

Test steps:

1. Coating substrate: 1) Take appropriate volume of substrate tyrosine kinase (PTK) substitute (poly–Glu-Tyr), dilute 10 times with PBS, and dilute the concentration from 250 mg/mL to 25 mg/mL. . Add to a high adsorption 96-well plate at 125 μL per well. Place the coating in an incubator at 37 ° C overnight. 2) After 24 hours, the 96-well plate was taken out, the liquid in the 96-well plate was drained, washed 3 times with washing buffer, and the incubator was inverted and dried for 2 hours at 37 °C.

2. Preparation and transfer of the compound: 1) Compound dilution: Take 10 mM of the test compound storage solution, and dilute the compound in multiple steps in DMSO in a 96-well compound plate to obtain a compound having an initial concentration of 100×, and then The concentration of the compound was the first concentration, and a 4-fold gradient dilution was performed in DMSO, and a total of 6 concentrations were diluted; then 2 μL of the gradient dilution was added to 48 μL of 1× reaction buffer to prepare a 4× compound for use; 2) Transfer of 4× compound: Transfer 10 μL of 4× compound into the dried high-adsorption 96-well plate from the 96-well compound plate configured in the previous step; add 10 μL of the following liquid to the compound-free control well and the ATP-control well: 2 μL DMSO was added to 48 μL of 1× reaction buffer.

3. Enzyme reaction stage: 1) WEE1 kinase and ATP were separately prepared into a 2× enzyme solution and a 4× ATP solution using 1× reaction buffer. In this screening, the final concentration of WEE1 kinase was: 0.15 ng/μL, and the final concentration of ATP was: 12 μM; 2) 20 μL of 2 enzyme solution was added to the high-adsorption 96-well plate; 3) 96-well to high adsorption 10 μL of 4×ATP solution was added to the plate, and 10 μL of 1× reaction buffer was added to the ATP-control empty; 4) The plate was placed in a HERAEUS Multifuge X1R centrifuge and centrifuged at 2000 rpm for 20 s, and then left at room temperature for 60 min.

4. Reaction termination stage: 1) Pour off the reaction solution in the plate, add 200 μL washing buffer to each well, wash 5 times; add primary anti-P-Tyr (PY99) (dilution ratio 1:2000), 100 μL per well, room temperature 30 min . 2) Pour off the primary antibody in the plate, add 200 μL of washing buffer to each well, wash 5 times; add anti-mouse IgG HRP-linked Antibody (diluted 1:2000), 100 μL per well, room temperature for 30 min. 3) Pour off the secondary antibody in the plate, wash 5 times with washing buffer, add TMB, 100 μL per well, and develop color for 10 to 30 minutes, depending on the color depth. The reaction was stopped with 1 N sulfuric acid before reading.

5. Detection and data processing: 1) Read the light absorption at a wavelength of 450 nM on a Thermo Scientific MultiScan GO while reading the background at 650 nM. 2) Log (inhibitor) vs. response-Variable slope (four parameters) curve fitting was performed using Graphpad Prism 5.0, and the corresponding IC50 (half maximal inhibitory concentration) was calculated.

Second, the compound inhibits COLO 205 cell line in vitro

Test Methods:

The inhibitory effect of the compound on the proliferation of the p53-deficient cell line COLO 205 was examined by Luminescence ATP Detection method. Four compounds were screened on the cell line to evaluate the inhibitory activity of the test compound on proliferation of the cell line in vitro. During the detection, the initial concentration of the test compound was selected as 10 μM, 9 gradient dilution concentrations were selected, and the gradient dilution multiple was 3 times. Two replicate wells per concentration were used for detection, and MK-1775 was used as a standard control.

COLO 205, human colon cancer cell, purchased from the Chinese Academy of Sciences cell bank, catalog number: TCHu102; ATPlite 1step Single Addition Luminescence ATP Detection Assay system, purchased from PerkinElemer, catalog number: 6016739; RPMI 1640, purchased from GIBCO, article number: A10491-01; Strep/pen, purchased from GIBCO, article number: 15240-062; fetal bovine serum FBS, purchased from GIBCO, article number: 10099-141; 96-well black bottom-permeable cell culture plate, purchased from Corning, Cat. No.: 3603; 96-well compound plate , purchased from Thermo Scientific, article number: 267245.

Test steps:

1. Cell culture and inoculation: Take normal cultured cells, and digest and disperse them under the exponential growth state, adjust the cell density to 8.8×10 ³ cells/mL, and inoculate 90 μL per well in 96-well cell culture plates; inoculation is completed. The microplate was then placed at 37 ° C under 5% CO ₂ ;

2. Dosing the cells: remove the microplate from the incubator, add 10× compound to each well of the microplate, add 10 μL to each well, and each dosing concentration is 2 replicate wells, each The compound has a total of 9 administration concentrations. According to different cell lines, the initial concentration of each compound is different. After completion, the microplate is placed at 37 ° C, 5% CO ₂ for 72 h;

3. Data collection: The microplate was taken out of the incubator and equilibrated at room temperature for 30 min. 100 μl of room temperature equilibrated ATPlite reaction solution was added to each well, and shaken at 1300 rpm for 2 min at room temperature. Then, the microplate was placed in a HERAEUS Multifuge X1R centrifuge and centrifuged at 2000 rpm for 1 min; after equilibration at room temperature for 10 min, the fluorescence signal value was measured on EnVisionTM.

4. Calculate the in vitro inhibitory activity of the compound according to the following formula:

Cell proliferation inhibition rate: inhibition rate (%) = (signal value control - signal value administration) / signal value control × 100%. According to the inhibition rate of each concentration, the 50% inhibitory concentration (IC ₅₀ ) was calculated by the LOGIT method. Cell viability calculation: Cell viability (%) = signal value administration / signal value control x 100%. Log (inhibitor) vs. response-Variable slope (four parameters) curve fitting was performed on the fluorescence signal values at each concentration using Graphpad Prism 5.0, and the corresponding IC ₅₀ (half maximal inhibitory concentration) was calculated.

Inhibition of compounds on 5-FU-treated COLO 205 cell line in vitro

Test Methods:

This report uses the Luminescence ATP Detection method to detect the inhibitory effect of compounds on the proliferation of 5-FU-treated p53-deficient cell line COLO 205. Four compounds were screened on the cell line to evaluate the inhibitory activity of the test compound against proliferation of the cell line in vitro after the combination with 5-FU. During the detection process, the initial concentration of 5-FU was selected to be 100 μM, 9 gradient dilution concentrations were selected, the gradient dilution factor was 3 times, and 2 replicate wells per concentration were tested. The test compounds were used in two concentrations of 300 nM and 100 nM respectively. The concentration of 5-FU combined. MK-1775 was used as a standard control.

COLO 205, human colon cancer cell, purchased from the Chinese Academy of Sciences cell bank, catalog number: TCHu102; ATPlite 1step Single Addition Luminescence ATP Detection Assay system, purchased from PerkinElemer, catalog number: 6016739; RPMI 1640, purchased from GIBCO, article number: A10491-01; Strep/pen, purchased from GIBCO, article number: 15240-062; fetal bovine serum FBS, purchased from GIBCO, article number: 10099-141; 96-well black bottom-permeable cell culture plate, purchased from Corning, Cat. No.: 3603; 96-well compound plate , purchased from Thermo Scientific, article number: 267245;

Test steps:

2. Dosing the treated cells: remove the microplate from the incubator, add 10×5-FU to each well of the microplate, add 10 μL to each well, and each dosing concentration is 2 replicate wells. A total of 9 administration concentrations of each compound were added to the medium containing the same proportion of the solvent DMSO. After completion, the microplate was placed at 37 ° C, 5% CO ₂ for 72 h;

3. Dosing the cells: remove the microplate from the incubator, add 3300 nM or 1100 nM compound (11× compound) to the 9 gradient 5-FU treated cells and the control wells in the microplate, and add each well. 10 μL, after completion, the microplate was placed at 37 ° C, 5% CO ₂ for 72 h;

4. Data collection: The microplate was taken out of the incubator and equilibrated at room temperature for 30 min. 100 μL of room-balanced ATPlite reaction solution was added to each well, and shaken at 1300 rpm for 2 min at room temperature. Then, the microplate was placed in a HERAEUS Multifuge X1R centrifuge and centrifuged at 2000 rpm for 1 min; after equilibration at room temperature for 10 min, the fluorescence signal value was measured on EnVisionTM.

5. Calculate the in vitro inhibitory activity of the compound according to the following formula:

Fourth, the test results data.

The structure of the control sample used in the test is shown in Table 2.

Table 2 Control sample structure

The test results are detailed in Table 3.

Table 3 WEE1 enzyme inhibitory activity and cytostatic activity test results

While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims

A pyrazolone pyrimidine compound of the formula I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof or a prodrug thereof, characterized in that

Where X is N or CH;

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

Y is N or CH;

R 1 is H, halogen, fluorenyl, nitro, cyano, -NR 1-1 R 1-2 , -OR 1-3 , -C(=O)R 1-4 , -C(=NR 1-11 R 1 5 , -S(=O)R 1-6 , -S(=O) 2 R 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 , unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, not Substituted or R 1-17 substituted C 2 -C 7 alkenyl, unsubstituted or R 1-18 substituted C 2 -C 8 alkynyl, unsubstituted or R 1-19 substituted C 1 -C 7 alkylsilyl , unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl, unsubstituted or R 1-21 substituted "hetero atom" is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus or a plurality of C 3 -C 7 heterocycloalkyl groups having 1 to 4 hetero atoms, unsubstituted or R 1-22 substituted C 6 -C 10 aryl groups, unsubstituted or R 1 - 23 substituted" The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms, unsubstituted or R 1-24 Substituted C 1 -C 7 alkoxy, or unsubstituted or R 1-25 substituted C 1 -C 7 alkyl fluorenyl;

All R 1-1 , R 1-2 and R 1-3 are independently hydrogen, -C(=O)NR 1-1-1 R 1-1-2 , unsubstituted or substituted by R 1-1-3 C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and One or more of phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium , one or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

All R 1-1-1 , R 1-1-2 and R 1-1-3 are independently C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or a "hetero atom" , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms";

All R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl, halogen Substituted C 1 -C 7 alkyl, halogen, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 7 alkoxy, "hetero atom" One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms, or NR 1-4- 1 R 1-4-2 ;

All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 ring An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 ～C 10 aryl or “hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 —C 7 heteroaryl group having 1 to 4 hetero atoms”;

All R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, unsubstituted or R 1 1-1-1 substituted C 1 -C 7 alkyl group, C 3 -C 7 cycloalkyl group, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, hetero atom a number of 1 to 4 C 3 -C 7 heterocycloalkyl", a C 6 -C 10 aryl group, or "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus or a plurality of C 1 -C 7 heteroaryl groups having a hetero atom number of 1 to 4";

All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ～4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;

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 1-24 and R 1- 25 independently is halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, unsubstituted or R 1 -16- 7 substituted C 3 -C 7 cycloalkyl, unsubstituted or R 1-16-6 substituted "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", a C 6 -C 10 aryl group, "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Or a plurality of C 1 -C 7 heteroaryl groups having 1 to 4 hetero atoms", C 1 -C 7 alkoxy groups, C 1 -C 7 alkanoyl groups, -NR 1-16-1 R 1- 16-2 , -OR 1-16-3 , -SR 1-16-4 or -(C=O)R 1-16-5 ;

All R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 and R 1-16-7 are independently hydrogen, hydroxy, Halogen, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon or oxygen , one or more of sulfur, selenium, nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, and halogenated "heteroatoms are boron," One or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, "hetero atom" Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms",
-NR 1-16-5-1 R 1-16-5-2 or -OR 1-16-5-3 ;

All R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen , unsubstituted or substituted with R C 1-16-5-1- 1 1 ~ C 7 alkyl group, C 2 ~ C 7 alkenyl group, C 2 ~ C 7 alkynyl group, C 3 ~ C 7 cycloalkyl, " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, and C 6 to C 10 aromatic Or "heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

z is 0, 1 or 2;

All R 2 are independently halogen, hydroxy, cyano, amino, unsubstituted or R 2-1 -substituted C 1 -C 7 alkyl, unsubstituted or R 2-2 substituted C 2 -C 8 alkenyl, Unsubstituted or R 2-3 substituted C 2 -C 7 alkynyl, unsubstituted or R 2-4 substituted C 1 -C 7 alkyl, unsubstituted or R 2-5 substituted C 6 -C 10 aryl The "hetero atom" which is substituted by a base, unsubstituted or R 2-6 is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 to C 7 having a hetero atom number of 1 to 4 a heteroaryl group, a C 3 -C 7 cycloalkyl group, or an unsubstituted or R 2-7 substituted C 1 -C 7 alkoxy group;

All of R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ～ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-2 , -OR 2-1-3 , -SR 2-1-4 or -(C=O)R 2-1-5 ;

All R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C 1 -C 7 heteroaryl groups";

All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

Alternatively, two R 2 linkages are taken together on the same carbon atom to form an unsubstituted or R 2-8 substituted C 3 -C 7 cycloalkyl group, or an unsubstituted or R 2-9 substituted C 1 -C 7 heterocyclic ring. alkyl;

All R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. salt, solvate, metabolite or prodrug thereof, wherein, when R 1 is substituted by R 1-16 is C 1 ~ C 7 alkyl, said R is a number of 1-16 Or a plurality, when there are a plurality of R 1-16 , the R 1-16 is the same or different;

And/or, when R 1 is an unsubstituted or R 1-16 substituted C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And / or, when R 1 is substituted with R & lt 1-17 C 2 ~ C 7 alkenyl group, the number of R & lt 1-17 for one or more, when there are a plurality 1-17 R, the R 1-17 is the same or different;

And/or, when R 1 is an unsubstituted or R 1-17 substituted C 2 -C 7 alkenyl group, the C 2 -C 7 alkenyl group is a C 2 -C 4 alkenyl group;

And / or, when R 1 is substituted with R & lt 1-18 C 2 ~ C 8 alkynyl group, the number of the R & lt 1-18 for one or more, when there are a plurality 1-18 R, the R 1-18 is the same or different;

And/or, when R 1 is an unsubstituted or R 1-18 substituted C 2 -C 8 alkynyl group, the C 2 -C 8 alkynyl group is a C 2 -C 4 alkynyl group;

And / or, when R 1 is substituted with R & lt 1-19 is C 1 ~ C 7 alkylsilyl, the number of R & lt 1-19 for one or more, when there is a plurality 1-19 R, Said R 1-19 are the same or different;

And/or, when R 1 is a R 1-20 substituted C 3 -C 7 cycloalkyl group, the number of R 1-20 is one or more, when a plurality of R 1-20 are present, Said R 1-20 are the same or different;

And/or, when R 1 is an unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl group, the C 3 -C 7 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. Or cyclohexyl;

And/or when R 1 is R 1-21 substituted "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 having 1 to 4 hetero atoms When -C 7 heterocycloalkyl", the number of R 1-21 is one or more, and when a plurality of R 1-21 are present, the R 1-21 is the same or different;

And/or, when R 1 is unsubstituted or substituted by R 1-21 , the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 When the C 3 -C 7 heterocycloalkyl group", the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1-4. C 3 ~ C 7 heterocycloalkyl "as" hetero atom nitrogen and / or oxygen, the number of hetero atoms of 1 or 2 of C 3 ~ C 5 heterocycloalkyl ";

And / or, when C 6 ~ C 10 aryl group R 1 is substituted with R & lt 1-22, the number of R & lt according to one or more 1-22, 1-22 when there are plural R, the R 1-22 is the same or different;

And/or, when R 1 is R 1-23 substituted "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 having 1 to 4 hetero atoms when heteroaryl ~ C 7 aryl group ", the R is a number of 1-23 or more, when a plurality of R 1-23, R is the same or different from 1-23;

And / or, when R 1 is substituted with R & lt 1-24 is C 1 ~ C 7 alkoxy group, the number of R & lt 1-24 for one or more, when there is a plurality 1-24 R, Said R 1-24 are the same or different;

And / or, when R 1 is substituted by R 1-25, C 1 ~ C 7 alkylmercapto, said R is a number of 1-25 or more, when a plurality of R 1-25 is present, the R 1-25 is the same or different;

And/or, when R 1-1 , R 1-2 or R 1-3 is unsubstituted or R 1-1-3 substituted C 1 -C 7 alkyl, the C 1 -C 7 alkyl group Is a C 1 -C 4 alkyl group;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 1 -C 7 alkyl group, The C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl When the number of halogens is one or more, when a plurality of halogens are present, the halogens are the same or different;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl When said "halogen" is independently fluorine, chlorine, bromine or iodine;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl When the C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 2 -C 7 alkynyl group, The C 2 -C 7 alkynyl group is a C 2 -C 4 alkynyl group;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 1 -C 7 alkoxy group, The C 1 -C 7 alkoxy group is a C 1 -C 4 alkoxy group;

And/or, when R 1-4-1 or R 1-4-2 is a C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And/or when R 1-11 , R 1-12 , R 1-13 , R 1-14 or R 1-15 is a R 1-11-1 substituted C 1 -C 7 alkyl group, The number of R 1 - 11-1 is one or more, and when a plurality of R 1-11-1 are present, the R 1-11-1 is the same or different;

And/or, when R 1-11 , R 1-12 , R 1-13 , R 1-14 or R 1-15 is unsubstituted or R 1-11-1 substituted C 1 -C 7 alkyl, The C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And/or when 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 1-24 or When R 1-25 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or when 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 1-24 or When R 1-25 is a C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a trimethylsilyl group;

And/or when 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 1-24 or R 1-25 R 1-16- 6 is substituted with "one or more hetero atoms, number of heteroatoms boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus in the range of 1 to 4 C 3 ~ When C 7 heterocycloalkyl", the number of R 1-16-6 is one or more, and when a plurality of R 1-16-6 are present, the R 1-16-6 is the same or different;

And/or when 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 1-24 or R 1-25 is unsubstituted or substituted by R 1-16-6 . The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4. When C 3 -C 7 heterocycloalkyl", the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. 3 —C 7 heterocycloalkyl” is a C 3 —C 5 heterocycloalkyl group having a hetero atom of nitrogen and/or oxygen and having 1 to 2 hetero atoms;

And/or when R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 or R 1-16-7 are C 1 ～ When C 7 alkyl, the C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And/or when R 1-16-5 is "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having a hetero atom number of 1 to 4 In the case of 7 heterocycloalkyl, the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms. "heterocycloalkyl" is a C 3 -C 7 heterocycloalkyl group in which the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and has 1 to 4 hetero atoms. And it is linked to a carbonyl group through a nitrogen atom";

And/or, when R 1-16-5 is halogenated, the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. When 3 to C 7 heterocycloalkyl", the number of said halogens is one or more, and when a plurality of halogens are present, said halogens are the same or different;

And/or, when R 1-16-5 is halogenated, the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. When 3 to C 7 heterocycloalkyl", said "halogen" is independently fluorine, chlorine or bromine;

And/or, when R 1-16-5 is halogenated, the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. When 3 to C 7 heterocycloalkyl", the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 having 1 to 4 hetero atoms. ～C 7 heterocycloalkyl” is a C 3 —C 7 heterocycloalkyl group having a hetero atom of nitrogen and having 1 to 2 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom”;

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 When R 1-16-5-1-1 is substituted by C 1 -C 7 alkyl, the number of said R 1-16-5-1-1 is one or more, when a plurality of R 1- are present When 16-5-1-1 , the R 1-16-5-1-1 is the same or different;

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 When the C 1 -C 7 alkyl group is unsubstituted or substituted by R 1-16-5-1-1 , the C 1 -C 7 alkyl group is a C 1 -C 4 alkyl group;

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 In the case of a C 2 -C 7 alkynyl group, the C 2 -C 7 alkynyl group is a C 2 -C 4 alkynyl group.
A pyrazolone pyrimidine compound I according to claim 2, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein R 1 is a C 1 -C 7 alkyl group substituted by R 1-16 , and the number of said R 1-16 is At a time, the plurality of said ones are two, three or four;

And/or, when R 1 is an unsubstituted or R 1-16 substituted C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group. , n-butyl, isobutyl, sec-butyl or tert-butyl;

And / or, when R 1 is substituted by R 1-17 is C 2 ~ C 7 alkenyl group, and the number of R 1-17 is a plurality of said plurality is two, three, or 4;

And/or, when R 1 is an unsubstituted or R 1-17 substituted C 2 -C 7 alkenyl group, the C 2 -C 7 alkenyl group is a 2-propenyl group;

And / or, when R 1 is substituted by R 1-18 is C 2 ~ C 8 alkynyl group, and the number of R 1-18 is a plurality of said plurality is two, three, or 4;

And/or, when R 1 is an unsubstituted or R 1-18 substituted C 2 -C 8 alkynyl group, the C 2 -C 8 alkynyl group is a 2-propynyl group;

And/or, when R 1 is a C 1 -C 7 alkyl group substituted by R 1-19 , and the number of the R 1-19 is plural, the plurality is 2 or 3 Or 4;

And/or, when R 1 is a C 1 -C 7 cycloalkyl group substituted by R 1-20 , and the number of the R 1-20 is plural, the plurality of the plurality is 2 or 3 Or 4;

And/or, when R 1 is an unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl group, the C 3 -C 7 cycloalkyl group is a cyclobutyl group;

And/or when R 1 is R 1-21 substituted "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 having 1 to 4 hetero atoms -C 7 heterocycloalkyl", and when the number of the above R 1-21 is plural, the plurality of the plurality is two, three or four;

And/or, when R 1 is unsubstituted or substituted by R 1-21 , the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 When the C 3 -C 7 heterocycloalkyl group", the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1-4. C 3 ~ C 7 heterocycloalkyl "as" hetero atom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ~ C 5 heterocycloalkyl "or" hetero atom is oxygen, the number of hetero atoms is 1 to 2 C 3 -C 5 heterocycloalkyl";

And / or, when R 1 is substituted by R 1-22 is C 6 ~ C 10 aryl group, and the number of R 1-22 is a plurality of said plurality is two, three, or 4;

And/or, when R 1 is R 1-23 substituted "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 having 1 to 4 hetero atoms ~ C 7 heteroaryl ", and the number of R 1-23 is two or more, the plurality is 2, 3 or 4;

And / or, when R 1 is substituted by R 1-24 is C 1 ~ C 7 alkoxy, and R is the number of 1-24 plurality, the plurality is 2, 3 Or 4;

And / or, when R 1 is substituted by R 1-25 is C 1 ~ C 7 alkylmercapto, R 1-25 and said number is plural, said plurality is two, three, or 4;

And/or, when R 1-1 , R 1-2 or R 1-3 is unsubstituted or R 1-1-3 substituted C 1 -C 7 alkyl, the C 1 -C 7 alkyl group Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 1 -C 7 alkyl group, The C 1 -C 7 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl When the number of the halogens is plural, the plurality of the plurality is two, three or four;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl When said "halogen" is independently fluorine, chlorine, bromine or iodine;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl The C 1 -C 7 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 2 -C 7 alkynyl group, The C 2 -C 7 alkynyl group is 2-propynyl or 1-propynyl;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 1 -C 7 alkoxy group, The C 1 -C 7 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

And/or, when R 1-4-1 or R 1-4-2 is a C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a methyl group, an ethyl group, a n-propyl group or a different group. Propyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or when R 1-11 , R 1-12 , R 1-13 , R 1-14 or R 1-15 is R 1-11-1 substituted C 1 -C 7 alkyl, and When the number of R 1- 11-1 is plural, the plurality of the plurality is 2, 3 or 4;

And/or, when R 1-11 , R 1-12 , R 1-13 , R 1-14 or R 1-15 is unsubstituted or R 1-11-1 substituted C 1 -C 7 alkyl, The C 1 -C 7 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or when 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 1-24 or When R 1-25 is halogen, the halogen is fluorine;

And/or when 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 1-24 or R 1-25 R 1-16- 6 is substituted with "one or more hetero atoms, number of heteroatoms boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus in the range of 1 to 4 C 3 ~ C 7 heterocycloalkyl ", and the number of 1-16-6 R is plural, the plurality is 2, 3 or 4;

And/or when 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 1-24 or R 1-25 is unsubstituted or substituted by R 1-16-6 . The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4. When C 3 -C 7 heterocycloalkyl", the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. 3 —C 7 heterocycloalkyl” is a C 3 —C 5 heterocycloalkyl group in which the hetero atom is nitrogen, and the number of hetero atoms is 1 to 2, and the hetero atom is oxygen, and the number of hetero atoms is 1 to 2 C 3 -C 5 heterocycloalkyl" or

And/or when R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 or R 1-16-7 are C 1 ～ When C 7 alkyl, the C 1 -C 7 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or when R 1-16-5 is "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having a hetero atom number of 1 to 4 In the case of 7 heterocycloalkyl, the "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms. Heterocycloalkyl"

And/or, when R 1-16-5 is halogenated, the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. 3 ~ C 7 heterocycloalkyl ", and the number of 1-16-5 R is plural, the plurality is 2, 3 or 4;

And/or, when R 1-16-5 is halogenated, the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. When 3 to C 7 heterocycloalkyl", said "halogen" is independently fluorine;

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 When R 1-16-5-1-1 is substituted with C 1 -C 7 alkyl groups, and the number of the above R 1-16-5-1-1 is plural, the plurality of the plurality is 2 , 3 or 4;

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 In the case of unsubstituted or substituted C 1 -C 7 alkyl group of R 1-16-5-1-1 , the C 1 -C 7 alkyl group is methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, sec-butyl or tert-butyl;

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 In the case of a C 2 -C 7 alkynyl group, the C 2 -C 7 alkynyl group is a 2-propynyl group or a 1-propynyl group.
A pyrazolone pyrimidine compound I according to claim 3, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, characterized in that when R 1 is an unsubstituted or R 1-16 substituted C 1 -C 7 alkyl group, the C 1 -C 7 alkane The base is methyl, ethyl, n-propyl or isopropyl;

And/or, when R 1 is unsubstituted or substituted by R 1-21 , the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having 1 to 4 hetero atoms When the "heterocycloalkyl group" is "C 3 -C 5 heterocycloalkyl group having a hetero atom of nitrogen and having 1 to 2 hetero atoms", the "hetero atom is nitrogen" and the number of hetero atoms is 1 to 2 of a C 3 ~ C 5 heterocycloalkyl "as" hetero atom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ~ C 5 heterocycloalkyl and heterocycloalkyl attached via a nitrogen atom and Y " Or "a hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a carbon atom";

And/or, when R 1 is unsubstituted or substituted by R 1-21 , the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having 1 to 4 hetero atoms When the "heterocycloalkyl group" is "C 3 -C 5 heterocycloalkyl group having a hetero atom of 1 or 2," the "hetero atom is oxygen, and the number of hetero atoms is 1 to 2". C 3 -C 5 heterocycloalkyl"

And/or, when R 1-1 , R 1-2 or R 1-3 is unsubstituted or R 1-1-3 substituted C 1 -C 7 alkyl, the C 1 -C 7 alkyl group Is methyl, ethyl, n-propyl or isopropyl;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 1 -C 7 alkyl group, The C 1 -C 7 alkyl group is a methyl group;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl When the C 1 -C 7 alkyl group is a methyl group;

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 is a C 1 -C 7 alkoxy group, The C 1 -C 7 alkoxy group is a methoxy group;

And/or, when R 1-4-1 or R 1-4-2 is a C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a methyl group;

And/or when 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 1-24 or R 1-25 is unsubstituted or substituted by R 1-16-6 . The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4. C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having a hetero atom number of 1 to 4" When the heterocycloalkyl group is a C 3 -C 5 heterocycloalkyl group in which the hetero atom is nitrogen and the number of hetero atoms is 1 or 2, the "hetero atom is nitrogen" and the number of hetero atoms is 1 or 2 a C 3 ~ C 5 alkyl heterocycloalkyl heterocycloalkyl connected to another group "of" nitrogen hetero atom, hetero atom number of 1 to 2 is C 3 ~ C 5 heterocycloalkyl and via a nitrogen atom Or "a hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a carbon atom";

And/or when 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 1-24 or R 1-25 is unsubstituted or substituted by R 1-16-6 . The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4. C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having a hetero atom number of 1 to 4" When the heterocycloalkyl group is "C 3 -C 5 heterocycloalkyl group in which the hetero atom is oxygen and the number of hetero atoms is 1 or 2", the "hetero atom is oxygen, and the number of hetero atoms is 1 or 2". C 3 -C 5 heterocycloalkyl"

And/or when R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 or R 1-16-7 are C 1 ～ In the case of C 7 alkyl, the C 1 -C 7 alkyl group is a methyl group;

And/or, when R 1-16-5 is halogenated, the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C. When 3 to C 7 heterocycloalkyl", the "halogenated hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl"

And/or when R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 or R 1-16-5-5 When the C 1 -C 7 alkyl group which is unsubstituted or substituted by R 1-16-5-1-1 , the C 1 -C 7 alkyl group is a methyl group or an ethyl group.
A pyrazolone pyrimidine compound I according to claim 4, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein R 1 is unsubstituted or R 1-21 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", and "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus species, the number of hetero atoms of 1 to 4 C 3 ~ C 7 heterocycloalkyl "as" hetero atom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ~ C 5 heterocycloalkyl "," heteroaryl is a nitrogen atom, a hetero atom number of 1 to 2 is C 3 ~ C 5 heterocycloalkyl "as" hetero atom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ~ C 5 heterocycloalkyl and When a heterocycloalkyl group is bonded to Y through a nitrogen atom, the "hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded through a nitrogen atom. Y connection" is

And/or, when R 1 is unsubstituted or substituted by R 1-21 , the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having 1 to 4 hetero atoms 7 heterocycloalkyl "is" C 3 ~ C 5 heterocycloalkyl group is nitrogen, the number of hetero atoms is 1 to 2 "and" hetero atom is nitrogen, the number of hetero atoms of 1 to 2 C 3 When the "C 5 heterocycloalkyl group" is a C 3 -C 5 heterocycloalkyl group having a hetero atom of 1 or 2 and a heterocycloalkyl group is bonded to Y through a carbon atom, The "hetero atom is nitrogen, the C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and the heterocycloalkyl group is bonded to Y through a carbon atom"

And/or, when R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 or R 1-10 are halogen-substituted C 1 -C 7 alkyl The halogen-substituted C 1 -C 7 alkyl group is a trifluoromethyl group;

And/or when 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 1-24 or R 1-25 is unsubstituted or substituted by R 1-16-6 . The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4. C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having a hetero atom number of 1 to 4" The heterocycloalkyl group is a C 3 -C 5 heterocycloalkyl group in which the hetero atom is nitrogen, the hetero atom number is 1 or 2, and the hetero atom is nitrogen and the C 3 of the hetero atom is 1 or 2. "C 5 heterocycloalkyl" is a C 3 -C 5 heterocycloalkyl group having a hetero atom of 1 to 2 and a heterocycloalkyl group bonded to another group via a nitrogen atom," a hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a nitrogen atom"

And/or when 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 1-24 or R 1-25 is unsubstituted or substituted by R 1-16-6 . The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1-4. C 3 -C 7 heterocycloalkyl", "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having a hetero atom number of 1 to 4" The heterocycloalkyl group is a C 3 -C 5 heterocycloalkyl group in which the hetero atom is nitrogen, the hetero atom number is 1 or 2, and the hetero atom is nitrogen and the C 3 of the hetero atom is 1 or 2. When C 5 heterocycloalkyl is "a C 3 -C 5 heterocycloalkyl group having a hetero atom of 1 or 2 and a heterocycloalkyl group is bonded to another group through a carbon atom", a hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a carbon atom"
A pyrazolone pyrimidine compound I according to claim 5, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein R 1 is any of the following groups: hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyl Ethyl, 2-methoxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, cyanomethyl, cyano, acetyl, 2-propenyl, 2-propynyl, Dimethylamino, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxyl, methylsulfonyl, 2,2,2-trifluoroacetyl, cyclobutyl, cyclopropylmethyl , cyclopropyl, diethylamino, di-n-propylamino, dimethylaminomethyl, methoxy, hydroxy, carboxymethyl,
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein X is CH;

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

And / or, Y is N;

And/or, R 1 is H, cyano, -NR 1-1 R 1-2 , -OR 1-3 , -C(=O)R 1-4 , -S(=O) 2 R 1-7 , unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 8 alkynyl, C 3 -C 7 cycloalkyl, or unsubstituted or R 1 -21 substituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms";

And/or, all R 1-1 , R 1-2 and R 1-3 are independently hydrogen, -C(=O)NR 1-1-1 R 1-1-2 , or, unsubstituted or R 1-1-3 substituted C 1 ~ C 7 alkyl group; all of the R 1-1-1, R 1-1-2 and R 1-1-3 are independently C 1 ~ C 7 alkyl or C 6 ～C 10 aryl;

And/or all of R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 Alkoxy, or, NR 1-4-1 R 1-4-2 ; all R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl;

And/or all of R 1-16 and R 1-21 are independently halogen, cyano, C 1 -C 7 alkyl, unsubstituted or R 1-16-7 substituted C 3 -C 7 cycloalkyl The unsubstituted or substituted R 1-16-6 "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having 1 to 4 hetero atoms. 7 heterocycloalkyl", -NR 1-16-1 R 1-16-2 , -OR 1-16-3 , -SR 1-16-4 or -(C=O)R 1-16-5 ; All R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 and R 1-16-7 are independently hydrogen or C 1 ～C 7 alkyl; all R 1-16-5 are independently hydroxy, “a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ～ 4 C 3 -C 7 heterocycloalkyl", halogenated "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C 3 -C 7 heterocycloalkyl",
-NR 1- 16-5-1 R 1-16-5-2 or -OR 1-16-5-3 ; all R 1-16-5-1 , R 1-16-5-2 , R 1 -16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen, unsubstituted or hydroxy C 1 -C 7 alkyl, C 2 -C 7 alkynyl Or, C 3 -C 7 cycloalkyl;

And / or, z is 0.
A pyrazolone pyrimidine compound I according to claim 7, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein m and n are independently 0, 1, 2 or 3, and m+n is 3;

And / or, Y is N, and the atom connected to Y in R 1 is not N;

And/or R 1 is -NR 1-1 R 1-2 , R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";

And/or, all R 1-1 , R 1-2 and R 1-3 are independently hydrogen, -C(=O)NR 1-1-1 R 1-1-2 , or, unsubstituted or C 6 to C 10 aryl-substituted C 1 -C 7 alkyl; all R 1-1-1 and R 1-1-2 are independently C 1 -C 7 alkyl;

And/or all of R 1-16 and R 1-21 are independently halogen, cyano, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, unsubstituted or substituted by R 1-16-6 "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", -NR 1- 16-1 R 1-16-2 , -OR 1-16-3 , -SR 1-16-4 or -(C=O)R 1-16-5 ; all R 1- 16-1 , R 1 -16-2 , R 1-16-3 , R 1-16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl; all R 1-16-5 are independently hydroxy "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", halogenated" The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms",
-NR 1-16-5-1 R 1-16-5-2 or -OR 1-16-5-3 ; all R 1- 16-5-1 , R 1-16-5-2 , R 1 -16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen, unsubstituted or hydroxy C 1 -C 7 alkyl, C 2 -C 7 alkynyl Or, C 3 -C 7 cycloalkyl.
A pyrazolone pyrimidine compound I according to claim 8, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein m and n are independently 1 or 2, and m+n is 3;

And/or all of R 1-1 , R 1-2 and R 1-3 are independently hydrogen, or an unsubstituted or C 6 -C 10 aryl substituted C 1 -C 7 alkyl group;

And/or all of R 1-16 and R 1-21 are independently halogen, cyano, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, unsubstituted or substituted by R 1-16-6 "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", -NR 1- 16-1 R 1-16-2 , -SR 1-16-4 or -(C=O)R 1-16-5 ; all R 1-16-1 , R 1- 16-2 , R 1- 16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl; all R 1-16-5 are independently hydroxy, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms",
Or -NR 1-16-5-1 R 1-16-5-2 ; all R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-4 and R 1 -16-5-5 is independently hydrogen, unsubstituted or hydroxy C 1 -C 7 alkyl, C 2 -C 7 alkynyl, or C 3 -C 7 cycloalkyl.
A pyrazolone pyrimidine compound I according to claim 9, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein "m is 2, n is 1" or "m is 1, n is 2";

And/or all of R 1-1 and R 1-2 are independently hydrogen, or an unsubstituted or C 6 -C 10 aryl substituted C 1 -C 7 alkyl group;

And/or, all R 1-16 and R 1-21 are independently C 1 -C 7 alkyl, unsubstituted or R 1-16-6 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium , one or more of nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms or "(C=O)R 1-16-5 ; all R 1- 16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently
All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein X is CH;

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

Y is N or CH;

R 1 is H, cyano, -NR 1-1 R 1-2 , -OR 1-3 , -C(=O)R 1-4 , -S(=O) 2 R 1-7 , unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 8 alkynyl, C 3 -C 7 cycloalkyl, or unsubstituted or R 1-21 substituted "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms";

All of R 1-1 , R 1-2 and R 1-3 are independently hydrogen, or an unsubstituted or C 6 -C 10 aryl substituted C 1 -C 7 alkyl group;

All R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, Or, NR 1-4-1 R 1-4-2 ;

All R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl;

All R 1-16 and R 1-21 are independently halogen, cyano, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, unsubstituted or R 1 16-6 substituted "heteroatom" Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", -NR 1-16-1 R 1-16-2 , -SR 1-16-4 or -(C=O)R 1-16-5 ;

All R 1-16-1 , R 1-16-2 , R 1-16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl;

All of R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl",
Or -NR 1-16-5-1 R 1-16-5-2 ;

All R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen, unsubstituted or hydroxy C 1 -C 7 alkyl, C 2 -C 7 alkynyl, or C 3 -C 7 cycloalkyl;

z is 0.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein X is CH;

m is 2 and n is 1;

Y is N or CH;

R 1 is -NR 1-1 R 1-2 , R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";

All of R 1-1 and R 1-2 are independently hydrogen, or unsubstituted or C 6 -C 10 aryl substituted C 1 -C 7 alkyl;

All R 1-16 and R 1-21 are independently C 1 -C 7 alkyl, unsubstituted or R 1-16-6 substituted "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, a C 3 -C 7 heterocycloalkyl group having a hetero atom number of 1 to 4" or -(C=O)R 1- 16-5 ;

All R 1-16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently
All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl;

z is 0.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein X is N or CH;

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

Y is N or CH;

R 1 is H, halogen, fluorenyl, nitro, cyano, -NR 1-1 R 1-2 , -OR 1-3 , -C(=O)R 1-4 , -C(=NR 1-11 R 1 5 , -S(=O)R 1-6 , -S(=O) 2 R 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 , unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, not Substituted or R 1-17 substituted C 2 -C 7 alkenyl, unsubstituted or R 1-18 substituted C 2 -C 8 alkynyl, unsubstituted or R 1-19 substituted C 1 -C 7 alkylsilyl , unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl, unsubstituted or R 1-21 substituted "hetero atom" is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus or a plurality of C 3 -C 7 heterocycloalkyl groups having 1 to 4 hetero atoms, unsubstituted or R 1-22 substituted C 6 -C 10 aryl groups, unsubstituted or R 1 - 23 substituted" The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms, unsubstituted or R 1-24 Substituted C 1 -C 7 alkoxy, or unsubstituted or R 1-25 substituted C 1 -C 7 alkyl fluorenyl;

All R 1-1 , R 1-2 and R 1-3 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 a cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 to C 10 aryl or "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

All R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl, halogen Substituted C 1 -C 7 alkyl, halogen, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 7 alkoxy, "hetero atom" One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms, or NR 1-4- 1 R 1-4-2 ;

All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 ring An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 ～C 10 aryl or “hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 —C 7 heteroaryl group having 1 to 4 hetero atoms”;

All R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, unsubstituted or R 1 1-1-1 substituted C 1 -C 7 alkyl group, C 3 -C 7 cycloalkyl group, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, hetero atom a number of 1 to 4 C 3 -C 7 heterocycloalkyl", a C 6 -C 10 aryl group, or "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus or a plurality of C 1 -C 7 heteroaryl groups having a hetero atom number of 1 to 4";

All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ～4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;

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 1-24 and R 1- 25 independently is halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 a cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 to C 10 aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms" , C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, -NR 1-16-1 R 1-16-2 , -OR 1-16-3 , -SR 1-16-4 or -( C=O)R 1-16-5 ;

All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C 1 -C 7 heteroaryl groups";

All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, and halogenated "heteroatoms are boron," One or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, "hetero atom" Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", -NR 1-16-5-1 R 1-16-5-2 or -OR 1-16-5-3 ;

All R 1-16-5-1 , R 1-16-5-2 and R 1-16-5-3 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, C 6 -C 10 aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and One or more of phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

z is 0, 1 or 2;

All R 2 are independently halogen, hydroxy, cyano, amino, unsubstituted or R 2-1 -substituted C 1 -C 7 alkyl, unsubstituted or R 2-2 substituted C 2 -C 8 alkenyl, Unsubstituted or R 2-3 substituted C 2 -C 7 alkynyl, unsubstituted or R 2-4 substituted C 1 -C 7 alkyl, unsubstituted or R 2-5 substituted C 6 -C 10 aryl The "hetero atom" which is substituted by a base, unsubstituted or R 2-6 is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 to C 7 having a hetero atom number of 1 to 4 a heteroaryl group, a C 3 -C 7 cycloalkyl group, or an unsubstituted or R 2-7 substituted C 1 -C 7 alkoxy group;

All of R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ～ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-2 , -OR 2-1-3 , -SR 2-1-4 or -(C=O)R 2-1-5 ;

All R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C 1 -C 7 heteroaryl groups";

All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

Alternatively, two R 2 linkages are taken together on the same carbon atom to form an unsubstituted or R 2-8 substituted C 3 -C 7 cycloalkyl group, or an unsubstituted or R 2-9 substituted C 1 -C 7 heterocyclic ring. alkyl;

All R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein X is N or CH;

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

Y is N or CH;

R 1 is H, halogen, fluorenyl, nitro, cyano, -NR 1-1 R 1-2 , -OR 1-3 , -C(=O)R 1-4 , -C(=NR 1-11 R 1 5 , -S(=O)R 1-6 , -S(=O) 2 R 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 , R 1-16 substituted or unsubstituted C 1 -C 7 alkyl, R 1 -17 substituted or unsubstituted C 2 -C 7 alkenyl, R 1-18 substituted or unsubstituted C 2 -C 8 alkynyl, R 1-19 substituted or unsubstituted C 1 -C 7 alkyl, R 1- 20 substituted or unsubstituted C 3 -C 7 cycloalkyl, R 1-21 substituted or unsubstituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, hetero atom a number of 1 to 4 C 3 -C 7 heterocycloalkyl", R 1-22 substituted or unsubstituted C 6 -C 10 aryl, R 1-23 substituted or unsubstituted "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", R 1 24 substituted or unsubstituted C 1 -C 7 alkane group, or, R 1-25 substituted or unsubstituted C 1 ~ C 7 alkylmercapto;

R 1-1 , R 1-2 and R 1-3 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 naphthenic The "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 - a C 10 aryl group or "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl, halogen, C 2 to C 7 alkenyl group, C 2 -C 7 alkynyl group, C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 atoms, a C 6 -C 10 aryl group, and "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. , a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms, or NR 1-4-1 R 1-4-2 ;

All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 ring An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 ～C 10 aryl or “hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 —C 7 heteroaryl group having 1 to 4 hetero atoms”;

R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, R 1-11-1 Or unsubstituted C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ～4 C 3 —C 7 heterocycloalkyl”, C 6 —C 10 aryl, or “a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ～4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;

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 1-24 and R 1- 25 independently is halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 a cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 to C 10 aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms" , C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, -NR 1-16-1 R 1-16-2 , -OR 1-16-3 , -SR 1-16-4 or -( C=O)R 1-16-5 ;

All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C 1 -C 7 heteroaryl groups";

All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

z is 0, 1 or 2;

All R 2 are independently halogen, hydroxy, cyano, amino, R 2-1 substituted or unsubstituted C 1 -C 7 alkyl, R 2-2 substituted or unsubstituted C 2 -C 8 alkenyl, R 2 -3 substituted or unsubstituted C 2 -C 7 alkynyl, R 2-4 substituted or unsubstituted C 1 -C 7 alkyl, R 2-5 substituted or unsubstituted C 6 -C 10 aryl, R 2 - 6 substituted or unsubstituted "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms", or , R 2-7 substituted or unsubstituted C 1 -C 7 alkoxy;

All of R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ～ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-2 , -OR 2-1-3 , -SR 2-1-4 or -(C=O)R 2-1-5 ;

All R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ~4 C 1 -C 7 heteroaryl groups";

All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";

Alternatively, the two R 2 linkages together form the R 2-8 substituted or unsubstituted C 3 -C 7 cycloalkyl group, or the R 2-9 substituted or unsubstituted C 1 -C 7 heterocycloalkyl group on the same carbon atom. ;

All R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein X is CH;

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

Y is N;

R 1 is H, cyano, -NR 1-1 R 1-2 , -C(=O)R 1-4 , R 1-16 substituted or unsubstituted C 1 -C 7 alkyl, C 2 -C 7 Alkenyl, or, C 2 -C 7 alkynyl;

R 1-1 and R 1-2 are independently C 1 -C 7 alkyl;

R 1-4 is independently C 1 -C 7 alkyl or C 2 -C 7 alkynyl;

All R 1-16 are independently cyano, -NR 1-16-1 R 1-16-2 or -OR 1-16-3 ;

All R 1-16-1 , R 1-16-2 and R 1-16-3 are independently hydrogen or C 1 -C 7 alkyl;

z is 0.
A pyrazolone pyrimidine compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to claim 1. a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, wherein the compound I is any one of the following compounds:
A method for producing a compound I according to at least one of claims 1 to 16, which is any of the following methods:

method one:

The method comprises the steps of: oxidizing compound 1A to obtain compound 1B, and substituting to obtain compound 1D, and deprotecting to obtain compound 1E;

Wherein PG is an amino protecting group;

Method Two:

The method comprises the steps of: oxidizing compound 1A to obtain compound 1B, and reacting with 2A to obtain compound 2B;

Method three:

When R 1 is unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, unsubstituted or R 1-17 substituted C 2 -C 7 alkenyl, unsubstituted or R 1-18 substituted C 2 ～ a C 8 alkynyl group, or an unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl group, which comprises the steps of: compound 1E and R 1 in an organic solvent in the presence of a reducing agent -CHO is subjected to a reductive amination reaction to obtain a compound I;

Wherein Y is N and said R 1 ' -CH 2 - is equivalent to R 1 ;

Method four:

When R 1 is unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, unsubstituted or R 1-17 substituted C 2 -C 7 alkenyl, unsubstituted or R 1-18 substituted C 2 ～ When C 8 alkynyl, unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl, cyano or acetyl group, it comprises the steps of: compound 1E in an organic solvent in the presence of a base Substituting a reaction with R 1 -X 1 to obtain a compound I;

Wherein X 1 is halogen; Y is N;

Method five:

When R 1 is -C(=O)R 1-4 , and R 1-4 is C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl or C 3 -C 7 In the case of a cycloalkyl group, it comprises the steps of: in a organic solvent, in the presence of a condensing agent, compound 1E,
Carrying out a condensation reaction to obtain a compound I;

Where Y is N.
A compound as shown in Formula 1C, 1D or 2A:

Wherein PG, m, n, z, Y, R 1 and R 2 are as defined in any one of claims 1 to 17.
A compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to at least one of claims 1 to 16. Use of a salt, a solvate thereof, a metabolite thereof or a prodrug thereof for the preparation of a medicament or a kinase inhibitor;

The medicament is for treating and/or preventing a disease associated with WEE1 kinase, or the medicament is for treating and/or preventing cancer.
A pharmaceutical composition comprising the compound I according to at least one of claims 1 to 16, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, A pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof or a prodrug thereof, and a pharmaceutical excipient.
A combination comprising the compound I according to at least one of claims 1 to 16, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically thereof thereof An acceptable salt, a solvate thereof, a metabolite thereof or a prodrug thereof, and an anticancer drug.
Use of a combination according to claim 21 for the preparation of a medicament for the treatment and/or prevention of cancer.
A compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable thereof, according to at least one of claims 1 to 16. Use of a salt, a solvate thereof, a metabolite thereof or a prodrug thereof for the preparation of a medicament for the treatment and/or prevention of cancer in combination with "an anticancer drug according to claim 21."
Use of an anticancer drug according to claim 21 for the preparation of a medicament for "and combining the compound I according to at least one of claims 1 to 16, an enantiomer thereof And a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof or a prodrug thereof, for treating and/or preventing cancer.
A pharmaceutical composition comprising the combination and pharmaceutical excipient of claim 21.
A combination kit comprising a pharmaceutical composition A and a pharmaceutical composition B;

The pharmaceutical composition A includes the compound I according to at least one of claims 1 to 16, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof or a prodrug thereof, and a pharmaceutical excipient;

The pharmaceutical composition B includes the anticancer drug and the pharmaceutically acceptable adjuvant according to claim 21.