CN109810111B

CN109810111B - Pyrazolopyrimidine compound, and preparation method and application thereof

Info

Publication number: CN109810111B
Application number: CN201811382194.0A
Authority: CN
Inventors: 王倩; 夏广新; 霍国永; 舒思杰; 石辰; 张霖; 葛辉; 张智慧; 毛煜; 余建鑫; 刘彦君
Original assignee: Shanghai Pharmaceuticals Holding Co Ltd
Current assignee: Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2017-11-20
Filing date: 2018-11-20
Publication date: 2023-10-27
Anticipated expiration: 2038-11-20
Also published as: WO2019096322A1; CN109810111A

Abstract

The invention discloses pyrazolopyrimidine compound, a preparation method and application thereof. The invention provides pyrazolopyrimidine compound shown in a formula I, enantiomer, diastereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof, and the compound has better inhibitory activity on WEE1 kinase.

Description

Pyrazolopyrimidine compound, and preparation method and application thereof

Technical Field

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

Background

Cell cycle is closely related to the DNA damage repair process. The cell cycle refers to the whole process undergone by cell division, and is divided into two phases, namely an interphase (interphase) and a mitotic phase (M). Cell cycle checkpoint (checkpoint) is a key point in regulating the cell cycle, and is mainly used to ensure that each event in the cycle can be completed in time and order, and that the cell state is regulated to adapt to the external environment. The main checkpoints of the cells are: 1) G ₁ S checkpoint: in mammals, designated as point R (restriction), control cells from resting G ₁ The phase enters a DNA synthesis phase; 2) S-phase test point: whether the DNA replication is complete; 3) G ₂ Check point/M: is a control point that regulates the entry of cells into the dividing phase; 4) Mid-late checkpoint: also known as spindle assembly checkpoint, can cause disruption of the cell cycle if the centromere is not properly attached to the spindle. If fineDuring the cell division cycle, abnormalities such as DNA damage exist in certain processes, and the checkpoint can sense and initiate repair in time. P53 protein is regulatory G ₁ Important proteins of the test point, when DNA is damaged, prevent cells from entering S phase, activate DNA repair mechanism, and are important for maintaining the integrity of cell genome. However, since tumor cells often have P53 mutation, which makes G1 checkpoint defective, cell division cycle regulation in P53 mutated cells is dependent on G ₂ Check point/M. WEE1 kinase is a cell cycle regulating protein, can regulate the phosphorylation state of cyclin-dependent kinase 1 (CDK 1), thus regulating the activity of CDK1 and cyclin B (cyclin B) complex, thus realizing the regulation of cell cycle, and has important regulation function on DNA damage check points. WEE1 is G ₂ The key genes of/M phase retardation play an important role in monitoring, and over-expression, inhibition or down-regulation of WEE1 kinase can trigger mitosis disasters in some cancers, so that WEE1 kinase inhibitors play a key role in anticancer treatment and are now hot spots for developing anticancer agents.

International patent applications WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, WO2004007499 and the like disclose partial small molecule WEE1 kinase inhibitors, but no small molecule WEE1 kinase inhibitors are currently marketed, and there is a need in the art to develop novel WEE1 kinase inhibitors with good anticancer activity and high safety.

Disclosure of Invention

The invention aims to solve the technical problem that the existing compound has poor inhibitory activity on WEE1 kinase, so the invention provides a pyrazolopyrimidine compound, a preparation method and application thereof, and the compound has good inhibitory activity on WEE1 kinase.

The invention provides pyrazolopyrimidine compound shown in a formula I, enantiomer, diastereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or 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{ e.g., m+n is 2 or 3; for another 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" };

Y is N or CH;

R ¹ is H, halogen, mercapto, 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 { wherein R ^1-16 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16 When said R is ^1-16 The same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl, in turn, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, in turn, e.g. methyl, ethyl, n-propyl or isopropyl }, unsubstituted or R ^1-17 Substituted C ₂ ～C ₇ Alkenyl { wherein R ^1-17 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-17 When said R is ^1-17 The same or different; wherein said "C ₂ ～C ₇ Alkenyl radicals "such as C ₂ ～C ₄ Alkenyl radicals, e.g. 2-propenyl, unsubstituted or R ^1-18 Substituted C ₂ ～C ₈ Alkynyl { wherein R ^1-18 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-18 When said R is ^1-18 The same or different; wherein said "C ₂ ～C ₇ Alkynyl radicals "such as C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl }, unsubstituted or R ^1-19 Substituted C ₁ ～C ₇ Alkylsilyl { wherein R ^1-19 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-19 When said R is ^1-19 Identical or different }, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl { wherein R ^1-20 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-20 When said R is ^1-20 The same or different; the said "C ₃ ～C ₇ Cycloalkyl "e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and also e.g. cyclobutyl }, unsubstituted or R ^1-21 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "{ wherein R ^1-21 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-21 When said R is ^1-21 The same or different; the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocyclyl "for example" having 1 to 2 hetero atoms C as nitrogen and/or oxygen ₃ ～C ₅ Heterocyclylalkyl groups, also for example "heteroatom is nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocyclyl "or" heteroatom is oxygen, C having 1-2 heteroatoms ₃ ～C ₅ Heterocycloalkyl group). The hetero atom is nitrogen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocyclylalkyl "for example" heteroatoms are nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ A heterocycloalkyl group wherein the heterocycloalkyl group is linked to Y through a nitrogen atom or a heteroatom is nitrogen, and the number of heteroatoms is 1 to 2C ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is attached to Y through a carbon atom. The hetero atom is nitrogen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is attached to Y through a nitrogen atom, e.gThe hetero atom is nitrogen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is attached to Y via a carbon atom, e.g +.>The hetero atom is oxygen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocyclylalkyl radicals such as->Unsubstituted or R ^1-22 Substituted C ₆ ～C ₁₀ Aryl { wherein R ^1-22 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-22 When said R is ^1-22 Identical or different }, unsubstituted or R ^1-23 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^1-23 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-23 When said R is ^1-23 Identical or different }, unsubstituted or R ^1-24 Substituted C ₁ ～C ₇ Alkoxy { wherein R ^1-24 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-24 When said R is ^1-24 Identical or different }, or, unsubstituted or R ^1-25 Substituted C ₁ ～C ₇ Alkylmercapto { wherein R ^1-25 Is one or more [ e.g. 2, 3 or 4 ] ]When there are a plurality of R ^1-25 When said R is ^1-25 Same or different };

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl,also, for example, methyl, ethyl, n-propyl or isopropyl }, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-1-1 、R ^1-1-2 And R is ^1-1-3 Independently C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-4 、R ^1-5 、R ^1-6 、R ^1-7 、R ^1-8 、R ^1-9 And R is ^1-10 Independently is hydroxy, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, e.g. methyl }, halogen-substituted C ₁ ～C ₇ Alkyl { wherein the number of halogens is one or more [ e.g., 2, 3 or 4 ]]When a plurality of halogens are present, the halogens are the same or different; the "halogen" is independently fluorine, chlorine, bromine or iodine; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and methyl; said "halogen-substituted C ₁ ～C ₇ Alkyl "such as trifluoromethyl }, halogen, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl { exampleSuch as C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl or 1-propynyl }, C ₃ ～C ₇ Cycloalkyl, C ₁ ～C ₇ Alkoxy { e.g. C ₁ ～C ₄ Alkoxy, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, e.g. methoxy }, "heteroatom(s) being one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, heteroatom number C being 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', or NR ^1-4-1 R ^1-4-2 ；

All R ^1-4-1 And R is ^1-4-2 Independently hydrogen, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, also such as the methyl radical }, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-11 、R ^1-12 、R ^1-13 、R ^1-14 And R is ^1-15 Independently H, cyano, hydroxy, C ₁ ～C ₇ Alkoxy, unsubstituted or R ^1-11-1 Substituted C ₁ ～C ₇ Alkyl { wherein R ^1-11-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-11-1 When said R is ^1-11-1 The same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl radicals, also e.g. methylEthyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl or C with 1-4 hetero atoms, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus ₁ ～C ₇ Heteroaryl ";

all R ^1-11-1 Independently halogen, hydroxy, cyano, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl, C ₁ ～C ₇ Heterocycloalkyl, C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "or C ₁ ～C ₇ An alkoxy group;

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 is ^1-25 Independently halogen { e.g. fluorine, chlorine, bromine or iodine, also e.g. 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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "{ wherein R ¹ ^-16-6 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16-6 When said R is ^1-16-6 The same or different; the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is 1 to the whole rangeC of 4 ₃ ～C ₇ Heterocyclyl "for example" having 1 to 2 hetero atoms C as nitrogen and/or oxygen ₃ ～C ₅ Heterocyclylalkyl groups, also for example "heteroatom is nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocycloalkyl, C having 1 to 2 hetero atoms, in which the hetero atoms are oxygen ₃ ～C ₅ Heterocycloalkyl "orThe hetero atom is nitrogen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocyclylalkyl "for example" heteroatoms are nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is bound to other groups through nitrogen atoms [ e.g. C ₁ ～C ₇ Alkyl group]C having 1-2 hetero atoms attached to the "or" hetero atom being nitrogen ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is bound to other groups through carbon atoms [ e.g. C ₁ ～C ₇ Alkyl group]And (5) connection. The hetero atom is nitrogen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is linked to other groups via a nitrogen atom "e.g. +.>The hetero atom is nitrogen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is linked to other groups via a carbon atom "e.g. +.>The hetero atom is oxygen and C with 1-2 hetero atoms ₃ ～C ₅ Heterocyclylalkyl radicals such as->}、C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ", C ₁ ～C ₇ Alkoxy radicalRadical, 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 ；

All R ^1-16-1 、R ^1-16-2 、R ^1-16-3 、R ^1-16-4 、R ^1-16-6 And R is ^1-16-7 Independently hydrogen, hydroxy, halogen, cyano, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, also such as the methyl radical }, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-16-5 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocyclyl "{ for example" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C having 1 to 4 heteroatoms ₃ ～C ₇ Heterocycloalkyl which is bound to the carbonyl group by a nitrogen atom, and "heteroatom is one or more of oxygen, sulfur and nitrogen, and C having 1 to 2 heteroatoms ₃ ～C ₇ Heterocycloalkyl, and which is bound to the carbonyl group via a nitrogen atom ", e.g.The "hetero atom" is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is 1C of 4 ₃ ～C ₇ Heterocycloalkyl "{ wherein, the" halogen "is independently fluoro, chloro or bromo; the number of halogens being one or more [ e.g. 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 hetero atom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "for example" heteroatoms are nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₇ Heterocycloalkyl, and which is attached to the carbonyl group through a nitrogen atom. The halogenated heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl radicals such as->}、C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', I/O>-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 is ^1-16-5-5 Independently is hydrogen, unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ Alkyl { wherein R ^1-16-5-1-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16-5-1-1 When said R is ^1-16-5-1-1 The same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl radicals, in turn, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, in turn, such as the methyl or ethyl radical, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl { e.g. C ₂ ～C ₄ Alkynyl radicals, also e.g. 2-propynyl or 1-Propynyl }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-16-5-1-1 Independently halogen, hydroxy, cyano, amino, C ₁ ～C ₇ Alkyl, C ₁ ～C ₇ Alkoxy, C ₁ ～C ₇ Alkylthio, C ₁ ～C ₇ Alkyl silicon group, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

z is 0, 1 or 2;

all R ² Independently is halogen, hydroxy, cyano, amino, unsubstituted or R ^2-1 Substituted C ₁ ～C ₇ Alkyl { wherein R ^2-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-1 When said R is ^2-1 Identical or different }, unsubstituted or R ^2-2 Substituted C ₂ ～C ₈ Alkenyl { wherein R ^2-2 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-2 When said R is ^2-2 Identical or different }, unsubstituted or R ^2-3 Substituted C ₂ ～C ₇ Alkynyl { wherein R ^2-3 Is one or more [ e.g. 2, 3 or 4 ] ]When there are a plurality of R ^2-3 When said R is ^2-3 Identical or different }, unsubstituted or R ^2-4 Substituted C ₁ ～C ₇ Alkyl silicon base{ wherein R is ^2-4 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-4 When said R is ^2-4 Identical or different }, unsubstituted or R ^2-5 Substituted C ₆ ～C ₁₀ Aryl { wherein R ^2-5 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-5 When said R is ^2-5 Identical or different }, unsubstituted or R ^2-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^2-6 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-6 When said R is ^2-6 Identical or different }, C ₃ ～C ₇ Cycloalkyl, or, optionally, R ^2-7 Substituted C ₁ ～C ₇ Alkoxy { wherein R ^2-7 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-7 When said R is ^2-7 Same or different };

{ when z is 2, two R ² Are hydroxyl and are bound to the same carbon atom, which represents two R ² Together with the carbon atoms to which they are attached form a carbonyl }

All R ^2-1 、R ^2-2 、R ^2-3 、R ^2-4 、R ^2-5 、R ^2-6 And R is ^2-7 Independently halogen, nitro, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ", C ₁ ～C ₇ Alkoxy, C ₁ ～C ₇ Alkylmercapto, -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 is ^2-1-4 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^2-1-5 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

alternatively, two R ² Attached to the same carbon atom together to form unsubstituted or R ^2-8 Substituted C ₃ ～C ₇ Cycloalkyl { wherein R ^2-8 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-8 When said R is ^2-8 Identical or different }, or, unsubstituted or R ^2-9 Substituted C ₁ ～C ₇ Heterocycloalkyl { wherein R ^2-9 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-9 When said R is ^2-9 The same or different; the said "C ₁ ～C ₇ Heterocyclyl "for example" heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, the number of heteroatoms being 1 to 4C of (2) ₃ ～C ₇ Heterocycloalkyl "};

all R ^2-8 And R is ^2-9 Independently halogen, cyano, mercapto, hydroxy, amino, C ₁ ～C ₇ Alkoxy or C ₁ ～C ₇ Alkylthio groups.

In one embodiment, each group in compound I, its enantiomer, its diastereomer, its tautomer, its crystalline form, its pharmaceutically acceptable salt, its solvate, its metabolite, or prodrug thereof, may be defined as follows (the unannotated definition is as in any of the foregoing):

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 R ¹ Wherein the atom attached to Y 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, unsubstitutedOr R is ^1-21 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl group).

R ¹ is-NR ^1-1 R ^1-2 、R ^1-16 Substituted C ₁ ～C ₇ Alkyl, or, unsubstituted or R ^1-21 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl group).

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ An alkyl group;

all R ^1-1-1 、R ^1-1-2 And R is ^1-1-3 Independently C ₁ ～C ₇ Alkyl or C ₆ ～C ₁₀ Aryl groups.

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group;

all R ^1-1-1 And R is ^1-1-2 Independently C ₁ ～C ₇ An alkyl group.

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group.

All R ^1-1 And R is ^1-2 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group; all R ^1-1-1 And R is ^1-1-2 Independently C ₁ ～C ₇ An alkyl group.

all R ^1-1 And R is ^1-2 Independently hydrogen, or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group.

all R ^1-4 And R is ^1-7 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 is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group.

All R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, unsubstituted or R ^1-16-7 Substituted C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^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 is ^1-16-7 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatoms "are boron, silicon, oxygen, sulfur, seleniumOne or more of nitrogen and phosphorus, C having 1-4 hetero atoms 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 is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkynyl, or, C ₃ ～C ₇ Cycloalkyl groups.

all R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^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 is ^1-16-6 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 heteroatom number ₃ ～C ₇ Heterocycloalkyl group”、-NR ^1-16-5-1 R ^1-16-5-2 OR-OR ¹ ^-16-5-3 ；

all R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^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 is ^1-16-6 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and heteroatom number is C of 1-4 ₃ ～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 is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkynyl, or, C ₃ ～C ₇ Cycloalkyl groups.

all R ^1-16 And R is ^1-21 Independently C ₁ ～C ₇ Alkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "-OR ^1-16-3 Or- (c=o) R ^1-16-5 ；

All R ^1-16-3 And R is ^1-16-6 Independently C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently isAll R ^1-16-5-4 And R is ^1-16-5-5 Independently C ₁ ～C ₇ An alkyl group.

All R ^1-16 And R is ^1-21 Independently C ₁ ～C ₇ Alkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "or- (c=o) R ^1-16-5 ；

All R ^1-16-6 Independently C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently isAll R ^1-16-5-4 And R is ^1-16-5-5 Independently C ₁ ～C ₇ An alkyl group.

R ¹ is any one 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-trifluoroethyl, methoxyacyl, methylsulfonyl, 2-trifluoroacetyl, cyclobutyl, cyclopropylmethyl, cyclopropyl, diethylamino, di-n-propylamino, dimethylaminomethyl, 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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-1-1 、R ^1-1-2 And R is ^1-1-3 Independently C ₁ ～C ₇ Alkyl or C ₆ ～C ₁₀ An aryl group;

All R ^1-4-1 And R is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 heteroatom number 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 is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy 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 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 Substitution ofC of (2) 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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-1-1 And R is ^1-1-2 Independently C ₁ ～C ₇ An alkyl group;

All R ^1-4-1 And R is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently a hydroxyl group, a heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a heteroatomC with 1-4 number ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 heteroatom number ₃ ～C ₇ Heterocycloalkyl ",-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 R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group;

All R ^1-4-1 And R is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

All R ^1-16-5-1 、R ^1-16-5-2 、R ^1-16-5-4 And R is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkynyl, or, C ₃ ～C ₇ Cycloalkyl;

z is 0.

x is CH;

m is 2, 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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-1 And R is ^1-2 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ An alkyl group; all R ^1-1-1 、R ^1-1-2 And R is ^1-1-3 Independently C ₁ ～C ₇ Alkyl or C ₆ ～C ₁₀ An aryl group;

All R ^1-16-3 And R is ^1-16-6 Independently C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently isAll R ^1-16-5-4 And R is ^1-16-5-5 Independently C ₁ ～C ₇ An alkyl group;

z is 0.

x is CH;

m is 2, n is 1;

y is N or CH;

all R ^1-1 And R is ^1-2 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group; all R ^1-1-1 And R is ^1-1-2 Independently C ₁ ～C ₇ An alkyl group;

z is 0.

x is CH;

m is 2, n is 1;

y is N or CH;

all R ^1-1 And R is ^1-2 Independently hydrogen, or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group;

All R ^1-16-6 Independently C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently isAll R ^1-16-5-4 And R is ^1-16-5-5 Independently C ₁ ～C ₇ An alkyl group;

z is 0.

wherein X is N or CH;

m and n are independently 0, 1, 2, or 3, and m+n is 2, 3, or 4{ e.g., "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, mercapto, 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 { wherein R ^1-16 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16 When said R is ^1-16 The same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl, in turn, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, in turn, e.g. methyl, ethyl, n-propyl or isopropyl }, unsubstituted or R ^1-17 Substituted C ₂ ～C ₇ Alkenyl { wherein R ^1-17 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-17 When said R is ^1-17 The same or different; wherein said "C ₂ ～C ₇ Alkenyl radicals "such as C ₂ ～C ₄ Alkenyl radicals, e.g. 2-propenyl, unsubstituted or R ^1-18 Substituted C ₂ ～C ₈ Alkynyl { wherein R ^1-18 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-18 When said R is ^1-18 The same or different; wherein said "C ₂ ～C ₇ Alkynyl radicals "such as C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl }, unsubstituted or R ^1-19 Substituted C ₁ ～C ₇ Alkyl silicon group { itWherein R is ^1-19 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-19 When said R is ^1-19 Identical or different }, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl { wherein R ^1-20 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-20 When said R is ^1-20 The same or different; the said "C ₃ ～C ₇ Cycloalkyl "e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and also e.g. cyclobutyl }, unsubstituted or R ^1-21 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "{ wherein R ^1-21 Is one or more [ e.g. 2, 3 or 4 ] ]When there are a plurality of R ^1-21 When said R is ^1-21 The same or different; the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "for example" heteroatoms are nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocyclylalkyl groups, also for example "heteroatom is nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is attached to Y through a nitrogen atom ", e.g.Or->}, unsubstituted or R ^1-22 Substituted C ₆ ～C ₁₀ Aryl { wherein R ^1-22 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-22 When said R is ^1-22 Identical or different }, unsubstituted or R ^1-23 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^1-23 Is one or more [ e.g. 2, 3 ]One or 4]When there are a plurality of R ^1-23 When said R is ^1-23 Identical or different }, unsubstituted or R ^1-24 Substituted C ₁ ～C ₇ Alkoxy { wherein R ^1-24 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-24 When said R is ^1-24 Identical or different }, or, unsubstituted or R ^1-25 Substituted C ₁ ～C ₇ Alkylmercapto { wherein R ^1-25 Is one or more [ e.g. 2, 3 or 4 ] ]When there are a plurality of R ^1-25 When said R is ^1-25 Same or different };

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl radicals, in turn, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, in turn, such as the methyl, ethyl, n-propyl or isopropyl radical, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-4 、R ^1-5 、R ^1-6 、R ^1-7 、R ^1-8 、R ^1-9 And R is ^1-10 Independently is hydroxy, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, e.g. methyl }, halogen-substituted C ₁ ～C ₇ Alkyl { wherein the number of halogens is one or more [ e.g., 2, 3 or 4 ]]When a plurality of halogens are present, the halogens are the same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl, another exampleSuch 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 { e.g. C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl or 1-propynyl }, C ₃ ～C ₇ Cycloalkyl, C ₁ ～C ₇ Alkoxy { e.g. C ₁ ～C ₄ Alkoxy, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, e.g. methoxy }, "heteroatom(s) being one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, heteroatom number C being 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', or NR ^1-4-1 R ^1-4-2 ；

all R ^1-11 、R ^1-12 、R ^1-13 、R ^1-14 And R is ^1-15 Independently H, cyano, hydroxy, C ₁ ～C ₇ Alkoxy, unsubstituted or R ^1-11-1 Substituted C ₁ ～C ₇ Alkyl { wherein R ^1-11-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-11-1 When said R is ^1-11-1 Identical or different }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl or C with 1-4 hetero atoms, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus ₁ ～C ₇ Heteroaryl ";

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 is ^1-25 Independently halogen { e.g. fluorine, chlorine, bromine or iodine, also e.g. 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 }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocyclyl "{ for example," heteroatom is nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocyclylalkyl groups, also for example "heteroatom is nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is bound to other radicals, e.g. C, through nitrogen atoms ₁ ～C ₇ Alkyl, attached ", also for example }、C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C 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 ；

All R ^1-16-1 、R ^1-16-2 、R ^1-16-3 And R is ^1-16-4 Independently hydrogen, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, also such as the methyl radical }, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-16-5 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocyclyl "{ for example" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C having 1 to 4 heteroatoms ₃ ～C ₇ Heterocycloalkyl group, and its useThe pernitrogen atom being bound to the carbonyl group ", and" the hetero atom being one or more of oxygen, sulfur and nitrogen ", for example, C having 1 to 2 hetero atoms ₃ ～C ₇ Heterocycloalkyl, and which is bound to the carbonyl group via a nitrogen atom ", e.g.The "hetero atom" being one or more of B, si, O, S, se, N and P, C having 1-4 hetero atoms ₃ ～C ₇ Heterocycloalkyl "{ wherein the number of halogen is one or more [ e.g. 2, 3 or 4 ]]When a plurality of halogens are present, the halogens are the same or different; the "halogen" is independently fluorine, chlorine or bromine; the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "for example" heteroatoms are nitrogen, C having 1 to 2 heteroatoms ₃ ～C ₇ Heterocycloalkyl, and which is attached "to the carbonyl group through a nitrogen atom; the halogenated heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl radicals such as->}、C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', 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 is ^1-16-5-3 Independently is hydrogen, unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ Alkyl { wherein R ^1-16-5-1-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16-5-1-1 When said R is ^1-16-5-1-1 The same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl groupAlso for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl }, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl { e.g. C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl or 1-propynyl }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

z is 0, 1 or 2;

all R ² Independently is halogen, hydroxy, cyano, amino, unsubstituted or R ^2-1 Substituted C ₁ ～C ₇ Alkyl { wherein R ^2-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-1 When said R is ^2-1 Identical or different }, unsubstituted or R ^2-2 Substituted C ₂ ～C ₈ Alkenyl { wherein R ^2-2 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-2 When said R is ^2-2 Identical or different }, unsubstituted or R ^2-3 Substitution ofC of (2) ₂ ～C ₇ Alkynyl { wherein R ^2-3 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-3 When said R is ^2-3 Identical or different }, unsubstituted or R ^2-4 Substituted C ₁ ～C ₇ Alkylsilyl { wherein R ^2-4 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-4 When said R is ^2-4 Identical or different }, unsubstituted or R ^2-5 Substituted C ₆ ～C ₁₀ Aryl { wherein R ^2-5 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-5 When said R is ^2-5 Identical or different }, unsubstituted or R ^2-6 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^2-6 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-6 When said R is ^2-6 Identical or different }, C ₃ ～C ₇ Cycloalkyl, or, optionally, R ^2-7 Substituted C ₁ ～C ₇ Alkoxy { wherein R ^2-7 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-7 When said R is ^2-7 Same or different };

alternatively, two R ² Attached to the same carbon atom together to form unsubstituted or R ^2-8 Substituted C ₃ ～C ₇ Cycloalkyl { wherein R ^2-8 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-8 When said R is ^2-8 Identical or different }, or, unsubstituted or R ^2-9 Substituted C ₁ ～C ₇ Heterocycloalkyl { wherein R ^2-9 Is one or more ofOne [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-9 When said R is ^2-9 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{ e.g., 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 atoms" are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atoms are C with 1-4 ₃ ～C ₇ Heterocycloalkyl group).

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, C ₃ ～C ₇ Cycloalkyl or "hetero atoms" are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atoms are C with 1-4 ₃ ～C ₇ Heterocycloalkyl group).

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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl group).

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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-1 And R is ^1-2 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16 Independently C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₁ ～C ₇ Heterocycloalkyl ', NR', a ^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 unsubstituted or R ^1-16 Substituted C ₁ ～C ₇ Alkyl, or, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl;

all R ^1-16 And R is ^1-20 Independently C ₃ ～C ₇ Cycloalkyl groups.

R ¹ is unsubstituted or R ^1-16 Substituted C ₁ ～C ₇ Alkyl, -NR ^1-1 R ^1-2 Or' hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with hetero atom number of 1-4 ₃ ～C ₇ Heterocycloalkyl group).

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen or C ₁ ～C ₇ An alkyl group.

All R ^1-1 And R is ^1-2 Independently hydrogen or C ₁ ～C ₇ An alkyl group.

all R ^1-4 And R is ^1-7 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 is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group.

all R ^1-4 And R is ^1-7 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 is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group.

All R ^1-16 Independently halogen, cyano, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₁ ～C ₇ Heterocycloalkyl ', NR', a ^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 is ^1-16-4 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is' hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with hetero atom number of 1-4 ₃ ～C ₇ Heterocyclyl "or-NR ^1-16-5-1 R ^1-16-5-2 ；

All R ^1-16-5-1 And R is ^1-16-5-2 Independently is 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 Independently a hydroxyl group.

all R ^1-16 Independently is halogen, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₁ ～C ₇ Heterocycloalkyl ', NR', a ^1-16-1 R ^1-16-2 Or- (c=o) R ^1-16-5 ；

All R ^1-16-1 And R is ^1-16-2 Independently C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is' hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with hetero atom number of 1-4 ₃ ～C ₇ Heterocycloalkyl ", or-NR ^1-16-5-1 R ^1-16-5-2 ；

All R ^1-16-5-1 And R is ^1-16-5-2 Independently hydrogen, unsubstituted orR ^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 Independently a hydroxyl group.

all R ^1-16 Independently C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₁ ～C ₇ Heterocycloalkyl ', NR', a ^1-16-1 R ^1-16-2 、-OR ^1-16-3 、-SR ^1-16-4 Or- (c=o) R ^1-16-5 ；

All R ^1-16-5-1 And R is ^1-16-5-2 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkynyl or C ₃ ～C ₇ Cycloalkyl groups.

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 atoms" are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atoms are C with 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

All R ^1-4-1 And R is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

all R ^1-16-5-1-1 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, C ₃ ～C ₇ Cycloalkyl or "hetero atoms" are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atoms are C with 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-4 And R is ^1-7 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 is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

All R ^1-16-1 And R is ^1-16-2 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16-5-1-1 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{ e.g., 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 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-16 、R ^1-20 And R is ^1-21 Independently halogen, nitro, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C 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 ；

All R ^1-16-1 、R ^1-16-2 、R ^1-16-3 And R is ^1-16-4 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

all R ^1-16-5 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals'The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 heteroatom number ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', 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 is ^1-16-5-3 Independently is 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 radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

z is 0.

x is CH;

m and n are independently 0, 1, 2, or 3, and m+n is 3{ e.g., m is 2, n is 1};

y is CH;

all R ^1-16 Independently C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^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 Independently halogen, nitro, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ", C ₁ ～C ₇ Alkoxy, C ₁ ～C ₇ Alkane mercaptoRadical, -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 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 heteroatom number ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', 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 is ^1-16-5-3 Independently is 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 radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl group”、C ₆ ～C ₁₀ Aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

z is 0.

X may be CH;

m+n may be 2 or 3;

y may be CH or N;

R ¹ can 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, selenium, nitrogen and phosphorusOne or more of C having 1 to 4 hetero atoms ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-1 And R is ^1-2 Can be independently hydrogen, C ₁ ～C ₇ Alkyl or C ₃ ～C ₇ Cycloalkyl;

all R ^1-4 、R ^1-5 And R is ^1-6 Independently C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, C ₂ ～C ₇ Alkenyl, 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 is ^1-4-2 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

R ^1-11 is H;

all R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 And R is ^1-21 Independently cyano, -NR ^1-16-1 R ^1-16-2 、-OR ^1-16-3 、-SR ¹ ^-16-4 、C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 is ^1-16-4 Independently hydrogen, C ₃ ～C ₇ Cycloalkyl or C ₁ ～C ₇ An alkyl group;

all R ^1-16-5 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, "hetero atoms being boronOne or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 hetero atoms ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', NR ^1-16-5-1 R ^1-16-5-2 OR ^1-16-5-3 ；

z may be 0.

x may 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 may be N;

R ¹ can 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 ^1-20 Substituted or unsubstituted C ₃ ～C ₇ Cycloalkyl;

R ^1-1 and R is ^1-2 Can be independently C ₁ ～C ₇ An alkyl group;

R ^1-4 independently C ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl;

all R ^1-16 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 is ^1-16-3 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

z may be 0.

x may 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 may be C;

R ¹ can be H, cyano, -NR ^1-1 R ^1-2 、-C(＝O)R ^1-4 Unsubstituted or R ^1-16 SubstitutedC ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl, or, unsubstituted or R ^1-21 The substituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ A heterocycloalkyl group;

R ^1-1 and R is ^1-2 Can be independently C ₁ ～C ₇ An alkyl group;

R ^1-4 independently C ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl;

all R ^1-16 Independently cyano, -NR ^1-16-1 R ^1-16-2 、-OR ^1-16-3 Or hetero atoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atoms are C with 1-4 ₃ ～C ₇ A heterocycloalkyl group;

z may be 0.

wherein X is N or CH;

Y is N or CH;

R ¹ is H, halogen, mercapto, 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 { wherein R ^1-16 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16 When said R is ^1-16 The same or different; the said "C ₁ ～C ₇ Alkyl "such as C ₁ ～C ₄ Alkyl, in turn, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, in turn, e.g. methyl, ethyl, n-propyl or isopropyl }, R ^1-17 Substituted or unsubstituted C ₂ ～C ₇ Alkenyl { wherein R ^1-17 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-17 When said R is ^1-17 The same or different; wherein said "C ₂ ～C ₇ Alkenyl radicals "such as C ₂ ～C ₄ Alkenyl radicals, also e.g. 2-propenyl radical, R ^1-18 Substituted or unsubstituted C ₂ ～C ₈ Alkynyl { wherein R ^1-18 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-18 When said R is ^1-18 The same or different; wherein said "C ₂ ～C ₇ Alkynyl radicals "such as C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl }, R ^1-19 Substituted or unsubstituted C ₁ ～C ₇ Alkylsilyl { wherein R ^1-19 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-19 When said R is ^1-19 Identical or different }, R ^1-20 Substituted or unsubstituted C ₃ ～C ₇ Cycloalkyl { wherein R ^1-20 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-20 When said R is ^1-20 Identical or different }, R ^1-21 The substituted or unsubstituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "{ wherein R ^1-21 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-21 When said R is ^1-21 Identical or different }, R ^1-22 Substituted or unsubstituted C ₆ ～C ₁₀ Aryl { wherein R ^1-22 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-22 When said R is ^1-22 Identical or different }, R ^1-23 The substituted or unsubstituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^1-23 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-23 When said R is ^1-23 Identical or different }, R ^1-24 Substituted or unsubstituted C ₁ ～C ₇ Alkoxy { wherein R ^1-24 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-24 When said R is ^1-24 Identical or different }, or R ^1-25 Substituted or unsubstituted C ₁ ～C ₇ Alkylmercapto { wherein R ^1-25 Is one or more [ e.g. 2, 3 or 4 ] ]When there are a plurality of R ^1-25 When said R is ^1-25 Same or different };

R ^1-1 、R ^1-2 and R is ^1-3 Independently hydrogen, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, also such as the methyl radical }, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl or "hetero atoms" asOne or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C with 1-4 hetero atoms ₁ ～C ₇ Heteroaryl ";

R ^1-4 、R ^1-5 、R ^1-6 、R ^1-7 、R ^1-8 、R ^1-9 and R is ^1-10 Independently is hydroxy, C ₁ ～C ₇ Alkyl { e.g. C ₁ ～C ₄ Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radicals, such as the methyl radical, halogen, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl { e.g. C ₂ ～C ₄ Alkynyl, e.g. 2-propynyl or 1-propynyl }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', or NR ^1-4-1 R ^1-4-2 ；

All R ^1-4-1 And R is ^1-4-2 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

R ^1-11 、R ^1-12 、R ^1-13 、R ^1-14 and R is ^1-15 Independently H, cyano, hydroxy, C ₁ ～C ₇ Alkoxy, R ^1-11-1 Substituted or unsubstituted C ₁ ～C ₇ Alkyl { wherein R ^1-11-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-11-1 When said R is ^1-11-1 Identical or different }, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl or C with 1-4 hetero atoms, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus ₁ ～C ₇ Heteroaryl ";

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 is ^1-25 Independently halogen, nitro, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C 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 ；

all R ^1-16-5 Independently is hydroxy, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

z is 0, 1 or 2;

all R ² Independently is halogen, hydroxy, cyano, amino, R ^2-1 Substituted or unsubstituted C ₁ ～C ₇ Alkyl { wherein R ^2-1 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-1 When said R is ^2-1 Identical or different }, R ^2-2 Substituted or unsubstituted C ₂ ～C ₈ Alkenyl { wherein R ^2-2 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-2 When said R is ^2-2 Identical or different }, R ^2-3 Substituted or unsubstituted C ₂ ～C ₇ Alkynyl { wherein R ^2-3 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-3 When said R is ^2-3 Identical or different }, R ^2-4 Substituted or unsubstituted C ₁ ～C ₇ Alkylsilyl { wherein R ^2-4 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-4 When said R is ^2-4 Identical or different }, R ^2-5 Substituted or unsubstituted C ₆ ～C ₁₀ Aryl { wherein R ^2-5 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-5 When said R is ^2-5 Identical or different }, R ^2-6 The substituted or unsubstituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^2-6 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-6 When said R is ^2-6 Identical or different }, or R ^2-7 Substituted or unsubstituted C ₁ ～C ₇ Alkoxy { wherein R ^2-7 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-7 When said R is ^2-7 Same or different };

All R ^2-1 、R ^2-2 、R ^2-3 、R ^2-4 、R ^2-5 、R ^2-6 And R is ^2-7 Independently halogen, nitro, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is1 to 4C ₁ ～C ₇ Heteroaryl ", C ₁ ～C ₇ Alkoxy, C ₁ ～C ₇ Alkylmercapto, -NR ^2-1-1 R ^2-1-2 、-OR ^2-1-3 、-SR ^2-1-4 Or- (c=o) R ^2-1-5 ；

alternatively, two R ² To the same carbon atom together form R ^2-8 Substituted or unsubstituted C ₃ ～C ₇ Cycloalkyl { wherein R ^2-8 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-8 When said R is ^2-8 Identical or different }, or R ^2-9 Substituted or unsubstituted C ₁ ～C ₇ Heterocycloalkyl { wherein R ^2-9 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^2-9 When said R is ^2-9 Same or different };

X may be CH.

m+n may be 2 or 3.

m may be 0 and n may be 2.

m may be 1 and n may be 1.

m may be 2 and n may be 0.

m may be 1 and n may be 2.

m may be 2 and n may be 1.

y may be N.

R ¹ Can 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 also 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 groups.

R ^1-1 and R is ^1-2 Can be independently hydrogen, C ₁ ～C ₇ Alkyl or C ₃ ～C ₇ Cycloalkyl, again independently C ₁ ～C ₇ An alkyl group.

R ^1-4 、R ^1-5 and R is ^1-6 Independently C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, C ₂ ～C ₇ Alkenyl or C ₂ ～C ₇ Alkynyl; and can be independently C ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl groups.

R ^1-11 H.

all R ^1-16 、R ^1-17 、R ^1-18 And R is ^1-20 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 is ^1-16-3 Independently hydrogen, C ₃ ～C ₇ Cycloalkyl or C ₁ ～C ₇ An alkyl group; and can be independently hydrogen or C ₁ ～C ₇ An alkyl group.

z may be 0.

wherein X is CH;

y is N or CH;

R ¹ is H, halogen, mercapto, 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 { wherein R ^1-16 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-16 When said R is ^1-16 Identical or different }, R ^1-17 Substituted or unsubstituted C ₂ ～C ₇ Alkenyl { wherein R ^1-17 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-17 When said R is ^1-17 Identical or different }, R ^1-18 Substituted or unsubstituted C ₂ ～C ₈ Alkynyl { wherein R ^1-18 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ¹ ^-18 When said R is ^1-18 Identical or different }, R ^1-19 Substituted or unsubstituted C ₁ ～C ₇ Alkylsilyl { wherein R ^1-19 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-19 When said R is ^1-19 Identical or different }, R ^1-20 Substituted or unsubstituted C ₃ ～C ₇ Cycloalkyl { wherein R ^1-20 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-20 When said R is ^1-20 Identical or different }, R ^1-21 The substituted or unsubstituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "{ wherein R ^1-21 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-21 When said R is ^1-21 Identical or different }, R ^1-22 Substituted or unsubstituted C ₆ ～C ₁₀ Aryl { wherein R ^1-22 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-22 When said R is ^1-22 Identical or different }, R ^1-23 The substituted or unsubstituted hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl "{ wherein R ^1-23 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-23 When said R is ^1-23 Identical or different }, R ^1-24 Substituted or unsubstituted C ₁ ～C ₇ Alkoxy { wherein R ^1-24 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-24 When said R is ^1-24 Identical or different }, or R ^1-25 Substituted or unsubstituted C ₁ ～C ₇ Alkylmercapto { wherein R ^1-25 Is one or more [ e.g. 2, 3 or 4 ]]When there are a plurality of R ^1-25 When said R is ^1-25 Same or different };

R ^1-1 、R ^1-2 and R is ^1-3 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

R ^1-4 、R ^1-5 、R ^1-6 、R ^1-7 、R ^1-8 、R ^1-9 and R is ^1-10 Independently is hydroxy, C ₁ ～C ₇ Alkyl, halogen, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl', or NR ^1-4-1 R ^1-4-2 ；

All R ^1-4-1 And R is ^1-4-2 Independently hydrogen, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₃ ～C ₇ Cycloalkyl radicalsThe hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 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 hetero atom number is C of 1-4 ₁ ～C ₇ Heteroaryl ";

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 is ^1-25 Independently halogen, nitro, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl groups、C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, wherein the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the hetero atom number is C of 1-4 ₁ ～C 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, 1 or 2;

alternatively, two R ² To the same carbon atom together form R ^2-8 Substituted or unsubstituted C ₃ ～C ₇ Cycloalkyl { wherein R ^2-8 Is one or more [ e.g. 2, 3 or 4 ]Personal (S)]When there are a plurality of R ^2-8 When said R is ^2-8 Identical or different }, or R ^2-9 Substituted or unsubstituted C ₁ ～C ₇ Heterocycloalkyl { wherein R ^2-9 Is one or more [ e.g. 2, 3 or 4 ] ]When there are a plurality of R ^2-9 When said R is ^2-9 Same or different };

x may be CH;

m+n may be 2 or 3;

y may be CH or N;

R ¹ can 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 is ^1-2 Can be independently hydrogen, C ₁ ～C ₇ Alkyl or C ₃ ～C ₇ Cycloalkyl;

R ^1-4 、R ^1-5 and R is ^1-6 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 ofR ^1-16 、R ^1-17 、R ^1-18 And R is ^1-20 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 is ^1-16-3 Independently hydrogen, C ₃ ～C ₇ Cycloalkyl or C ₁ ～C ₇ An alkyl group;

z may be 0.

X may be CH;

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

y may be N;

R ¹ can 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 is ^1-2 Can be independently C ₁ ～C ₇ An alkyl group;

R ^1-4 independently C ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl;

all R ^1-16 Independently cyano, -NR ^1-16-1 R ^1-16-2 OR-OR ^1-16-3 ；

z may be 0.

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

/>

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

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

the method comprises the following steps:

which comprises the following steps: oxidizing the compound 1A to obtain a compound 1B, substituting to obtain a compound 1D, and deprotecting to obtain a compound 1E;

wherein Y is N. Said m, n, z and R ² Is as defined above; the conditions for each step in the reaction scheme may be conventional conditions for such reactions in the art.

PG in the compound shown in the formula 1C can be various conventional amino protecting groups in the field, preferably Boc, the purpose of which is thatWhen reacting with Compound 1BLeaving certain reactive groups (e.g., amino groups) thereon unreacted;

the conditions for the reaction for removing the protecting group may be conventional conditions for removing various protecting groups in the art, such as hydrolysis conditions, aminolysis conditions, hydrogenation conditions, etc.;

after the reaction for removing the protecting group is finished, the method can further comprise post-treatment operation; the methods and conditions of the post-treatment may be conventional in the art for such post-reaction treatments, preferably: washing, drying, filtering and evaporating the solvent from the reaction system, and then performing column chromatography; or evaporating the reaction system to remove the solvent, washing and filtering; or evaporating the reaction system to remove the solvent and performing thin layer chromatography;

wherein the conditions of the method of the reaction of each step in the reaction scheme can be carried out according to the conventional conditions of the methods of the reactions in the art;

the second method is as follows:

which comprises the following steps: oxidizing the compound 1A to obtain a compound 1B, and reacting with the compound 2A to obtain a compound 2B;

/>

Wherein, the m, n, z, Y, R ¹ And R is ² Is as defined above; the conditions for each step in the reaction scheme may be conventional conditions for such reactions in the art.

And a third method:

when R is 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 ～C ₈ Alkynyl, or, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ In the case of cycloalkyl, the preparation method of the compound shown in the formula I comprises the following steps: in an organic solvent (e.g. 1, 2-dichloroethane, dichloromethane, methanolAnd one or more of dioxane), in the presence of a reducing agent (e.g., sodium triacetoxyborohydride and/or sodium cyanoborohydride), compounds 1E and R ¹ Performing reductive amination reaction on CHO to obtain a compound I; the conditions for the reductive amination reaction may be those conventional in the art for such reactions;

wherein Y is N, said R ^1’ -CH ₂ -is equivalent to R ¹ . M, n, z, R described in ¹ 、R ² Is as defined above; the conditions for each step in the reaction scheme may be conventional conditions for such reactions in the art.

The method four:

when R is 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 ～C ₈ Alkynyl, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ When cycloalkyl, cyano or acetyl is used, the preparation method of the compound shown in the formula I comprises the following steps: compound 1E is combined with R in the presence of a base such as potassium carbonate, cesium carbonate, N-diisopropylethylamine or triethylamine in an organic solvent such as one or more of methanol, dichloromethane, acetonitrile and DMF ¹ -X ¹ Carrying out substitution reaction to obtain a compound I; the substitution reaction conditions may be those conventional in the art; said X ¹ Halogen (e.g., chlorine or bromine);

wherein Y is N. M, n, z, R described in ¹ 、R ² Is as defined above; the conditions of each step in the reaction scheme can be those of the type in the artConventional conditions.

And a fifth method:

when R is ¹ is-C (=O) R ^1-4 And R is ^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 cycloalkyl, the preparation method of the compound shown in the formula I comprises the following steps: in an organic solvent (e.g., one or more of 1, 4-dioxane, dichloromethane and DMF), in the presence of a condensing agent (e.g., DMAP and EDCI), the compound 1E is reacted withPerforming condensation reaction to obtain a compound I; the conditions for the condensation reaction may be those conventional in the art for such reactions; / >

Wherein Y is N. M, n, z, R described in ¹ 、R ² Is as defined above; the conditions for each step in the reaction scheme may be conventional conditions for such reactions in the art.

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

therein, PG, m, n, z, Y, R ¹ And R is ² The definitions of which are as described above.

The invention also provides the use of a compound 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 as described above for the preparation of an inhibitor of a kinase (e.g. WEE1 kinase).

The invention also provides application of the compound I, enantiomer, diastereomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof in preparing medicaments for treating and/or preventing diseases related to WEE1 kinase.

Such diseases associated with WEE1 kinase, e.g., cancer. Such as brain, head and neck, esophagus, thyroid, small cell, non-small cell, breast, lung, stomach, gall bladder-bile duct, liver, pancreas, colon, rectum, ovary, villous epithelium, uterus, cervix, renal pelvis-ureter, bladder, prostate, penis, testis, embryo, nephroblastoma, skin, malignant melanoma, neuroblastoma, osteosarcoma, ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, or hodgkin's lymphoma, as well as breast, lung, pancreas, colon, ovary, acute leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, hodgkin's lymphoma, and colon or ovarian cancer.

The invention also provides an application of the compound I, the enantiomer, the diastereoisomer, the tautomer, the crystal form, the pharmaceutically acceptable salt, the solvate, the metabolite or the prodrug thereof in preparing medicines, wherein the medicines are used for treating and/or preventing cancers.

Such as brain, head and neck, esophagus, thyroid, small cell, non-small cell, breast, lung, stomach, gall bladder-bile duct, liver, pancreas, colon, rectum, ovary, villous epithelium, uterus, cervix, renal pelvis-ureter, bladder, prostate, penis, testis, embryo, nephroblastoma, skin, malignant melanoma, neuroblastoma, osteosarcoma, ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, or hodgkin's lymphoma, as well as breast, lung, pancreas, colon, ovary, acute leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, hodgkin's lymphoma, and colon or ovarian cancer.

The invention also provides a pharmaceutical composition comprising compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof, or a prodrug thereof, as described above, and pharmaceutical adjuvant(s).

The present invention provides a combination comprising compound I as described above, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof or a prodrug thereof, and an anticancer drug.

The anticancer drug may be one or more of anticancer drugs conventional in the art, such as anticancer alkylating agents, anticancer metabolic antagonists, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, anticancer camptothecine derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxyurea, pravastatin, retinoic acid, alfasitet, alfada Bei Ting, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pipadatany sodium, dimesleukin 2, aldesleukin, thyrotropina, arsenic trioxide, bortezomib, capecitabine and goserelin, and also such as anticancer metabolic antagonists.

The anticancer alkylating agent may be one or more of the anticancer alkylating agents conventional in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milflan, busulfan, dibromomannitol, carboquinone, thiotepa, ramustine, nimustine, temozolomide and carmustine.

The anticancer metabolic antagonist may be one or more of the anticancer metabolic antagonists conventional in the art, such as methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine sodium phosphate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium, and further such as 5-fluorouracil.

The anticancer antibiotic may be one or more of the anticancer antibiotics conventional in the art, such as actinomycin D, doxorubicin, daunorubicin, neocarcinomycin, bleomycin, pelomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, clobetadine Ding Sizhi, idarubicin, sirolimus and valrubicin.

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

The anticancer platinum coordination compound may be one or more of the conventional anticancer platinum coordination compounds in the art, such as cisplatin, carboplatin, nedaplatin, and oxaliplatin.

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

The anti-cancer tyrosine kinase inhibitor may be an anti-cancer tyrosine kinase inhibitor conventional 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 one or more of interferon conventional in the art, such as interferon alpha, interferon alpha-2 a, interferon alpha-2 b, interferon beta, interferon gamma-1 a and interferon gamma-n 1.

The biological response modifier can be a conventional biological response modifier in the art, such as one or more of coriolus versicolor polysaccharide, lentinan, siropyran, sartorine, and Wu Benmei.

The components of the combination may be used simultaneously or separately (e.g., sequentially); when the components of the combination are used simultaneously, the components of the combination may be mixed homogeneously (i.e., a mixture of the components).

The components of the combination may be formulated as a single pharmaceutical composition for simultaneous use, or the components may be formulated separately as separate pharmaceutical compositions (e.g., in kit form) for simultaneous use or separate use (e.g., for sequential use).

The invention also provides application of the combination in preparing a medicament for preventing and/or treating cancer.

In the use according to the invention, the above-mentioned compound I, its enantiomer, its diastereomer, its tautomer, its crystalline form, its pharmaceutically acceptable salt, its solvate, its metabolite or prodrug thereof, and the above-mentioned anticancer drugs may be administered simultaneously or separately (for example sequentially).

The invention also provides application of the compound I, enantiomer, diastereomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof in preparing medicaments for preventing and/or treating cancers in combination with the anticancer medicaments.

The invention also provides application of the anticancer drug in preparing a drug for preventing and/or treating cancers in combination with the compound I, enantiomer, diastereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof.

The invention also provides a pharmaceutical composition comprising the combination and (one or more) pharmaceutical excipients.

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

The invention also provides a combined medicine box, which comprises a medicine composition A and a medicine composition B;

the pharmaceutical composition A comprises the compound I, enantiomer, diastereomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof and (one or more) pharmaceutical auxiliary materials;

the medicine composition B comprises the anticancer medicine and (one or more) medicinal auxiliary materials.

The combined kit can be composed of the medicine composition A and the medicine composition B.

The medicine composition A can be composed of the compound I, enantiomer, diastereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof and pharmaceutic adjuvant;

The medicine composition B can be composed of the anticancer medicine and pharmaceutic adjuvant.

The individual pharmaceutical compositions in the combination kit may be used simultaneously or separately (e.g., sequentially).

On the basis of not violating the common sense in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

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

Unless otherwise indicated, the following terms appearing in the present specification and claims have the following meanings:

the term "halogen" refers to fluorine, chlorine, bromine or iodine.

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

The term "alkenyl" refers to a compound having at least one unsaturated site, i.e., carbon-carbon sp ² Straight-chain or branched monovalent hydrocarbon radicals of two to twelve carbon atoms of the double bond (e.g. C ₂ -C ₆ Alkenyl radicals, also e.g. C ₂ -C ₄ Alkenyl) and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples 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 monovalent hydrocarbon radical of two to twelve carbon atoms (e.g., C ₂ -C ₆ Alkynyl radicals, also e.g. C ₂ -C ₄ Alkynyl). Examples include, but are not limited to, ethynyl and propynyl.

The term "alkylsilyl" refers to an alkyl group attached through a silicon bridge; the definition of the alkyl is the same as that of the alkyl; c (C) ₁ -C ₇ Alkyl silicon group meansWherein R is ^A 、R ^B And R is ^C Independently C ₁ -C ₇ An alkyl group. />

The term "cycloalkyl" refers to a monovalent, non-aromatic, saturated cyclic hydrocarbon radical having three to twenty carbon atoms (e.g., C ₃ -C ₆ Cycloalkyl). Examples of monocyclic carbocyclic radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The term "cycloalkyl" also includes polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, a bicyclic carbocycle having 7 to 12 atoms may be arranged, for example, as a bicyclo [4,5 ]、[5,5]、[5,6]Or [6,6 ]]Systems, or arrangements, as bridged ring systems, e.g. bis [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane.

The term "heterocycloalkyl" refers to a saturated carbocyclic group having 3 to 12 ring atoms, wherein at least one ring atom is a heteroatom independently selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, with the remaining ring atoms being C. The group may be a carbon group or a heteroatom group (i.e., it may be C-linked or N-linked, as long as it is possible). Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thiaxalkyl, and piperazinyl. Spiro moieties and bridged ring moieties are also included within the scope of this definition. For example, the groups derived from tetrahydropyrrole may be either tetrahydropyrrole-1-yl (N-linked) or tetrahydropyrrole-3-yl (C-linked). For example a monocyclic 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 is optionally substituted by one or more oxygen atoms to give an image NO, BOH, PO, PO ₂ A group of SeO; n may optionally be quaternized; the S atom may optionally be substituted with Substituted by one or more oxygen or nitrogen atoms to give a compound like SO, SO ₂ 、S(＝O)(＝NR ^a ),S(＝NR ^b ) Or S (=NR) ^c ) ₂ At the same time, R ^a 、R ^b And R is ^c Independently cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocyclyl, C having 1-4 hetero atoms, which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus ₁ ～C ₇ Heteroaryl ", C ₆ ～C ₁₀ Aryl or C ₁ ～C ₇ An alkoxy group; at the same time, -CH ₂ The-group may optionally be-C (=o) -, -C (=s) -or-C (=nr ^d ) -instead, R ^d Independently cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms of which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C with the hetero atoms of 1-4 ₃ ～C ₇ Heterocyclyl, C having 1-4 hetero atoms, which are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus ₁ ～C ₇ Heteroaryl ", C ₆ ～C ₁₀ Aryl or C ₁ ～C ₇ An alkoxy group; when the ring is a three-membered ring, only one of which is a heteroatom), or a bicyclic 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 is optionally substituted by one or more oxygen atoms to give a compound of formula NO, BOH, SO, SO ₂ ，PO，PO ₂ Groups of SeO, simultaneously, -CH ₂ The group may optionally be replaced by-C (=o) -. Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group, i.e., a heterocyclylene group.

The term "aryl" refers to any stable mono-or bi-cyclic carbocycle of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthracyl, or acenaphthyl (acenaphthyl). It will be appreciated that where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is through an aromatic ring.

The term "heteroaryl" refers to stable mono-or bi-rings of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazole, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl. "heteroaryl" shall also be understood to include any N-oxide derivative of a nitrogen-containing heteroaryl. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or contains no heteroatoms, it is understood that the linking occurs through the aromatic ring separately. The heteroaromatic ring systems may be cyclic in fused form. Wherein N, S, B, P or Se is optionally substituted with one or more oxygen atoms to give a compound like NO, SO ₂ 、BOH、PO、PO ₂ The group SeO, the N atom may be quaternized. Heteroaryl groups may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. Depending on the structure, heteroaryl groups may be monovalent or divalent, i.e., heteroarylene.

The term "alkoxy" refers to an alkyl group attached through an oxygen bridge; the definition of the alkyl is the same as that above.

The term "alkylthio" refers to an alkyl group attached through a sulfur bridge; the definition of the alkyl is the same as that above.

The term "pharmaceutically acceptable salt" refers to salts formed from suitable non-toxic organic acids, inorganic acids, organic bases or inorganic bases with compound I, which retain the biological activity of compound I. The organic acid may be various organic acids capable of forming salts, which are conventional in the art, preferably one or more of methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid and salicylic acid. The mineral acid may be any of a variety of mineral acids conventionally known in the art capable of salt formation, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base can be various organic bases capable of forming salts, which are conventional in the art, and preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines. 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 capable of forming salts, which are conventional in the art, preferably one or more of alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate. 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 tert-butoxide and sodium tert-butoxide.

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

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

The term "pharmaceutical excipients" refers to those excipients which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers 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 excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The term "active ingredient" refers to the active ingredient in the pharmaceutical composition or combination kit of the invention, i.e. compound I, its enantiomer, its diastereomer, its tautomer, its crystalline form, its pharmaceutically acceptable salt, its solvate, its metabolite or prodrug thereof, an anticancer drug, or a combination thereof.

The invention has the positive progress effects that: the compounds of the invention have better inhibitory activity on WEE1 kinase.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The structures of all the compounds of the invention can be changed by nuclear magnetic resonance ¹ H NMR) and/or mass spectrometry detection (MS) identification. ¹ H NMR chemical shifts (delta) were recorded in PPM (10 ^-6 ). NMR was performed by Bruker AVANCE-400 spectrometer.

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

The thin layer silica gel plate is a good minister silica source HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses 200-300 mesh silica gel of yellow sea as carrier.

Example 1

The first step:

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6-methylthiopyrazolo [3,4-d ]]Pyrimidine-3-one (270 mg,0.75 mmol) (compound shown in 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 (29 mg,2.26 mmol) and tert-butyl 6-amino-3, 4-dihydro-1H-isoquinoline-2-carboxylate (243 mg,0.98 mmol) (compound shown in formula 2) were added, stirring was continued at room temperature for 16 hours, the reaction solution was concentrated, and the compound shown in formula I-1-a was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100% to 50%) to give tert-butyl 6- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl ] compound shown in formula I-1-a]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]-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(400MHz,CDCl ₃ )δ8.88(s,1H),7.91(t,J＝7.9Hz,1H),7.85–7.70(m,2H),7.63–7.47(m,1H),7.42(d,J＝7.6Hz,1H),7.37(s,1H),7.11(d,J＝8.3Hz,1H),5.73(dq,J＝10.2,6.1Hz,1H),5.08(d,J＝10.1Hz,1H),4.96(d,J＝17.0Hz,1H),4.79(d,J＝6.2Hz,2H),4.59(s,2H),3.70(d,J＝4.5Hz,2H),2.86(t,J＝5.5Hz,2H),1.62(s,6H),1.53(s,9H)。

And a second step of:

tert-butyl 6- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid ethyl ester (250 mg,0.45 mmol) (compound of formula I-1-a) was dissolved in dichloromethane (10 ml), dioxane solution (2 ml, 4M) of hydrochloric acid was added, stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated and dried to give 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl of compound of formula I-1 ]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidin-3-one (200 mg,0.44 mmol). LC-MS: M/z (M+H) ⁺ ＝458.2， ¹ H NMR(400MHz,DMSO-d ₆ )δ10.37(s,1H),9.48(s,2H),8.96–8.90(m,1H),8.08(t,J＝7.9Hz,1H),7.80(d,J＝7.8Hz,2H),7.66(d,J＝7.6Hz,1H),7.51(d,J＝8.3Hz,1H),7.19(d,J＝8.4Hz,1H),5.69(qd,J＝11.1,5.7Hz,1H),5.02(d,J＝10.4Hz,1H),4.84(d,J＝17.0Hz,1H),4.72(d,J＝5.6Hz,2H),4.23(s,4H),3.39(d,J＝5.0Hz,2H),3.04(t,J＝6.0Hz,2H),1.49(s,6H)。

Example 2

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound of formula I-1) was dissolved in methanol (5 ml), followed by addition of an aqueous formaldehyde solution (0.1 ml, 40%) and sodium triacetylborohydride (46 mg,0.22 mmol), and stirring at room temperature for 4 hours. The reaction solution is concentrated, dissolved by a mixed solution (10/1, 20 ml) of dichloromethane and methanol, washed twice by saturated sodium bicarbonate, and the organic layer is dried by anhydrous sodium sulfate, filtered and concentrated to obtain a compound 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl shown in a formula I-2]-6- [ (2-methyl-3, 4-dihydro-1H-isoquinolin-6-yl) amino group]Pyrazolo [3,4-d]Pyrimidin-3-one (40 mg,0.085 mmol). LC-MS: M/z (M+H) ⁺ ＝472.3, ¹ H NMR(400MHz,DMSO-d ₆ )δ10.23(s,1H),8.89(s,1H),8.05(t,J＝7.9Hz,1H),7.80(d,J＝8.0Hz,1H),7.66(m,2H),7.40(d,J＝7.6Hz,1H),7.01(d,J＝8.3Hz,1H),5.75–5.63(m,1H),5.35(s,1H),5.02(d,J＝10.2Hz,1H),4.84(d,J＝17.5Hz,1H),4.72(d,J＝5.8Hz,2H),3.46(s,2H),2.84(t,J＝5.5Hz,2H),2.62(t,J＝5.8Hz,2H),2.36(s,3H),1.49(s,6H)。

Example 5

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound of formula I-1) was dissolved in methylene chloride (5 ml), then acetone (0.1 ml, 40%) and sodium triacetylborohydride (46 mg,0.22 mmol) were added, warmed to reflux and stirred for 48 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane/methyl acetate) Alcohol=100% to 10%, and then dichloromethane/methanol/methanolic ammonia solution=100/10/1.5) to obtain the compound 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl shown as the formula I-5]-6- [ (2-isopropyl-3, 4-dihydro-1H-isoquinolin-6-yl) amino group]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＝11.0,6.2Hz,1H),5.06(d,J＝10.1Hz,1H),4.95(s,1H),4.84(d,J＝6.1Hz,2H),4.26(s,2H),3.58–3.49(m,1H),3.42(t,J＝5.8Hz,2H),3.16(t,J＝5.8Hz,2H),1.60(s,6H),1.42(d,J＝6.6Hz,6H)。

Example 11

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound represented by formula I-1) was dissolved in a mixed solvent of methylene chloride (5 ml) and methanol (5 ml), followed by addition of 2-bromoethanol (43 mg,0.34 mmol) and potassium carbonate (72 mg,0.52 mmol), and stirring at 60℃for 16 hours. The reaction was concentrated and purified by thin layer chromatography on silica gel preparation plate (dichloromethane: methanol=10:1) to give the compound (18 mg,0.036 mmol) as shown in formula I-11. The yield thereof was found to be 41%. LC-MS: M/z (M+H) ⁺ ＝502.3, ¹ H NMR(400MHz,MeOD-d ₄ )δ8.84(s,1H),8.00(t,J＝7.9Hz,1H),7.85–7.79(m,1H),7.70–7.60(m,2H),7.38(dd,J＝8.3,2.0Hz,1H),7.05(d,J＝8.4Hz,1H),5.72(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.96–4.89(m,1H),4.85(s,2H),3.83(s,2H),3.80(s,2H),2.97(s,4H),2.82(s,2H),1.59(s,6H)。

Example 12

2-allyl-1- [6- (1-hydroxy-1-methyl- ]Ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound of formula I-1) was dissolved in N, N-dimethylformamide (5 ml), followed by addition of 2-bromoethyl methyl ether (48 mg,0.34 mmol) and potassium carbonate (72 mg,0.52 mmol), and stirring at 75℃for 16 hours. The reaction solution was concentrated, and purified by thin layer chromatography on silica gel preparation plate (dichloromethane: methanol=10:1) to give the compound (8 mg,0.016 mmol) represented by formula I-12. The yield thereof was found to be 18%. LC-MS: M/z (M+H) ⁺ ＝516.3, ¹ H NMR(400MHz,MeOD-d ₄ )δ8.84(s,1H),8.03(t,J＝7.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.68(d,J＝7.7Hz,1H),7.63(s,1H),7.38(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,1H),5.80–5.66(m,1H),5.06(d,J＝10.2Hz,1H),4.95(d,J＝1.1Hz,1H),4.83(s,2H),3.75(s,2H),3.68(t,J＝5.5Hz,2H),3.41(s,3H),2.94(dd,J＝12.2,4.8Hz,4H),2.83(t,J＝5.6Hz,2H),1.60(s,6H)。

Example 14

The first step:

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (110 mg,0.24 mmol) (compound shown in formula I-1) and N-Boc-methylaminoacetaldehyde (83 mg,0.48 mmol) (compound shown in formula 3) were dissolved in methanol (5 ml), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (127 mg,0.60 mmol) was added, stirring was continued at room temperature for 16 hours, and the reaction solution was concentrated to give compound N- [2- [6- [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl ] as shown in formula I-14-a]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]-3, 4-dihydro-1H-isoquinolin-2-yl]Ethyl group]-tert-butyl N-methyl-carbamate (150 mg,0.24 mmol). LC-MS: M/z (M+H) ⁺ ＝615.4。

And a second step of:

n- [2- [6- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl ]]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]-3, 4-dihydro-1H-isoquinolin-2-yl]Ethyl group]-N-methyl-aminomethylTert-butyl (140 mg,0.23 mmol) of the acid (compound of formula I-14-a) was dissolved in an aqueous solution of hydrochloric acid (6 ml, 2M), stirred at room temperature for 16 hours, adjusted to pH 7 by adding a saturated aqueous solution of sodium hydrogencarbonate, and a mixed solution of dichloromethane and methanol (DCM/CH ₃ OH=10/1), the organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and dried to obtain the compound 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl shown in formula I-14]-6- [ [2- [2- (methylamino) ethyl ]]-3, 4-dihydro-1H-isoquinolin-6-yl]Amino group]Pyrazolo [3,4-d]Pyrimidin-3-one (90 mg,0.17 mmol). LC-MS: M/z (M+H) ⁺ ＝515.3, ¹ H NMR(400MHz,DMSO-d ₆ )δ10.26(s,1H),8.90(s,1H),8.05(t,J＝7.9Hz,1H),7.80(d,J＝8.1Hz,1H),7.67(m,2H),7.39(d,J＝8.5Hz,1H),7.02(d,J＝8.4Hz,1H),5.69(dq,J＝11.7,6.1Hz,1H),5.37(s,1H),5.01(d,J＝10.1Hz,1H),4.84(d,J＝17.2Hz,1H),4.72(d,J＝5.6Hz,2H),3.54(s,2H),2.83(t,J＝5.2Hz,2H),2.70(t,J＝6.0Hz,4H),2.57(t,J＝6.3Hz,2H),2.34(s,3H),1.48(s,6H)。

Example 15

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- [ [2- [2- (methylamino) ethyl ]]-3, 4-dihydro-1H-isoquinolin-6-yl]Amino group]Pyrazolo [3,4-d]Pyrimidine-3-one (40 mg,0.116 mmol) (a compound represented by formula I-14) was dissolved in methanol (5 ml), followed by addition of an aqueous solution of formaldehyde (0.1 ml, 40%) and sodium triacetoxyborohydride (61 mg,0.30 mmol), and stirring at room temperature for 4 hours. The reaction solution was concentrated, dissolved in a mixture of dichloromethane and methanol (10/1, 20 ml), washed twice with saturated sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, and the column chromatographed (silica gel, UV254, DCM/CH) ₃ Oh=100% to 10%, then DCM/CH ₃ OH/NH ₃ .CH ₃ OH=100/10/1.5) purifying to obtain the compound shown as the formula I-15, namely 2-allyl-6- [ [2- (2-dimethylaminoethyl) -3, 4-dihydro-1H-isoquinolin-6-yl ]]Amino group]-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl ]Pyrazolo [3,4-d]Pyrimidin-3-one (30 mg,0.057 mmol). LC-MS: M/z (M+H) ⁺ ＝529.2, ¹ H NMR(400MHz,DMSO-d ₆ )δ10.35–10.16(m,1H),8.92–8.86(m,1H),8.07–8.01(m,1H),7.82–7.76(m,1H),7.74–7.63(m,2H),7.45–7.37(m,1H),7.05–7.00(m,1H),5.74–5.64(m,1H),5.36(s,1H),5.05–4.98(m,1H),4.88–4.80(m,1H),4.75–4.67(m,2H),3.63–3.58(m,2H),2.87–2.81(m,2H),2.78–2.69(m,4H),2.69–2.63(m,2H),2.44–2.32(m,6H),1.52–1.44(m,6H)。

Example 21

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound of 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. Concentrating the reaction solution, diluting with water, filtering, and drying the solid to obtain 6- [ (2-acetyl-3, 4-dihydro-1H-isoquinolin-6-yl) amino as shown in formula I-21]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (40 mg,0.085 mmol). LC-MS M/z (m+h) +=500.3, ¹ H NMR(400MHz,DMSO-d ₆ )δ10.29(s,1H),8.90(s,1H),8.11–8.02(m,1H),7.82–7.73(m,2H),7.65(d,J＝7.5Hz,1H),7.46(t,J＝8.1Hz,1H),7.15(d,J＝8.2Hz,1H),5.74–5.62(m,1H),5.35(s,1H),5.01(dd,J＝10.3,1.3Hz,1H),4.83(dd,J＝17.3,1.3Hz,1H),4.71(d,J＝7.7Hz,2H),4.61(s,1H),4.56(s,1H),3.68(t,J＝5.8Hz,2H),2.87(t,J＝6.2Hz,1H),2.76(t,J＝6.5Hz,1H),2.11(d,J＝4.5Hz,3H),1.48(s,6H)。

example 28

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidin-3-one (30 mg,0.066 mmol) (shown in formula I-1)To N, N-dimethylformamide (5 ml), followed by addition of 3-bromopropene (8 mg,0.66 mmol) and potassium carbonate (14 mg,0.1 mmol), and stirring at room temperature for 16 hours. The reaction was concentrated and purified by thin layer chromatography on silica gel (dichloromethane: methanol=10:1) to give the compound of formula I-28 (5 mg,0.016 mmol). The yield thereof was found to be 15%. ¹ H NMR(400MHz,MeOD-d ₄ )δ8.84(s,1H),8.03(t,J＝7.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.69(d,J＝7.7Hz,2H),7.41(dd,J＝8.3,1.8Hz,1H),7.06(d,J＝8.4Hz,1H),6.10–5.93(m,1H),5.73(ddd,J＝17.0,6.1,4.1Hz,1H),5.42(dd,J＝23.2,5.8Hz,2H),5.05(dd,J＝10.2,1.1Hz,1H),4.98–4.92(m,1H),4.84(d,J＝6.1Hz,2H),3.84(s,2H),3.43(d,J＝6.8Hz,2H),3.02(s,4H),1.60(s,6H).LC-MS:m/z:(M+H) ⁺ ＝498.3。

Example 37

The first step:

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6-methylthiopyrazolo [3,4-d ]]Pyrimidine-3-one (compound shown as 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 tert-butyl 2-amino-7, 8-dihydro-5H-1, 6-naphthyridine-6-carboxylate (243 mg,0.98 mmol) was added, the temperature was raised to 100℃and stirred for 16 hours, the reaction solution was concentrated, purified by silica gel column chromatography (petroleum ether/ethyl acetate=100% to 0%) and then purified by preparative liquid phase purification to give tert-butyl 2 [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl ] compound shown as formula I-6-a]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]-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。

And a second step of:

tert-butyl 2- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]7, 8-dihydro-5H-1, 6-naphthyridine-6-carboxylic acid ethyl ester (28 mg,0.05 mmol) (compound of formula I-37-a) was dissolved in dichloromethane(10 ml) to which a dioxane solution (2 ml, 4M) of hydrochloric acid was added, stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated and dried to give 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl, which is a compound represented by formula I-6 ]-6- (5, 6,7, 8-tetrahydro-1, 6-naphthyridin-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＝8.9Hz,1H),5.76(dq,J＝11.2,6.5Hz,1H),5.07(d,J＝9.5Hz,1H),4.95(s,1H),4.90(d,J＝8.0Hz,2H),4.50(s,2H),3.74(s,2H),3.49(s,2H),1.59(s,6H).LC-MS:m/z:(M+H) ⁺ ＝459.2。

Example 44

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (1.8 g,8 mmol) (compound of formula I-44-a) and ammonium acetate (6.2 g,81 mmol) were added to 80ml of methanol and stirred at room temperature for 2H. Sodium cyanoborohydride (600 mg,0.984 mmol) was then added and stirred overnight at room temperature. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and the pH was adjusted to be acidic with 1mol/L hydrochloric acid, and extraction was performed twice with 30ml of methylene chloride each time. The aqueous phase is brought to a pH of the base (pH=10-11) with 1mol/L sodium hydroxide solution. Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown liquid was obtained in 900mg, yield 50%. LC-MS: M/z (M+H) ⁺ ＝226。

And a second step of:

6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-amine (900 mg,3.98 mmol) (compound of formula I-44-b) was dissolved in 10ml of 37% formaldehyde and 16ml of formic acid, and heated under reflux for 4h. The solvent was evaporated under reduced pressure, and the crude product was dissolved in 30ml of water, then saturated sodium bicarbonate solution was added to adjust the pH to alkaline, extracted twice with 120ml of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and concentrated to give 800mg of a brown oil, which was directly used for the next reaction. The yield thereof was found to be 79%. LC-MS: M/z (M+H) ⁺ ＝254。

And a third step of:

6-bromo-N, N-dimethyl-1, 2,3, 4-tetrahydronaphthalen-2-amine (600 mg,2.36 mmol) (compound of formula I-44-c), benzophenone imine (470 mg,2.594 mmol), sodium t-butoxide (480 mg,5 mmol), pd ₂ (dba) ₃ (70 mg,0.0765 mmol) BINAP (150 mg,0.241 mmol) was added to 30ml toluene, purged three times with argon and then heated to 120℃overnight. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 10%), to obtain 600mg of a brown oil, yield 71%. LC-MS: M/z (M+H) ⁺ ＝355。

Fourth step:

6- ((benzhydryl) amino) -N, N-dimethyl-1, 2,3, 4-tetrahydronaphthalen-2-amine (compound of formula I-44-d) (600 mg,1.693 mmol) was dissolved in 30ml methanol, then sodium acetate (560 mg,6.83 mmol) and hydroxylamine hydrochloride (350 mg,5.04 mmol) were added and heated to 60℃for reaction for 3 hours. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 20%) to obtain 300mg of brown solid with a yield of 93%. LC-MS: M/z (M+H) ⁺ ＝191。

Fifth step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (Compound shown as formula 1A) (72 mg,0.2 mmol) to a solution of 15ml of toluene was added m-chloroperoxybenzoic acid (50 mg,0.22 mmol), and the resulting solution was stirred at room temperature for 1H to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] ]Toluene solution of pyrimidine-3-one (compound shown as formula 1B). To the above-obtained solution were added N, N-dimethyl-1, 2,3, 4-tetrahydronaphthalene-2, 6-diamine (40 mg,0.21 mmol) and 0.5ml of N, N-diisopropylethylamine, stirred at room temperature overnight, and then left at room temperature for 16 days. Concentrating under reduced pressure, separating and purifying the crude product by thin layer chromatography (7M ammonia methanol: dichloromethane=0-10%), and then preparing 10mg of compound shown as formula I-44 by high performance liquid phase, white solid, and yield 9%. LC-MS: M/z (M+H) ⁺ ＝500, ¹ H NMR(400MHz,MeOD-d ₄ )δ8.81(s,1H),8.54(s,1H),8.02(t,J＝7.9Hz,1H),7.80(d,J＝8.0Hz,1H),7.69(d,J＝7.7Hz,1H),7.62(s,1H),7.39(d,J＝7.9Hz,1H),7.11(d,J＝8.3Hz,1H),5.73(ddd,J＝17.0,6.0,4.2Hz,1H),5.05(d,J＝9.2Hz,1H),4.94(d,1H),4.83(d,J＝6.0Hz,2H),3.59(s,1H),3.19(d,J＝12.3Hz,1H),3.07–2.87(m,9H),2.35(m,1H),1.92(m,1H),1.60(s,6H)。

Example 49

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (20 mg,0.044 mmol) (compound of formula I-1) was dispersed in methylene chloride (5 ml), followed by addition of butynoic acid (3.7 mg,0.44 mmol), EDCI (17 mg,0.088 mmol), 4-dimethylaminopyridine (1 mg,0.008 mmol) and stirring at room temperature for 16 hours. The reaction was concentrated and purified by thin layer chromatography on silica gel preparation plate (dichloromethane: methanol=10:1) to give the compound (6 mg,0.01 mmol) represented by formula I-49. The yield thereof was found to be 26%. LC-MS: M/z (M+H) ⁺ ＝524.3, ¹ H NMR(400MHz,MeOD-d ₄ )δ8.86(s,1H),8.11–7.98(m,1H),7.82(d,J＝8.1Hz,1H),7.70(s,2H),7.48(d,J＝8.4Hz,1H),7.21–7.08(m,1H),5.74(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(d,J＝1.3Hz,1H),4.92(s,1H),4.84(d,J＝6.1Hz,2H),4.70(s,1H),4.06(t,J＝5.9Hz,1H),3.84(t,J＝6.1Hz,1H),2.92(dt,J＝24.8,5.9Hz,2H),2.11(s,3H),1.60(s,6H)。

Example 54

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl ]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound of formula I-1) was dissolved in methanol (6 ml), followed by the addition of cyclobutanone (9.2 mg,0.131 mmol) and sodium triacetoxyborohydride (37 mg,0.175 mmol) and stirring at room temperature for 4 hours. Concentrating the reaction solution, usingA mixture (10/1, 20 ml) of methylene chloride and methanol was dissolved, saturated sodium hydrogencarbonate was washed twice, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product obtained was concentrated and purified by thin layer chromatography (7M aminomethyl: methylene chloride=0-10%) to give the objective compound represented by the formula I-54 (12 mg,0.023 mmol), 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＝7.6Hz,1H),7.75–7.62(m,2H),7.44(dd,J＝8.3,1.9Hz,1H),7.10(d,J＝8.4Hz,1H),5.81–5.65(m,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.92(dd,J＝17.1,1.2Hz,1H),4.83(s,2H),3.80(s,2H),3.29(d,J＝7.8Hz,0H),2.99(dt,J＝11.7,6.1Hz,4H),2.36–2.23(m,1H),2.13(dd,J＝15.4,6.1Hz,1H),1.92–1.80(m,1H)。

Example 55

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6- (1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) pyrazolo [3,4-D]Pyrimidine-3-one (40 mg,0.087 mmol) (a compound of formula I-1) was dissolved in methanol (6 ml), followed by addition of cyclopropanecarbaldehyde (9.2 mg,0.131 mmol) and sodium triacetylborohydride (37 mg,0.175 mmol) and stirring at room temperature for 4 hours. The reaction mixture was concentrated, dissolved in a mixture of methylene chloride and methanol (10/1, 20 ml), washed twice with saturated sodium hydrogencarbonate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by thin layer chromatography (7M ammonia methanol: methylene chloride=0 to 10%) to give the objective compound represented by the formula I-55 (14 mg,0.023 mmol) in 31% yield. 1H NMR (400 MHz, meOD) delta 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, 1.9Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.74 (ddt, J=16.4, 10.3,6.1Hz, 1H), 5.05 (dd, J=10.2, 1.2Hz, 1H), 4.92 (dd, J=17.1, 1.3Hz, 1H), 4.83 (s, 2H), 3.80 (s, 2H), 2.97 (d, J=4.0 Hz, 4H), 2.55 (d, J=6.7 Hz, 2H), 1.70-1.49 (M, 6H), 1.04 (dd, J=10.2, 1.2Hz, 1.2H), 4.83 (s, 1.7 Hz, 1H), 4.7.7H (M, 1.7H), 1.7.7 Hz,1H (0.7.7.0H) ⁺ ＝512.3。

Example 56

The first step:

6-nitro-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (100 mg,0.47 mmol) (a compound represented by formula I-55-a) was dissolved in 10mL of methanol, then 1-ethoxy-1-trimethylsiloxycyclopropane (98 mg,0.56 mmol) and sodium cyanoborohydride (29 mg,0.46 mmol) were added and the reaction stirred at 60℃for 16h. After the completion of the reaction, the crude product was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (ethyl acetate: petroleum ether=0 to 15%) to give the objective compound, 56mg, as a yellow solid, in 46% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.00(d,J＝7.5Hz,2H),7.21(d,J＝8.5Hz,1H),3.91(s,2H),3.01(s,4H),1.87(s,1H),0.61(d,J＝6.0Hz,4H).LC-MS:m/z:(M+H) ⁺ ＝219.1。

And a second step of:

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) were dissolved in 10ml methanol and reacted under hydrogen balloon at room temperature with stirring at room temperature for 4 hours. After completion of the reaction, celite was filtered to give a yellow solid (48 mg,0.26 mmol) which was used directly in the next step in 100% yield. LC-MS: M/z (M+H) ⁺ ＝189.1。

And a third step of:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (86 mg,0.24 mmol) (compound represented by formula 1A) to a solution of 10ml of methanol was added m-chloroperoxybenzoic acid (65 mg,0.29 mmol), and the resulting solution was stirred at room temperature for 3 hours to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] ]Dichloromethane solution of pyrimidine-3-ketone (shown as a compound in formula 1B). To the above-obtained solution were added 2-cyclopropyl-1, 2,3, 4-tetraisoquinolin-6-amine (48 mg,0.26 mmol) (compound represented by formula I-55-c) and 0.13ml of N, N-diisopropylethylamine, and stirred at room temperature for 18 hours. Concentrating under reduced pressure, and separating and purifying the crude product by thin layer chromatography (7M ammonia methanol: dichloromethane=0-10%) to obtain I-56, 12mg of the title compound as yellow solid in 10% yield. LC-MS: M/z (M+H) ⁺ ＝498.3, ¹ H NMR(400MHz,CDCl ₃ )δ8.88(s,1H),7.91(s,1H),7.81(s,1H),7.65(s,1H),7.52(s,1H),7.39(d,J＝7.8Hz,1H),7.30(s,1H),7.05(d,J＝7.2Hz,1H),5.72(s,1H),5.07(d,J＝9.5Hz,1H),4.96(d,J＝17.8Hz,1H),4.78(s,2H),3.92(s,3H),3.03(d,J＝36.6Hz,4H),1.98(s,1H),1.28(s,6H),0.65(s,4H)。

Example 57

The first step:

5-nitroinden-2-one (280 mg,1.58 mmol) (compound of formula I-57-a) was dissolved in 5ml of methanol, 2ml (2M in methanol) of dimethylamine was added, after stirring at room temperature for about 2 hours, 298mg (4.74 mmol) of sodium cyanoborohydride was added, stirring at room temperature was continued for 16 hours, concentration was performed, dissolution was performed with 2N aqueous hydrochloric acid solution, dichloromethane extraction was performed, the pH of the aqueous layer was adjusted to 8 with 2N aqueous sodium hydroxide solution, extraction was performed with dichloromethane, and after drying the dichloromethane layer with anhydrous sodium sulfate, filtration was performed, concentration was performed to obtain 60mg of compound N, N-dimethyl-5-nitroindan-2-amine of formula I-57-b, yield 18% as a brown solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝207.1

And a second step of:

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

And a third step of:

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6-methylthioPyrazolo [3,4-d]Pyrimidine-3-one (20 mg0.056 mmol) (compound shown in formula 1A) was dissolved in 10ml dichloromethane, 10.6mg (0.062 mmol) of m-chloroperoxybenzoic acid was added, stirring was performed at room temperature for about 1 hour, then 10mg (0.056 mmol) of N2, N2-dimethylindene-2, 5-diamine (compound shown in formula I-57-c) and 14mg (0.11 mmol) of DIPEA were added, stirring was performed at room temperature for 4 days, the reaction solution was washed with water, the organic layer was dried over anhydrous sodium sulfate, concentrated, and column chromatography (silica gel, UV, petroleum ether/ethyl acetate=100% to 40%) was purified to obtain compound 2-allyl-6- [ [2- (dimethylamino) indan-5-yl shown in formula I-57]Amino group]-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one 15mg, 55% yield, yellow solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝486.2,1H NMR(400MHz,MeOD)δ8.85(s,1H),8.46(s,1H),8.03(t,J＝7.9Hz,1H),7.80(d,J＝8.4Hz,1H),7.75(s,1H),7.69(d,J＝7.7Hz,1H),7.49(dd,J＝8.2,1.8Hz,1H),7.23(d,J＝8.2Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.92(dd,J＝17.1,1.3Hz,1H),4.83(d,J＝6.1Hz,2H),4.03(p,J＝7.8Hz,1H),3.40(dt,J＝15.8,7.8Hz,2H),3.17(td,J＝15.0,7.5Hz,2H),2.88(s,6H),1.59(s,6H).

Example 58

The first step:

6-nitroinden-1-one (1 g,5.64 mmol) (compound represented by formula I-58-a) was dissolved in 10ml of methanol, 2ml (2M in methanol) of dimethylamine was added, after stirring at room temperature for about 2 hours, 1.06g (16.9 mmol) of sodium cyanoborohydride was added, the mixture was heated to 100℃under microwave conditions and stirred for 1 hour, concentrated, dissolved in 2N aqueous hydrochloric acid solution, extracted with dichloromethane, the aqueous layer was adjusted to pH=8 with 2N aqueous sodium hydroxide solution, extracted with dichloromethane, the dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound N, N-dimethyl-6-nitroindan-1-amine represented by formula I-58-2 in 500mg, yield 43% as a brown oil. LC-MS: M/z: [ M+1 ] ] ⁺ ＝207.1。

And a second step of:

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

And a third step of:

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6-methylthiopyrazolo [3,4-d ]]Pyrimidine-3-one (60 mg,0.17 mmol) (compound shown in formula 1A) was dissolved in 20ml of dichloromethane, 32mg (0.18 mmol) of m-chloroperoxybenzoic acid was added, stirring was performed at room temperature for about 1 hour, then N1, N1-dimethylindene-1, 6-diamine (30 mg,0.17 mmol) (compound shown in formula I-58-c) and (65 mg,0.50 mmol) of DIPEA were added, stirring was performed at room temperature for 4 days, the reaction solution was washed with water, the organic layer was dried over anhydrous sodium sulfate, concentrated, and after preparation and purification by high performance liquid phase, purification by thin layer chromatography (dichloromethane/methanol=10/1) was performed to obtain 2-allyl-6- [ [3- (dimethylamino) indan-5-yl ] compound shown in formula I-58 ]Amino group]-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one 4mg, 5% yield, yellow solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝486.2,1H NMR(400MHz,MeOD)δ8.88–8.83(m,1H),8.02–7.96(m,1H),7.83–7.78(m,1H),7.76–7.71(m,1H),7.70–7.65(m,1H),7.64–7.59(m,1H),7.28–7.22(m,1H),5.79–5.67(m,1H),5.08–5.02(m,1H),4.96–4.89(m,1H),4.83–4.80(m,2H),4.51–4.44(m,1H),3.06–2.96(m,1H),2.93–2.83(m,1H),2.37(s,6H),2.25(dd,J＝13.8,6.7Hz,2H),1.59(s,6H).

Example 59

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (0.7 g,3 mmol) (compound of formula I-59-a) and ammonium acetate (2.4 g,31 mmol) were added to 20ml of methanol and stirred at room temperature for 2H. Sodium cyanoborohydride (230 mg,3.77 mmol) was then added and stirred overnight at room temperature. After concentrating the reaction solution under reduced pressure, 20ml of water was added, and the pH was adjusted to acidity with 1mol/L hydrochloric acid, and extraction was performed twice with 30ml of methylene chloride each time. The aqueous phase is brought to pH with 2mol/L sodium hydroxide solution to alkali (pH=10-11). Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown liquid was obtained in 300mg and 40% yield. LC-MS: M/z (M+H) ⁺ ＝226。

And a second step of:

6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-amine (300 mg,1.33 mmol) (as the compound of formula I-59-b), 0.65ml of N, N-diisopropylethylamine and tert-butoxycarbonyl tert-butyl carbonate (400 mg,1.83 mmol) were stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the crude product obtained was purified by column chromatography (ethyl acetate: petroleum ether=0-15%) to give 400mg of a white solid. The yield thereof was found to be 92%. LC-MS: M/z (M+Na) ⁺ ＝348。

And a third step of:

tert-butyl (6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-yl) carbamate (600 mg,2.36 mmol) (compound of formula I-59-c), benzophenone imine (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) was added to 20ml toluene, purged three times with argon and then heated to 110℃overnight. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 10%), to obtain 170mg of brown oil, yield 40%. LC-MS: M/z (M+H) ⁺ ＝427。

Fourth step:

tert-butyl (6- ((diphenylmethylene) amino) -1,2,3, 4-tetrahydronaphthalen-2-yl) carbamate (170 mg,0.4 mmol) (compound of formula I-59-d) was dissolved in 20ml methanol, then sodium acetate (110 mg,1.34 mmol) and hydroxylamine hydrochloride (60 mg,0.86 mmol) were added and heated to 60 degrees for reaction overnight. The reaction solution was concentrated by filtration, and the crude product was purified by column chromatography (methanol: dichloromethane=0 to 20%) to obtain90mg of colorless oil was obtained in 86% yield. LC-MS: M/z (M-55) ⁺ ＝207。

Fifth step:

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

To the above-obtained solution were added tert-butyl (6-amino-1, 2,3, 4-tetrahydronaphthalen-2-yl) carbamate (90 mg,0.34 mmol) (compound represented by formula I-59-e) and 1ml of N, N-diisopropylethylamine, and stirred at room temperature overnight. Concentrated under reduced pressure, and the obtained crude product was purified by thin layer chromatography (methanol (dichloromethane: ethyl acetate=2:1) =1:10) }, to give 110mg of a white solid in 64% yield. LC-MS: M/z (M+H) ⁺ ＝572。

Sixth step:

(6- ((2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4)]Tert-butyl-d]Pyrimidin-6-yl) amino) -1,2,3, 4-tetrahydro-naphthalen-2-yl-carbamic acid (110 mg,0.19 mmol) (compound of formula I-59-f) was dissolved in a mixed solvent of 5ml of dichloromethane and 2ml of methanol, 10ml of 4mol/L dioxane hydrochloride was added, and the mixture was stirred at room temperature for 2 hours. After concentrating under reduced pressure, a mixed solvent (methanol: dichloromethane=10:1) composed of methanol and dichloromethane and 10ml saturated aqueous sodium carbonate solution were added, stirring was carried out at room temperature for 20min, and the organic layer was dried, concentrated and purified by column chromatography { methanol (dichloromethane: ethyl acetate=2:1) =0-20%) }, to give 40mg of a white solid in 44% yield. LC-MS: M/z (M+H) ⁺ ＝472,1H NMR(400MHz,CDCl3:MeOD＝2:1)δ8.85(d,J＝4.9Hz,1H),7.93(dd,J＝10.3,5.5Hz,1H),7.80(d,J＝8.0Hz,1H),7.57(d,J＝7.7Hz,1H),7.53(s,1H),7.38–7.31(m,1H),7.06(d,J＝8.3Hz,1H),5.70(dq,J＝10.4,6.0Hz,1H),5.05(d,J＝10.2Hz,1H),4.93(d,J＝17.1Hz,1H),4.82(d,J＝5.9Hz,2H),3.28–3.16(m,1H),3.03(dd,J＝15.9,4.6Hz,1H),2.91(dd,J＝7.7,4.8Hz,2H),2.60(dd,J＝15.6,9.6Hz,1H),2.10(d,J＝9.5Hz,1H),1.74–1.63(m,1H),1.61(d,J＝4.8Hz,6H).

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]Pyrimidine-3-one (20 mg,0.042 mmol) (a compound represented by formula I-59) was dissolved in methanol (6 mL), followed by addition of 40% acetaldehyde solution (1 mL) and sodium triacetylborohydride (45 mg,0.212 mmol), and stirring at room temperature for 4 hours. The reaction mixture was concentrated, dissolved in a mixture of methylene chloride and methanol (10/1, 20 ml), washed twice with saturated sodium hydrogencarbonate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by thin layer chromatography (7M ammonia methanol: methylene chloride=0 to 10%) to give the objective compound represented by the formula I-60 (4 mg,0.008 mmol) in 18% yield. LC-MS: M/z (M+H) ⁺ ＝528.3, ¹ H NMR(400MHz,MeOD)δ8.83(s,1H),8.01(t,J＝7.9Hz,1H),7.81(d,J＝7.8Hz,1H),7.68(d,J＝7.7Hz,1H),7.56(s,1H),7.34(d,J＝8.2Hz,1H),7.06(d,J＝8.3Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.10–5.02(m,1H),4.92(dd,J＝17.1,1.2Hz,1H),4.82(s,2H),3.14(d,J＝10.8Hz,0H),2.92(dt,J＝16.3,14.4Hz,1H),2.79(t,J＝12.2Hz,5H),2.17(d,J＝10.2Hz,0H),1.70(dd,J＝11.7,6.5Hz,0H),1.60(s,6H),1.17(t,J＝7.2Hz,6H)。

Example 61

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (400 mg,1.78 mmol) (compound of formula I-61-a) was dissolved in 18mL of methanol, followed by addition of ammonium acetate (1368 mg,17.8 mmol), stirring at room temperature for 2 hours, addition of sodium cyanoborohydride (120 mg,1.91 mmol), and stirring at room temperature for 16 hours. Concentrating the reaction solution under reduced pressure, adding30ml of water and brought to acidity with 1mol/L hydrochloric acid, extracted twice with 30ml of dichloromethane each time. The aqueous phase is brought to a pH of the base (pH=10-11) with 1mol/L sodium hydroxide solution. Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown oil (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。

And a second step of:

6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-amine (200 mg,0.84 mmol) (compound of formula I-61-b) and sodium cyanoborohydride (280 mg,4.46 mmol) were dissolved in 10mL of methanol, 0.5mL of propionaldehyde was added thereto, and the reaction was stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and the pH was adjusted to be acidic with 1mol/L hydrochloric acid, and extraction was performed twice with 30ml of methylene chloride each time. The aqueous phase is brought to a pH of the base (pH=10-11) with 1mol/L sodium hydroxide solution. Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown oil (190 mg,0.61 mmol) was obtained (compound of formula I-61-c) in 69% yield. LC-MS: M/z (M+H) ⁺ ＝310.1,312.1。

And a third step of:

6-bromo-N, N-dimethyl-1, 2,3, 4-tetrahydronaphthalen-2-amine (190 mg,0.61 mmol) (compound represented by formula I-61-c), benzophenone imine (122 mg,0.67 mmol), sodium t-butoxide (118 mg,1.22 mmol), pd ₂ (dba) ₃ (28 mg,0.03 mmol) BINAP (38 mg,0.06 mmol) was added to 10ml toluene, purged three times with argon, and then heated to 100℃for 18h. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 10%), to give a brown oil (220 mg,0.54 mmol) (compound represented by formula I-61-d), yield 87%. LC-MS: M/z (M+H) ⁺ ＝411.3。

Fourth step:

6- ((benzhydryl) amino) -N, N-dipropyl-1, 2,3, 4-tetrahydronaphthalen-2-amine (220 mg,0.54 mmol) (compound of formula I-61-d) was dissolved in 10ml of methanol, followed by addition of sodium acetate trihydrateThe compound (220 mg,1.62 mmol) and hydroxylamine hydrochloride (82 mg,1.18 mmol) were heated to 60℃for 5 hours. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 20%) to obtain brown oil (130 mg,0.53 mmol) (compound represented by formula I-61-e) in 98% yield. 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＝9.7Hz,1H),2.13–1.82(m,8H),1.03(t,J＝7.3Hz,6H)。

Fifth step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (72 mg,0.2 mmol) (compound represented by formula 1A) to a solution of 15ml of toluene was added m-chloroperoxybenzoic acid (50 mg,0.22 mmol), and the resulting solution was stirred at room temperature for 1H to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ]]Toluene solution of pyrimidin-3-one. To the above-obtained solution were added N, N-dipropyl-1, 2,3, 4-tetrahydronaphthalene-2, 6-diamine (65 mg,0.27 mmol) (compound represented by formula I-61-e) and 0.1ml of N, N-diisopropylethylamine, and stirred at room temperature for 18 hours. The crude product was concentrated under reduced pressure and purified by thin layer chromatography (7M methanolic ammonia: dichloromethane=0-10%) to give the target compound represented by I-61 (as the compound represented by formula I-61) 45mg as a yellow solid in 40% yield. LC-MS: M/z (M+H) ⁺ ＝556.3, ¹ H NMR(400MHz,CDCl ₃ )δ8.87(s,1H),7.90(t,J＝7.8Hz,1H),7.82(d,J＝8.1Hz,1H),7.49(s,1H),7.45(s,1H),7.39(d,J＝7.6Hz,1H),7.27(s,1H),7.09(d,J＝8.3Hz,1H),5.72(ddd,J＝16.4,11.3,5.0Hz,1H),5.07(d,J＝10.2Hz,1H),4.96(d,J＝17.1Hz,1H),4.78(d,J＝6.2Hz,2H),3.91(s,1H),3.06(s,1H),2.87(d,J＝30.3Hz,4H),2.57(s,4H),2.13(s,2H),1.61(s,6H),1.57(s,4H),0.94(t,J＝7.3Hz,6H)。

Example 62

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The first step:

6-amino-1, 4-dihydronaphthalene-1 (2H) -1 (148.9 mmol) (a compound represented by the formula I-62-a) was dissolved in methylene chloride (200 mL), N-diisopropylethylamine (446.7 mmol) was added to the reaction solution, the reaction solution was cooled to 0℃and acetyl chloride (223.3 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was evaporated to dryness to give a crude product, which was washed with ethyl acetate, filtered, and the cake was N- (5-oxo-5-, 6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (compound represented by formula I-62-b) (26.5 g), yield: 87.6%, gray solid as the objective compound. LC-MS: M/z: [ M+1 ]] ⁺ ＝204。

And a second step of:

n- (5-oxo-5-, 6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (25 mmol) (as shown in formula I-62-b) was dissolved in 1, 1-dimethoxy-N, N-dimethylamine (60 mL), and the reaction mixture was heated to reflux and stirred for 18 hours. The reaction solution is evaporated to dryness to obtain a crude product, the crude product is washed by ethyl acetate and filtered, and a filter cake is a target compound (E) -N- (6- ((dimethylamino) methylene) -5-oxo-5-, 6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (shown as a compound shown as a formula I-62-c) (5.8 g, 91%) and a gray solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝259。

And a third step of:

(E) -N- (6- ((dimethylamino) methylene) -5-oxo-5-, 6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (3.96 mmol) (a compound represented by formula I-62-c) was dissolved in methanol (15 mL), palladium on 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 solution was adjusted to ph=9 with saturated aqueous potassium carbonate, filtered, the filtrate was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the target compound 6- ((dimethylamino) methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (as shown in formula I-62-d) (150 mg, 19%) was purified by column chromatography (dichloromethane/methanol=20/1) as a yellow oil. LC-MS: M/z: [ M+1 ] ] ⁺ ＝205。

Fourth step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-D]Pyrimidin-3-one (0.56 mmol) (compound represented by formula 1A) was dissolved in 1, 2-dichloroethane (10 mL), and m-chloroperoxybenzene was addedFormic acid (0.62 mmol), the reaction stirred at room temperature for 0.5 h, 6- ((dimethylamino) methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (0.56 mmol) (as shown in formula I-62-d) and N, N-diisopropylethylamine (1.68 mmol) were added to the reaction, and the reaction heated to 70℃and stirred for 16h. Evaporating the reaction solution to obtain a crude product, and purifying the crude product by a TLC plate to obtain a target compound 2-allyl-6- ((6- ((dimethylamino) methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) amino) -1- (3- (2-hydroxy-propane-2-yl) phenyl) -1, 2-dihydro-3H-pyrazolo [3, 4-D)]Pyrimidin-3-one (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＝8.2,2.2Hz,1H),7.09(d,J＝8.2Hz,1H),5.73(ddt,J＝16.4,10.2,6.2Hz,1H),5.01(ddd,J＝18.3,13.6,1.2Hz,2H),4.78(d,J＝6.2Hz,2H),3.91(s,1H),2.96(dd,J＝16.7,4.8Hz,1H),2.86(dd,J＝7.8,4.3Hz,2H),2.44(dd,J＝16.2,10.4Hz,1H),2.31(s,8H),2.01(s,2H),1.61(s,6H).

Example 63

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (400 mg,1.78 mmol) (compound of formula I-63-a) was dissolved in 18mL of methanol, followed by addition of ammonium acetate (1368 mg,17.8 mmol), stirring at room temperature for 2 hours, then addition of sodium cyanoborohydride (120 mg,1.91 mmol), and stirring at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and the pH was adjusted to be acidic with 1mol/L hydrochloric acid, and extraction was performed twice with 30ml of methylene chloride each time. The aqueous phase is brought to a pH of the base (pH=10-11) with 1mol/L sodium hydroxide solution. Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown oil (compound of formula I-63-2) (150 mg,0.84 mmol) was obtained in 37% yield. LC-MS: M/z (M+H) ⁺ ＝226.0，228.0。

And a second step of:

6-bromo-1, 2,3, 4-tetrahydronaphthalene-2-amine (150 mg,0.67 mmol) (compound of formula I-63-b) and sodium cyanoborohydride (209 mg,3.3 mmol) were dissolved in 10mL methanol, 0.5mL acetone was added thereto, and the reaction was stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and the pH was adjusted to be acidic with 1mol/L hydrochloric acid, and extraction was performed twice with 30ml of methylene chloride each time. The aqueous phase is brought to a pH of the base (pH=10-11) with 1mol/L sodium hydroxide solution. Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown oil (170 mg,0.55 mmol) was obtained (compound of formula I-63-c) in 83% yield. LC-MS: M/z (M+H) ⁺ ＝268.1,270.1。

And a third step of:

6-bromo-N-isopropyl-1, 2,3, 4-tetrahydronaphthalen-2-amine (170 mg,0.5 mmol) (compound of formula I-63-c) and Boc ₂ O (137 mg,0.55 mmol) was dissolved in 10ml dichloromethane and 0.16ml N, N-diisopropylethylamine was added and the reaction stirred at room temperature to 40℃for 16h. After the reaction, the crude product was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (ethyl acetate: petroleum ether=0 to 10%) to give 176mg of the objective compound (compound represented by formula I-63-d), a yellow solid, and a yield of 76%. LC-MS: M/z (M+H) ⁺ ＝368.1,370.1。

Fourth step:

tert-butyl (6-bromo-1, 2,3, 4-tetrahydronaphthylamine-2-yl) (isopropyl) carbonate (176 mg,0.48 mmol) (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 10ml toluene, purged three times with argon, and then heated to 100℃for 18h. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 10%) to obtain a yellow solid (compound represented by formula I-63-e) (180 mg,0.38 mmol) in 81% yield. LC-MS: M/z (M+H) ⁺ ＝469.3。

Fifth step:

tert-butyl (6- ((benzhydryl) amino) -1,2,3, 4-tetrahydronaphthalen-2-yl) (isopropyl) carbonate (180 mg,0.38 mmol) (as the compound of formula I-63-e) was dissolved in 10ml methanol, followed by the addition of sodium acetate trihydrate(157 mg,1.15 mmol) and hydroxylamine hydrochloride (82 mg,0.85 mmol) were heated to 60℃for 5 hours. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 20%) to obtain a yellow solid (compound represented by formula I-63-f) (102 mg,0.34 mmol) in 87% yield. 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＝11.0Hz,1H),2.18(dt,J＝44.1,12.4Hz,2H),1.83(d,J＝10.1Hz,1H),1.50(s,9H),1.26(d,J＝16.4Hz,6H).LC-MS:m/z:(M+H) ⁺ ＝305.3。

Sixth step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ]Pyrimidin-3-one (Compound shown as formula 1A) (108 mg,0.3 mmol) to a solution of 15ml of toluene was added m-chloroperoxybenzoic acid (82 mg,0.47 mmol), and the resulting solution was stirred at room temperature for 1H to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ]]Toluene solution of pyrimidine-3-one (shown as formula 1B). To the above-obtained solution were added tert-butyl (6-amino-1, 2,3, 4-tetrahydronaphthylamine-2-yl) (isopropyl) carbonate (102 mg,0.33 mmol) (compound represented by formula I-63-g) and 0.16ml of N, N-diisopropylethylamine, and stirred at room temperature for 18 hours. The crude product was concentrated under reduced pressure and purified by thin layer chromatography (7M methanolic ammonia: dichloromethane=0-10%) to give 85mg of the target compound (compound represented by formula I-63-g), a yellow solid, yield 46%. LC-MS: M/z (M+H) ⁺ ＝614.3。

Seventh step:

(6- ((2-allyl-1- (6- (2-hydroxyisopropyl-2-yl) pyridin-2-yl) -3-one-2, 3-dihydro-1H-pyrazolo [3, 4-d)]Pyrimidin-6-yl) amino) -tert-butyl 1,2,3, 4-tetrahydronaphthalen-2-yl (isopropyl) carbonate (85 mg,0.3 mmol) (compound of formula I-63-g) was dissolved in 10mL dichloromethane, and 0.5mL of 4N hydrogen chloride dioxane solution was added thereto and stirred at room temperature for 4 hours. Concentrating under reduced pressure, dissolving the crude product with water, and extracting with dichloromethane. The aqueous layer was adjusted to ph=10 with 2N NaOH solution and filtered to give 70mg of the target compound of I-63 (compound of formula I-63) as a yellow solid in 98% yield. LC-MS: M/z (M+H) ⁺ ＝514.3, ¹ H NMR(400MHz,CDCl ₃ )δ8.87(s,1H),7.90(t,J＝7.8Hz,1H),7.82(d,J＝8.0Hz,1H),7.47(s,1H),7.39(d,J＝7.6Hz,1H),7.32–7.29(m,1H),7.07(d,J＝8.3Hz,1H),5.84–5.64(m,1H),5.06(d,J＝10.2Hz,1H),4.95(d,J＝17.1Hz,1H),4.78(d,J＝6.2Hz,2H),3.94(s,1H),3.25–2.99(m,3H),2.90(s,2H),2.70–2.56(m,1H),2.12(s,1H),1.61(s,6H),1.16(d,J＝6.1Hz,6H)。

Example 64

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (0.5 g,2.22 mmol) (as the compound of formula I-64-a) was added to 15ml of methanol, sodium borohydride (100 mg,2.65 mmol) was added under ice-bath, and stirred at room temperature for 1H. After the reaction solution was concentrated under reduced pressure, 10ml of a saturated aqueous ammonium chloride solution was added, and extraction was performed three times with 15ml of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the crude product obtained was purified by column chromatography (ethyl acetate: petroleum ether=0-50%). 380mg of a colorless liquid was obtained in 75% yield. LC-MS: M/z (M+Na) ⁺ ＝249。

And a second step of:

powdered potassium hydroxide (470 mg,8.39 mmol) and 6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (380 mg,1.67 mmol) (compound of formula I-64-b) were added to 7ml of anhydrous dimethyl sulfoxide and stirred at room temperature for 15min. Methyl iodide (700 mg,4.93 mmol) was then added and stirred overnight at room temperature. To the reaction mixture was added 20ml of saturated brine, and the mixture was extracted three times with dichloromethane (3×20 ml). The organic layer was washed three times (3×15 ml) and the solvent was evaporated under reduced pressure, and the crude product obtained was purified by column chromatography (ethyl acetate: petroleum ether=0-10%) to give 340mg of a colorless oil. The yield thereof was found to be 84%. LC-MS: M/z (M+Na) ⁺ ＝263。

And a third step of:

6-bromo-2-methoxy-1, 2,3, 4-tetrahydronaphthalene (340 mg,1.41 mmol) (compound of formula I-64-c), benzophenone imine (300 mg,1.66 mmol), sodium t-butoxide (220 mg,2.29 mmol), pd ₂ (dba) ₃ (45mg,0.05mmol),BINAP(90mg,0.14mmol) was added to 20ml of toluene, purged three times under argon, and then heated to 110 degrees overnight. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (ethyl acetate: petroleum ether=0 to 30%) to obtain 450mg of brown oil with a yield of 93%.1H NMR (400 MHz, CDCl 3) delta 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, 2.2Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 6.45 (dd, J=8.0, 2.0Hz, 1H), 3.60 (m, 1H), 3.42 (s, 3H), 3.00 (dd, J=16.3, 4.9Hz, 1H), 2.78 (dt, J=16.9, 5.7Hz, 1H), 2.65 (m, 2H), 2.04 (m, 1H), 1.80-1.68 (m, 1H).

Fourth step:

n- (6-methoxy-5, 6,7, 8-tetrahydronaphthalen-2-yl) -1, 1-benzophenone imine (450 mg,1.3 mmol) (a compound of formula I-64-d) was dissolved in 20ml of methanol, followed by addition of sodium acetate (340 mg,4.15 mmol) and hydroxylamine hydrochloride (210 mg,3 mmol) and heating to 60℃for reaction overnight. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (ethyl acetate: petroleum ether=0 to 30%), to obtain 220mg of a white solid, yield 94%. LC-MS: M/z (M+H) ⁺ ＝178。

Fifth step:

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

To the above-obtained solution were added 6-methoxy-5, 6,7, 8-tetrahydronaphthalen-2-amine (55 mg,0.31 mmol) (compound represented by formula I-64-e) and 1ml of N, N-diisopropylethylamine, and stirred at room temperature overnight. Concentrating under reduced pressure, purifying the crude product with column chromatography { methanol (dichloromethane: ethyl acetate=2:1) =1:15 }, and separating and purifying { methanol (dichloromethane: ethyl acetate=2:1) =0-15%) } by thin layer chromatography to obtain white solid 25mg in 17% yield. LC-MS: M/z (M+H) ⁺ ＝487，1H NMR(400MHz,DMSO)δ10.18(s,1H),8.87(s,1H),8.02(t,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.64(d,J＝7.7Hz,2H),7.41–7.33(m,1H),7.02(d,J＝8.3Hz,1H),5.75–5.60(m,1H),5.32(s,1H),5.00(dd,J＝10.3,1.2Hz,1H),4.83(dd,J＝17.1,1.3Hz,1H),4.70(d,J＝5.9Hz,2H),3.64(m,1H),3.32(s,3H),2.97(dd,J＝16.4,4.5Hz,1H),2.88–2.59(m,3H),2.08–1.96(m,1H),1.83–1.68(m,1H),1.47(s,6H).。

Example 65

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (0.6 g,2.66 mmol) (compound of formula I-64-a) was added to 15ml of methanol, sodium borohydride (110 mg,2.91 mmol) was added under ice-bath, and stirred at room temperature for 1H. After the reaction solution was concentrated under reduced pressure, 10ml of a saturated aqueous ammonium chloride solution was added, and extraction was performed three times with 15ml of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the crude product obtained was purified by column chromatography (ethyl acetate: petroleum ether=0-50%). 460mg of a colorless liquid was obtained in 75% yield. LC-MS: M/z (M-OH) ⁺ ＝209。

And a second step of:

imidazole (330 mg,4.85 mmol) and 6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (440 mg,1.94 mmol) (compound of formula I-64-b) were added to 5ml of N, N-dimethylformamide, followed by t-butyldimethylchlorosilane (360 mg,2.39 mmol) and stirred at room temperature overnight. To the reaction mixture was added 30ml of ethyl acetate. The organic layer was washed twice (2×15 ml), saturated brine was washed once (15 ml), the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether=0-10%) to give 540mg of colorless oil. The yield thereof was found to be 81%.1H NMR (400 MHz, CDCl 3) delta 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).

And a third step of:

dimethylsilane ((6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-yl) oxy) (t-butyl) dimethylsilane (540 mg,1.58 mmol) (compound of formula I-65-c), benzophenone imine (330 mg,1.82 mmol), t-butylSodium alkoxide (240 mg,2.5 mmol), pd ₂ (dba) ₃ (45 mg,0.05 mmol) BINAP (95 mg,0.15 mmol) was added to 20ml toluene, purged three times with argon, and then heated to 110℃overnight. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (ethyl acetate: petroleum ether=0 to 30%), to obtain 600mg of a brown oil, yield 85%.

Fourth step:

n- [2- [ tert-butyl (dimethyl) silyl group]Oxtetrahydronaphthalen-6-yl]1, 1-Diphenyl-azomethine (600 mg,1.36 mmol) (compound of formula I-65-d) was dissolved in 30ml methanol, followed by addition of sodium acetate (340 mg,4.15 mmol) and hydroxylamine hydrochloride (210 mg,3 mmol) and heating to 60℃for 2h. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (ethyl acetate: petroleum ether=0 to 30%) to obtain 350mg of a white solid with a yield of 92%. LC-MS: M/z (M+H) ⁺ ＝278。

Fifth step:

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

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) (compound represented by formula I-65-f) and 1ml tetra-n-butylammonium fluoride (1 mol/L in THF) were added to 5ml tetrahydrofuran and stirred at 35℃overnight. Concentrating under reduced pressure, purifying the crude product with column to obtain { methanol (dichloromethane: acetic acid)Ethyl=2:1) =0-20% }, then 28mg of white solid was prepared with high performance liquid phase in 34% yield. LC-MS: M/z (M+H) ⁺ ＝473。1H NMR(400MHz,DMSO)δ10.16(s,1H),8.86(s,1H),8.02(t,J＝7.9Hz,1H),7.78(d,J＝7.8Hz,1H),7.64(dd,J＝7.7,0.6Hz,1H),7.60(s,1H),7.36(dd,J＝8.3,1.9Hz,1H),7.00(d,J＝8.3Hz,1H),5.67(ddt,J＝16.2,10.3,5.9Hz,1H),5.32(s,1H),5.00(dd,J＝10.3,1.3Hz,1H),4.83(dd,J＝17.1,1.4Hz,1H),4.76(s,1H),4.70(d,J＝5.9Hz,2H),3.91(s,1H),2.86(ddd,J＝16.6,13.7,5.1Hz,2H),2.79–2.66(m,1H),2.56(dd,J＝16.1,8.1Hz,1H),1.98–1.88(m,1H),1.65(ddd,J＝12.5,9.0,3.4Hz,1H),1.47(s,6H).

Example 66

The first step:

6-acetamido-1, 2,3, 4-tetrahydro-1-naphthalenone (2000 mg,9.8406 mmol) (compound shown as formula 1-66-a) was dissolved in toluene (40 mL), followed by addition of ethyl glyoxylate (2 equiv.,19.681mmol,50 mass%) (shown as 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℃and stirred for 12 hours. 20ml of water was added for extraction, 2X20ml of ethyl acetate was used for extraction, 1X20ml of brine was used for washing the combined organic phases, and the mixture was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by normal phase silica gel column separation (eluent EA/pe=0% to 60%,12 CV) to give 2.0g of the target compound (compound represented by formula I-66-c), a yellow solid, yield 61%. LC-MS: M/z (M+H) ⁺ ＝288.0.

And a second step of:

ethyl (E) -2- (6-acetamido-1-oxo-3, 4-dihydronaphthalenone-2 (1 hydro) -methylene) acetate (2000 mg,6.961 mmol) (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 under a hydrogen atmosphere for 12 hours. Filtered and the filtrate pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate 2x20ml and the combined organic phases were washed with brine 1x20ml, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by normal phase silica gel column separation (eluent EA/pe=8% to 60%,12 CV) to give 0.7g of the target compound (compound represented by formula I-66-d), a yellow solid, and a yield of 36%.1H NMR (400 MHz, meOD) delta 7.27 (s, 1H), 7.23 (dd, J=8.2, 2.2Hz, 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, 4.3Hz, 2H), 2.44 (dd, J=15.8, 10.1Hz, 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, 10.8Hz, 1H), 1.29 (t, J=5.1 Hz, 3H).

And a third step of:

ethyl-2- (6-acetamide-1, 2,3, 4-dihydronaphthalen-2-yl) acetate (700 mg, 2.433 mmol) (a compound represented by formula I-66-d) was dissolved in a solution of ethanol (20 mL), followed by addition of a sulfuric acid solution (2 mL,70 mass%). The reaction was heated to reflux and stirred for 12 hours. Extraction with ethyl acetate 2X20ml, washing the combined organic phases with brine 1X20ml, drying over anhydrous sodium sulfate, filtration and concentration gave the title compound (as shown in formula I-66-e) as a brown oil, 0.56g, 99% yield. 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＝14.9,10.4,4.7,2.9Hz,1H),1.96–1.86(m,1H),1.49–1.37(m,1H),1.35–1.21(m,3H).

Fourth step:

2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridine]-6-methylsulfanyl-pyrazolo [3,4-d ]]Pyrimidine-3-one (70 mg,0.1959 mmol) (a compound represented by formula 1A) was dissolved in dichloroethane (2 mL), followed by addition of mCPBA (1.3 equiv.,0.2546mmol,77 mass%). The reaction was stirred at room temperature for 2 hours. After that, DIPEA (3 equiv.,0.5876 mmol) and ethyl 2- (6-amine-1, 2,3, 4-tetrahydronaphthalen-2-yl) acetate (a compound represented by formula I-66-e) (3 equiv.,0.5876 mmol) were added. The reaction was stirred at room temperature for 12 hours. Saturated sodium bisulphite 20ml is added for extraction, dichloromethane is used for extracting 2x20ml, the organic phase is combined for washing 1x20ml by brine, and the crude product is obtained by filtering and concentrating. The crude product was purified by Pre-HPLC (eluent acetonitrile/water (0.1% formic acid) =30% to 60%) to give 25mg of the target compound (compound of formula I-66), a white solid,the yield thereof was found to be 23.5%.1H NMR (400 MHz, DMSO). Delta.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=7.7 Hz, 2H), 7.36 (d, J=8.1 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.67 (dd, J=17.1, 10.3Hz, 1H), 5.33 (s, 1H), 5.00 (dd, J=10.3, 1.3Hz, 1H), 4.83 (dd, J=17.1, 1.3Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 2.80 (dd, J=16.0, 4.2Hz, 2.44, 2.3 Hz), 5.1 (dd, 1.3 Hz), 4.3 (M) and 1.45 (1.1.3 Hz, 1M), 4.3 (1.4.3 Hz, 1H), 4.3 (d, 1.3Hz, 1.4.3 Hz, 1H), 4.3 (1.3M (1.4M, 1.4H), 4.3 (1M, 1.4H), 1.3 (1.3 Hz,1H, 1M (1H) ⁺ ＝543。

Example 67

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 acetate (520 mg,0.9583 mmol) (a compound represented by formula I-66) was dissolved in a mixed solvent of methanol (5 ml) and tetrahydrofuran (5 ml), followed by hydrogenation of an aqueous lithium oxide solution (1 mol/L,5 ml). The reaction was stirred for 2 hours while heating to 50℃and 50 ℃. The reaction is quenched by 1N hydrochloric acid, the pH value of the reaction solution is adjusted to 6-7, a large amount of white solid is separated out in the process, the white solid is obtained by filtration, and the product is obtained by leaching with petroleum ether 5ml for 2 times. The product was further refined by Pre-HPLC (provided acetonitrile/water (0.1% formic acid) =30% -60%12cv) to give 400mg of the target compound (compound represented by formula I-67), a white solid, a yield of 81.1%.1H NMR (400 MHz, DMSO). Delta.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, 10.3Hz, 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, 4.6Hz, 3H), 2.39 (dd, 16.6,10.4Hz, 1H), 2.34 (d, 29.2 Hz, 7.2 Hz, 1H), 4.82 (d, 1H), 4.70 (d, J=17.9 Hz, 1H), 4.9 (d, 1H), 4.9 (2.9M (2M, 2H) ⁺ ＝515。

Example 68

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 acetic acid (40 mg,0.07773 mmol) (compound of formula I-67) was dissolved in DMF (2 ml), HATU (1 equiv.,0.07773 mmol) and DIPEA (2 equiv.,0.1555 mmol) were then added, and finally ethylamine (2 equiv.,0.1555 mmol) was added. The reaction was stirred at room temperature for 12 hours. 20ml of water was added for extraction, and extraction was performed twice with 20ml of ethyl acetate. The organic layer was washed twice with 20ml of brine, dried over sodium sulfate, filtered and concentrated to give a crude product. The crude product was further purified by Pre-HPLC (provided acetonitrile/water (0.1% formic acid) =30% -60%12 cv) to give the target (compound of formula I-68) 18mg, white solid, yield 41.5%). NMR (400 mhz, dmso) delta 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, 10.3,5.9hz, 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, 14.8.4 hz), 7.8.4 hz (d, 2.8 hz), 5.34 (s, 1H), 5.00 (d, j=23.0, 10.3hz, 1H), 4.90-4.76 (M, 1H), 4.70 (d, j=5.8 hz, 2H), 3.16-3.04 (2 hz, 1H), 3.12 (d, 3.8H) ⁺ ＝542。

Example 69

The same compound ethyl 2- (6- ((2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d) was used]Pyrimidin-6-yl) amine) -1,2,3, 4-tetrahydronaphthalen-2-yl-acetamide (e.g., a compound of formula I-67) 18mg of the title compound was obtained as a white solid in 41.5% yield. 1H NMR (400 MHz, DMSO). Delta.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=11.4 Hz, 1H), 4.82 (d, J=17.2 Hz, 1H), 4.73-4.65 (m, 2H), 3.42 (dd, J=11.8, 6.1Hz, 2H), 3.16 (d, J=5.9, 10.2Hz, 1H), 5.37-5.32 (m, 1H), 4.73-4.65 (m, 2H).42–2.28(m,3H),2.14(s,2H),2.14-2.05(m,1H),1.87(s,1H),1.44(t,J＝18.7Hz,6H),1.45-1.30(m,1H).LC-MS:m/z:(M+H) ⁺ ＝558。

Example 70

The same compound ethyl 2- (6- ((2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d) was used]Pyrimidin-6-yl) amine) -1,2,3, 4-tetrahydronaphthalen-2-yl-acetamide (e.g., the compound of formula I-67) 20mg of the target compound (e.g., the compound of formula I-70) was prepared in the same manner as described above, as a white solid, with a yield of 46.7%.1H NMR (400 mhz, dmso) δ10.20 (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=8.0 hz, 1H), 7.64 (d, j=7.6 hz, 2H), 7.35 (d, j=8.1 hz, 1H), 7.00 (d, j=8.1 hz, 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, 2.2H), 2.09 (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=2.7.9 hz, 2H), 2.32 (d, 2H), 2.7-2.8 hz, 2.7 (2H), 1H); M/z (M+H) ⁺ ＝554。

Example 71

The same compound ethyl 2- (6- ((2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d) was used]Pyrimidin-6-yl) amine) -1,2,3, 4-tetrahydronaphthalen-2-yl-acetamide (as shown in formula I-71) 15mg of the target compound (as shown in formula I-71) was prepared in the same manner as described in the above, and a white solid was obtained in a yield of 35.0%.1H NMR (400 mhz, dmso) δ10.20 (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, 10.4hz, 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

The same compound ethyl 2- (6- ((2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d) was used]Pyrimidin-6-yl) amine) -1,2,3, 4-tetrahydronaphthalen-2-yl-acetamide (e.g., a compound of formula I-67) 15mg of the title compound was obtained as a white solid in 31.1% yield. 1H NMR (400 MHz, DMSO). Delta.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=7.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 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), 5.00 (d, J=10.4 Hz, 1H), 4.82 (d, 1.70 (M, 1H), 4.45 (1.35/1H), 1.45 (M, 1H) ⁺ ＝624。

Example 73

The same compound ethyl 2- (6- ((2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d) was used]Pyrimidin-6-yl) amine) -1,2,3, 4-tetrahydronaphthalen-2-yl-acetamide (e.g., the compound of formula I-67) 15mg of the target (e.g., the compound of formula I-73) was prepared in the same manner as described above, as a white solid, in 31.2% yield. 1H NMR (400 MHz, DMSO). Delta.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, 1.9 Hz, 1H), 4.82 (M, 1H), 1.45 (m+1H) and 1.45 (m+1H) ⁺ ＝618。

Example 74

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (855 mg,3.8 mmol) (compound of formula I-74-a) and (400 mg,5.6 mmol) pyrrolidine were dissolved in 20mL dichloromethane, then (1.6 g,7.6 mmol) sodium borohydride acetate was added and the tube was sealed at 65℃and stirred overnight. Quenched with 5ml of water, washed sequentially with saturated aqueous sodium carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was dissolved in 20ml of ethyl acetate, and 4M dioxane hydrochloride solution was added dropwise until no solid precipitated from ethyl acetate. Filtration gave 1g of an off-white solid in 83% yield. LC-MS: M/z: [ M+1 ] ] ⁺ ＝280。

And a second step of:

1- (6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-yl) pyrrolidine hydrochloride (1 g,3.16 mmol) (compound of formula I-74-b), benzophenone imine (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 20ml toluene, purged three times with argon, and then heated to 110℃overnight. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (7M methanolic ammonia: dichloromethane=0-20%) to obtain 1g of brown oil, yield 83%. LC-MS: M/z (M+H) ⁺ ＝381。

And a third step of:

1, 1-diphenyl-N- (6- (pyrrolidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) azomethine (1 g,2.63 mmol) (compound of formula I-74-c) was dissolved in 30ml methanol, then sodium acetate (0.7 g,8.5 mmol) and hydroxylamine hydrochloride (370 mg,5.32 mmol) were added and heated to 60℃to react overnight. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (7M methanolic ammonia: dichloromethane=0-20%) to obtain 220mg of brown solid, yield 38%. LC-MS: M/z (M+H) ⁺ ＝217。

Fourth step:

to a solution of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (120 mg,0.336 mmol) (compound of formula 1A) in 15ml of toluene was added m-chloroperoxybenzoic acid (82 mg,0.367 mmol), and the resulting solution was stirred at room temperature for 2 hours to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one. This solution was used directly in the next reaction.

6- (pyrrolidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-amine (100 mg,0.46 mmol) (compound of formula I-74-d) and 0.5ml of N, N-diisopropylethylamine were added to 10ml of dichloromethane, stirred until the solution was clear, then added to the toluene solution obtained above, and stirred at room temperature for 40 hours. Concentrating under reduced pressure, separating and purifying {7M ammonia methanol (dichloromethane: ethyl acetate=5:1) =1:12 } by thin layer chromatography, and then preparing white solid 16mg by high performance liquid phase to obtain 7% yield. LC-MS: M/z (M+H) ⁺ ＝526， ¹ H NMR(400MHz,MeOD)δ8.85(s,1H),8.40(s,2H),8.14(s,1H),7.92(t,J＝7.7Hz,1H),7.77(d,J＝8.0Hz,1H),7.54–7.32(m,3H),7.08(d,J＝7.9Hz,1H),5.81–5.62(m,1H),5.07(d,J＝10.0Hz,1H),4.95(d,J＝16.9Hz,1H),4.77(d,J＝5.5Hz,2H),3.37(m,5H),3.19(d,J＝7.6Hz,2H),2.95(m,2H),2.37(s,1H),2.13(s,5H),1.62(s,6H).

Example 75

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (900 mg,4 mmol) (compound of formula I-75-a), azetidine hydrochloride (750 mg,8 mmol) and 20mL of water were added to 60mL of methanol, followed by addition of sodium acetate (1.31 g,16 mmol) and stirring at room temperature under nitrogen for 1H.

To the above reaction was added (1.5 g,16 mmol) of acetic acid and (500 mg,8.2 mmol) of sodium cyanoborohydride, and stirred overnight at room temperature under nitrogen. After concentrating under reduced pressure, adding 20ml of saturated aqueous sodium carbonate solution, extracting with dichloromethane three times (3 x 30 ml), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, purifying the crude product by column chromatography {7M ammonia methanol (dichloromethane: ea=2:1) =0-15% }, to obtain a brown oily substance with a yield of 700 mg: 65%. LC-MS: M/z: [ M ] +1] ⁺ ＝266。

And a second step of:

1- (6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-yl) azetidine (0.7 g,2.63 mmol) (compound of formula I-75-b), benzophenone imine (530 mg,2.92 mmol), sodium t-butoxide (410 mg,4.27 mmol), pd ₂ (dba) ₃ (80 mg,0.087 mmol) BINAP (165 mg,0.265 mmol) was added to 35ml toluene, purged three times with argon and then heated to 110℃overnight. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography {7M methanolic ammonia (dichloromethane: ea=2:1) =0-10% }, to obtain 0.85g of brown oil in 88% yield. LC-MS: M/z (M+H) ⁺ ＝367。

And a third step of:

1, 1-diphenyl-N- (6- (azetidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) azomethine (1 g,2.53 mmol) (a compound represented by formula I-75-c) was dissolved in 40ml methanol, followed by addition of sodium acetate (0.61 g,7.44 mmol) and hydroxylamine hydrochloride (340 mg,4.89 mmol) and heating to 60℃for reaction overnight. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (7M methanolic ammonia: dichloromethane=0-10%) to obtain 450mg of brown solid, yield 95%. LC-MS: M/z (M+H) ⁺ ＝203。

Fourth step:

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

After the reaction solution was concentrated, 6- (azetidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-amine (100 mg,0.49 mmol) (a compound represented by formula I-75-d), 0.2ml of trifluoroacetic acid and 5ml of dimethyl sulfoxide were added thereto, and stirred at 60℃for 24 hours.

Adding 10ml saturated sodium carbonate aqueous solution and 25ml water into the reaction solution, extracting with dichloromethane three times (3 x 20 ml), mixing organic phases, washing with 20ml water and 20ml saturated sodium chloride solution respectively, drying with anhydrous sodium sulfate, concentrating to obtain crude product, and making into capsulePurification by column chromatography {3M methanolic ammonia (dichloromethane: ethyl acetate=1:1) =0-15% }, followed by preparation of a brown solid 100mg in 39% yield using high performance liquid phase. LC-MS: M/z (M+H) ⁺ ＝512，1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.51(s,1H),8.03(s,1H),7.89(t,J＝7.9Hz,1H),7.76(d,J＝7.6Hz,1H),7.44(s,1H),7.41(d,J＝7.6Hz,1H),7.32(dd,J＝8.3,2.1Hz,1H),7.03(d,J＝8.3Hz,1H),5.71(ddt,J＝16.4,10.2,6.2Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(dd,J＝17.1,1.2Hz,1H),4.76(d,J＝6.2Hz,2H),4.01(t,J＝7.8Hz,4H),3.19–3.06(m,1H),3.06–2.75(m,4H),2.48(p,J＝7.5Hz,2H),2.13(d,J＝10.0Hz,1H),1.93–1.75(m,1H),1.61(s,6H).

Example 76

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (1 g,4.44 mmol) (as shown in formula I-76-a), piperidine (760 mg,8.93 mmol) and p-toluenesulfonic acid (90 mg,0.52 mmol) were added to 40mL of toluene, a water separator was fixed on the reaction flask, and stirred at 155℃under reflux overnight.

After the solvent toluene in the reaction was distilled off under reduced pressure, 40ml of methanol was added, and sodium borohydride (0.85 g,23 mmol) was slowly added under ice bath, and the ice bath was removed and stirred at room temperature for 2 hours. Concentrating under reduced pressure, adding 40ml of ethyl acetate and 30ml of 1mol/L hydrochloric acid, washing the organic layer twice (2 x 20 ml) with 1mol/L hydrochloric acid, alkalizing the combined acidic solution with 5mol/L sodium hydroxide, extracting with dichloromethane three times (3 x 30 ml), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product 900mg of brown oily substance, and directly using the crude product for the next step, wherein the yield is as follows: 70%. LC-MS: M/z: [ M+1 ] ] ⁺ ＝294。

And a second step of:

1- (6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-yl) piperidine (0.9 g,3.06 mmol) (compound of formula I-76-b), benzophenone imine (620 mg,3.42 mmol), sodium t-butoxide (470 mg,4.89 mmol), pd ₂ (dba) ₃ (90 mg,0.1 mmol) BINAP (190 mg,0.3 mmol) was added to 35ml toluene, purged three times with argon, and then heated to 110 degreesAnd (5) at night. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (7M methanolic ammonia: dichloromethane=0-10%) to obtain 1g of brown oil, yield 82.8%. LC-MS: M/z (M+H) ⁺ ＝395。

And a third step of:

1, 1-diphenyl-N- (6- (piperidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) azomethine (1 g,2.53 mmol) (compound of formula I-76-c) was dissolved in 40ml methanol, then sodium acetate (1 g,12.2 mmol) and hydroxylamine hydrochloride (360 mg,5.18 mmol) were added and heated to 60℃to react overnight. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (7M ammonia methanol: dichloromethane=0-20%) to obtain 500mg of brown solid, yield 90%. LC-MS: M/z (M+H) ⁺ ＝231。

Fourth step:

to a solution of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (178 mg,0.5 mmol) (compound of formula 1A) in 35ml of toluene was added m-chloroperoxybenzoic acid (122 mg,0.546 mmol), and the resulting solution was stirred at room temperature for 2 hours to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one.

The reaction solution was concentrated, and then 6- (piperidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-amine (130 mg, 0.56mmol) (a compound represented by formula I-76-d), 0.2ml of trifluoroacetic acid and 5ml of dimethyl sulfoxide were added thereto, followed by stirring at 60℃for 24 hours. 10ml of saturated aqueous sodium carbonate and 25ml of water were added to the above reaction solution, extraction was performed three times (3 x 20 ml) with methylene chloride, the organic phases were combined, washed with 20ml of water and 20ml of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, and the obtained crude product was purified by column chromatography {3M methanolic ammonia (methylene chloride: ethyl acetate=1:1) =0-15% }, and then prepared with a high-performance liquid phase to obtain 130mg of brown solid in a yield of 41%. LC-MS: M/z (M+H) ⁺ ＝540， ¹ H NMR(400MHz,CDCl ₃ )δ8.84(s,1H),8.56(s,1H),7.96(s,1H),7.90(t,J＝7.9Hz,1H),7.77(d,J＝8.0Hz,1H),7.48(s,1H),7.42(d,J＝7.6Hz,1H),7.31(dd,J＝8.4,2.0Hz,1H),7.06(d,J＝8.3Hz,1H),5.71(ddt,J＝16.4,10.2,6.2Hz,1H),5.11–5.02(dd,J＝10.2,1.1Hz,1H),4.94(dd,J＝17.1,1.1Hz,1H),4.77(d,J＝6.1Hz,2H),3.54(m,1H),3.04(m,8H),2.41(d,J＝11.9Hz,1H),1.99(s,4H),1.87(m,1H),1.63(d,8H).

Example 82

The first step:

(E) -N- (6- ((dimethylamino) methylene) -5-oxo-5-, 6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (4.6 mmol) (a compound represented by formula I-82-a) was dissolved in ethanol (20 mL), piperidine (14 mmol) was added to the reaction, the reaction was heated to reflux, and the reaction was stirred for 16 hours. The reaction solution was evaporated to dryness to give a crude product, which was washed with ethyl acetate, filtered, and the cake was the target compound (E) -N- (5-oxo-6- (piperidin-1-methylene) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (950 mg, 69%) as a gray solid. 1H NMR (400 MHz, CDCl 3) delta 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).

And a second step of:

(E) -N- (5-oxo-6- (piperidin-1-methylene) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (3.18 mmol) (a compound represented by formula I-82-b) was dissolved in anhydrous methanol (20 mL), pd/C (300 mg) and concentrated sulfuric acid (0.5 mL) were added to the reaction solution, and the reaction solution was heated to reflux in hydrogen gas and stirred for 18 hours. The reaction solution was adjusted to ph=9 with saturated sodium carbonate solution, pd/C was removed by filtration, the reaction solution was evaporated to dryness, separated with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, the crude product was evaporated to dryness to give a crude product, which was washed with ethyl acetate, filtered, and purified by column chromatography (petroleum ether/ethyl acetate=100/0-50/50) to give the objective compound 6- (piperidine-1-methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (250 mg, 32.1%) as a yellow oil. LC-MS: M/z: [ M+1 ]] ⁺ ＝245。

And a third step of:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-D]Pyrimidin-3-one (0.56 mmol) (chemical formula 1A)The compound) was dissolved in toluene (15 mL), m-chloroperoxybenzoic acid (0.62 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, the reaction was evaporated to dryness, the obtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10 mL), 6- (piperidine-1-methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (0.67 mmol) (compound represented by formula I-82-c) and trifluoroacetic acid (0.5 mL) were added, and the reaction was heated to 60℃and stirred for 16 hours. The reaction mixture was adjusted to ph=9 with saturated sodium carbonate solution, water (50 mL) was added to the mixture, ethyl acetate (50 mL) was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the target compound 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- ((6- (piperidin-1-methyl) -5,6,7, 8-tetrahydronaphthalen-2-yl) amino) -1, 2-dihydro 3H-pyrazolo [3,4-d ] was purified by column chromatography (dichloromethane/methanol=20/1) ]Pyrimidin-3-one (182.4 mg, 58.9%) as a gray solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝554。1H NMR(400MHz,CDCl3)δ8.86(s,1H),7.95-7.70(m,3H),7.46(s,1H),7.41-7.35(m,1H),7.24(dd,J＝8.2,2.1Hz,1H),7.08(d,J＝8.3Hz,1H),5.72(dd,J＝17.0,10.3Hz,1H),5.06(dd,J＝10.2,1.0Hz,1H),4.95(dd,J＝17.1,1.1Hz,1H),4.78(d,J＝6.2Hz,2H),3.99(s,1H),2.90(d,J＝4.6Hz,1H),2.84(dd,J＝8.0,4.2Hz,2H),2.43(dd,J＝15.5,10.4Hz,4H),2.32(d,J＝6.9Hz,2H),2.09-1.98(m,3H),1.68-1.58(m,10H),1.53-1.40(m,3H).

Example 87

The first step:

6-nitro-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (215 mg,1 mmol) (as the compound of formula I-87-a) and N, N-diisopropylethylamine (0.2 ml) were added to 15ml of dichloromethane and stirred until clear. 1-methyl-piperidin-4-one (170 mg,1.5 mmol), sodium borohydride acetate (422 mg,2 mmol) and 0.3ml acetic acid were then added and stirred at room temperature for 40h. The reaction solution was concentrated through a column {3mol/L aminomethylol (dichloromethane: ethyl acetate=5:1) =0-15% }, to obtain 185mg of a brown target product. The yield thereof was found to be 67%. LC-MS: m/z [ M+1 ]] ⁺ ＝276。

And a second step of:

2- (1-methylpiperidine)4-yl) -6-nitro-1, 2,3, 4-tetrahydroisoquinoline (180 mg,0.65 mmol) (compound of formula I-87-b) and Raney Nickel (0.2 g) were added to 30ml of ethanol, then hydrazine hydrate (0.5 ml) was slowly added dropwise to the solution, and after the dropwise addition was stirred at room temperature for 2 hours. The reaction solution was concentrated by filtration to give 150mg of crude product, which was used directly in the next step. The yield thereof was found to be 93%. LC-MS: M/z: [ M+1 ]] ⁺ ＝246。

And a third step of:

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

The reaction solution was concentrated, and then 2- (1-methylpiperidin-4-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (150 mg,0.61 mmol) (as the compound of formula I-87-c), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide were added thereto, followed by stirring at 60℃for 24 hours. 10ml of saturated aqueous sodium carbonate solution and 15ml of water were added to the above reaction solution, extraction was performed three times (3 x 20 ml) with methylene chloride, the organic phases were combined, washed with 20ml of water and 20ml of saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate and concentrated to obtain a crude product, the obtained crude product was separated once by a thin layer chromatography plate {3M methanolic ammonia (methylene chloride: ethyl acetate=1:1) =1:10 }, and then prepared by a high performance liquid phase to obtain 110mg of yellow solid in 44% yield. LC-MS: M/z (M+H) ⁺ ＝555， ¹ H NMR(400MHz,MeOD)δ8.84(s,1H),8.37(s,2H),8.02(t,J＝7.9Hz,1H),7.81(d,J＝7.6Hz,1H),7.73–7.65(m,2H),7.42(d,J＝8.2Hz,1H),7.08(d,J＝8.4Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.94(d,J＝J＝17.0,1.3Hz,1H),4.83(d,J＝6.1Hz,2H),3.98(s,2H),3.54(d,J＝12.5Hz,2H),3.12(t,J＝5.9Hz,2H),3.00(m,5H),2.82(s,3H),2.27(d,J＝12.6Hz,2H),1.99(dd,J＝22.9,11.1Hz,2H),1.60(s,6H).

Example 88

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridine-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) (a compound represented by the formula I-88-a), tetrahydro-4H-pyran-4-one (100 mg,1 mmol) and sodium acetate (60 mg,0.44 mmol) are added to 30ml of methanol. Sodium cyanoborohydride (110 mg,1.75 mmol) was then added and stirred at room temperature for 48h. The reaction solution was concentrated through a column {3mol/L aminomethylol (dichloromethane: ethyl acetate=5:1) =0-15% }, to give 70mg of a white target product. The yield thereof was found to be 59%. LC-MS: M/z (M+H) ⁺ ＝542，1H NMR(400MHz,CDCl3:MeOH＝3:1)δ8.85(s,1H),7.93(t,J＝7.9Hz,1H),7.79(d,J＝8.0Hz,1H),7.58(s,1H),7.54(d,J＝7.7Hz,1H),7.35(d,J＝8.3Hz,1H),7.04(d,J＝8.4Hz,1H),5.69(dq,J＝10.3,6.1Hz,1H),5.05(d,J＝10.2Hz,1H),4.92(d,J＝17.1Hz,1H),4.81(d,J＝5.9Hz,2H),4.16–4.03(m,2H),3.81(s,2H),3.47(t,J＝11.5Hz,2H),2.92(d,J＝4.4Hz,4H),2.72(dd,J＝15.4,7.3Hz,1H),1.93(d,J＝11.6Hz,2H),1.72(qd,J＝12.3,4.4Hz,2H),1.60(s,6H).

Example 103

The first step:

n- (5-oxo-5-, 6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (59 mmol) (a compound represented by the formula I-103-a) was dissolved in toluene (200 mL), and placed in a closed tube, ethyl glyoxylate (118 mmol), p-toluenesulfonic acid (5.9 mmol) and magnesium sulfate (395 mmol) were added to the reaction solution, and the reaction solution was heated to 120℃and stirred for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=100/0-50/50) to give ethyl (E) -2 (6-acetamido-1-oxo-3, 4-dihydronaphthalene-2 (1H) -methylene) acetate (9.5 g, 56%) as a target compound as a yellow solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝288。

And a second step of:

ethyl (E) -2 (6-acetamido-1-oxo-3, 4-dihydronaphthalene-2 (1H) -methylene) acetate (31 mmol) (a compound represented by the formula I-103-b) was dissolved in methanol (100 mL), pd/C (900 mg) and concentrated sulfuric acid (1.0 mL) were added to the reaction solution, and the reaction solution was subjected to hydrogen gasStirring is carried out for 18 hours. The reaction solution was adjusted to ph=9 with saturated sodium carbonate solution, pd/C was removed by filtration, the reaction solution was evaporated to dryness, water and ethyl acetate were used for layering, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, the crude product was evaporated to dryness to give crude product, the crude product was washed with ethyl acetate, filtered, and purified by column chromatography (petroleum ether/ethyl acetate=100/0-50/50) to give the objective compound 6- (piperidine-1-methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (4.0 g, 46.0%) as a white solid. LC-MS: M/z: [ M+1 ] ] ⁺ ＝276。

And a third step of:

6- (piperidin-1-methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (a compound represented by the formula I-103-c) (15.0 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0℃under the protection of liquid nitrogen, lithium aluminum (29 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours after the addition. The reaction solution was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the target compound N- (6- (2-hydroxyethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (2.70 g, 80.0%) was purified by column chromatography (petroleum ether/ethyl acetate=100/0-50/50) as a white solid. LC-MS: m/z [ M+1 ]] ⁺ ＝234。

Fourth step:

n- (6- (2-hydroxyethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (12 mmol) (a compound represented by formula I-103-d) was dissolved in methylene chloride (30 mL), and triethylamine (46 mmol), N, N-dimethylpyridin-4-amine (5.8 mmol) and p-toluenesulfonyl chloride (23 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. To the reaction was added 1N hydrochloric acid (200 mL), the mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the target compound, ethyl 2- (6-acetamido-1, 2,3, 4-tetrahydronaphthalen-2-yl) 4-methylbenzenesulfonate (2.40 g, 54.0%) was purified by column chromatography (petroleum ether/ethyl acetate=100/0-30/70) as a white solid. LC-MS: M/z: [ M+1 ] ] ⁺ ＝388。

Fifth step:

ethyl 2- (6-acetamido-1, 2,3, 4-tetrahydronaphthalen-2-yl) 4-methylbenzenesulfonate (1.03 mmol) (a compound represented by formula I-103-e) was dissolved in methanol (10 mL),sodium methoxide (2.07 mmol) was added thereto, and the reaction solution was heated to 50℃and stirred for 16 hours. The reaction solution was evaporated to dryness, and the target compound N- (6- (2-methoxyethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (250 mg, 97.93%) was purified by column chromatography (petroleum ether/ethyl acetate=100/0-50/50) as a yellow oil. LC-MS: M/z: [ M+1 ]] ⁺ ＝248。

Sixth step:

n- (6- (2-methoxyethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (1.01 mmol) (a compound represented by formula I-103-f) was dissolved in ethanol (10 mL), concentrated hydrochloric acid (10 mL) was added, and the reaction mixture was heated to reflux and stirred for 16 hours. The reaction solution was evaporated to dryness to give crude title compound 6- (2-methoxyethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (160 mg, 77.09%) as a gray solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝206。

Seventh step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-D]Pyrimidine-3-one (compound shown as formula 1A) (0.28 mmol) was dissolved in toluene (15 mL), m-chloroperoxybenzoic acid (0.31 mmol) was added, the reaction solution was stirred at room temperature for 0.5 hours, the reaction solution was evaporated to dryness, the obtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10 mL), 6- (piperidine-1-methyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (0.34 mmol) (compound shown as formula I-103-g) and trifluoroacetic acid (0.5 mL) were added, and the reaction solution was heated to 60℃and stirred for 16 hours. The reaction solution was adjusted to ph=9 with saturated sodium carbonate solution, water (50 mL) ethyl acetate (50 mL) was added, the layers were separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the liquid phase was prepared and purified to give the objective 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-pyrazole [3,4-d ]Pyrimidin-3-one (32 mg, 22.22%) as a gray solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝515。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.81(t,J＝38.9Hz,3H),7.53-7.36(m,2H),7.07(s,1H),5.72(s,1H),5.02(dd,J＝42.8,13.2Hz,2H),4.80(s,2H),3.55(t,J＝6.3Hz,2H),3.42-3.36(m,3H),2.89(d,J＝21.4Hz,3H),2.53-2.39(m,1H),1.96(d,J＝26.2Hz,4H),1.75-1.66(m,3H),1.61(s,6H).

Example 114

The first step:

6-nitro-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (214 mg,1 mmol) (as the compound of formula I-114-a), tert-butyl 3-oxoazetidine-1-carboxylate (190 mg,1.1 mmol), sodium borohydride acetate (428 mg,2 mmol) and N, N-diisopropylethylamine (0.5 ml) were added to 15ml of dichloromethane and stirred overnight at 70℃in a closed tube. The reaction solution was concentrated by column (ethyl acetate: petroleum ether=0-50%) to give 300mg of a pale yellow target product. The yield thereof was found to be 90%. LC-MS: M/z: [ M+1 ]] ⁺ ＝334。

And a second step of:

tert-butyl 3- (6-nitro-3, 4-dihydroisoquinolin-2 (1H) -yl) azetidine-1-carboxylate (300 mg,0.9 mmol) (compound of formula I-114-b) and 3ml trifluoroacetic acid were added sequentially to 3ml dichloromethane and stirred overnight at room temperature. After the reaction solution was concentrated, 10ml of 7mol/L ammonia methanol was added, followed by concentration to obtain 200mg of crude product, which was directly used in the next step. The yield thereof was found to be 95%. LC-MS: M/z: [ M+1 ]] ⁺ ＝234。

And a third step of:

2- (azetidin-3-yl) -6-nitro-1, 2,3, 4-tetrahydroisoquinoline (180 mg,0.77 mmol) (compound of formula I-114-c), 37% aqueous formaldehyde (0.2 ml) and sodium borohydride acetate (340 mg,1.6 mmol) were added to 15ml methanol and stirred overnight at room temperature. After the reaction solution was concentrated, 20ml of methylene chloride and 2ml of methanol were added, and the mixture was washed with 5ml of a saturated sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated to give 175mg of a white solid. The yield thereof was found to be 91%. LC-MS: M/z: [ M+1 ] ] ⁺ ＝248。

Fourth step:

2- (1-Methylaza-3-yl) -6-nitro-1, 2,3, 4-tetrahydroisoquinoline (170 mg,0.69 mmol) (a compound represented by the formula I-114-d) and Raney Nickel (0.2 g) were added to 30ml of ethanol, then hydrazine hydrate (0.5 ml) was slowly added dropwise to the solution, and after the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated by filtrationCrude product is obtained. The yield thereof was found to be 93%. LC-MS: M/z: [ M+1 ]] ⁺ ＝218。

Fifth step:

to a solution of 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) (compound of formula 1A) in 15ml of toluene was added m-chloroperoxybenzoic acid (100 mg,0.45 mmol), and the resulting solution was stirred at room temperature for 2 hours.

The reaction solution was concentrated, and then 2- (1-methylazein-3-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (90 mg,0.41 mmol) (as the compound represented by the formula I-114-e), 0.2ml trifluoroacetic acid and 5ml dimethyl sulfoxide were added thereto, followed by stirring at 60℃for 24 hours. 10ml of saturated aqueous sodium carbonate solution and 15ml of water are added to the reaction solution, extraction is carried out three times (3 x 20 ml) by methylene chloride, organic phases are combined, 20ml of water and 20ml of saturated aqueous sodium chloride solution are respectively used for washing, anhydrous sodium sulfate is dried and then concentrated to obtain crude products, {3M ammonia methanol (methylene chloride: ethyl acetate=1:1) =0-15% } is firstly separated by a thin layer chromatography plate, and then 65mg of yellow solid is prepared by using a high-efficiency liquid phase, and the yield is 31%. LC-MS: M/z (M+H) ⁺ ＝527， ¹ H NMR(400MHz,CDCl ₃ )δ8.84(s,1H),8.42(s,1H),7.92(t,J＝8.1Hz,1H),7.78(d,J＝8.0Hz,1H),7.64–7.54(m,2H),7.39(dd,J＝8.2,2.0Hz,1H),7.01(d,J＝8.1Hz,1H),5.76–5.61(m,1H),5.04(dd,J＝10.2,1.1Hz Hz,1H),4.91(dd,J＝17.0,1.2Hz,1H),4.82(d,J＝6.2Hz,2H),4.42–4.32(m,2H),3.87–3.76(m,2H),3.54(m,3H),2.94(t,J＝5.8Hz,2H),2.88(s,3H),2.68(t,J＝5.9Hz,2H),1.59(s,6H).

Example 115

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (400 mg,1.78 mmol) (compound of formula I-115-a) was dissolved in 18mL of methanol, followed by addition of ammonium acetate (1368 mg,17.8 mmol), stirring at room temperature for 2 hours, and then addition of sodium cyanoborohydride (120 mg,1.91 mmol), stirring at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, 30ml of water was added thereto, and 1mol/L of water was usedThe pH was brought to acidity with hydrochloric acid and extracted twice with 30ml of dichloromethane each time. The aqueous phase is brought to a pH of the base (pH=10-11) with 1mol/L sodium hydroxide solution. Three extractions with 40ml of dichloromethane each time. The organic phase was washed with 30ml of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step. A reddish brown oil (197mg, 0.87 mmol) was obtained in 48% yield. LC-MS: M/z (M+H) ⁺ ＝226.0，228.0。

And a second step of:

6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-amine (97 mg,0.43 mmol) (compound of formula I-115-b) was dissolved in 10ml of methylene chloride, and sodium carbonate (182 mg,1.72 mmol) was added thereto, and the reaction was stirred at room temperature for 18 hours. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and extraction was performed twice with 30ml of methylene chloride each time. The combined organic layers were concentrated and the resulting crude product was purified by column (ethyl acetate: petroleum ether=0-33%) to give a brown oil (90 mg,0.30 mmol) in 71% yield. LC-MS: M/z (M+H) ⁺ ＝297.1,299.1。

And a third step of:

3- (6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-yl) -1, 1-dimethylurea (90 mg,0.30 mmol) (compound of formula I-115-c), benzophenone imine (60 mg,0.33 mmol), sodium t-butoxide (58 mg,0.60 mmol), pd ₂ (dba) ₃ (14 mg,0.015 mmol) and BINAP (19 mg,0.03 mmol) were added to 10ml toluene, purged three times with argon, and then heated to 100deg.C for 16h. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 10%) to obtain a brown oil (76 mg,0.19 mmol) in 63% yield. LC-MS: M/z (M+H) ⁺ ＝398.3。

Fourth step:

3- (6- ((benzhydryl) amino-1, 2,3, 4-tetrahydronaphthalen-2-yl) -1, 1-dimethylurea (76 mg,0.19 mmol) (compound of formula I-115-d) was dissolved in 10ml methanol, then sodium acetate trihydrate (78 mg,0.57 mmol) and hydroxylamine hydrochloride (29 mg,0.42 mmol) were added, and the reaction mixture was heated to 60℃for 6 hours ⁺ ＝234.2。

Fifth step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (70 mg,0.2 mmol) (compound represented by formula 1A) to a solution of 15ml of toluene was added m-chloroperoxybenzoic acid (48 mg,0.22 mmol), and the resulting solution was stirred at room temperature for 1 hour, and the solvent was distilled off to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] ]Crude pyrimidin-3-one. To the above-obtained solution was added 5mL of dimethyl sulfoxide, 1mL of trifluoroacetic acid, 3- (6-amino-1, 2,3, 4-tetrahydronaphthalen-2-yl) -1, 1-dimethylurea (44 mg,0.19 mmol) (compound represented by formula I-115-e), and stirred at 60℃for 24 hours. The crude product was isolated and purified by thin layer chromatography (7M methanolic ammonia: dichloromethane=0-10%) to give the title compound as a yellow solid in 30% yield, 31 mg. 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＝8.0Hz,1H),7.64(d,J＝7.7Hz,2H),7.36(d,J＝7.4Hz,1H),7.01(d,J＝8.3Hz,1H),6.11(d,J＝7.5Hz,1H),5.67(ddd,J＝16.4,10.9,6.1Hz,1H),5.00(d,J＝10.5Hz,1H),4.82(d,J＝17.5Hz,1H),4.70(d,J＝5.7Hz,2H),3.80(s,1H),2.89(dd,J＝16.4,4.6Hz,2H),2.81(s,6H),2.69–2.52(m,2H),2.04–1.94(m,1H),1.71–1.56(m,1H),1.47(s,6H)。

Example 116

The first step:

6-bromo-1, 2,3, 4-tetrahydroisoquinoline (740 mg,3.49 mmol) (as a compound represented by formula I-114-a), tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g,5.4 mmol), sodium borohydride acetate (1.5 g,7.1 mmol) and acetic acid (0.2 ml) were added to 35ml of dichloromethane and stirred overnight at room temperature. The organic layer was washed with 20ml of saturated sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography (dichloromethane: triethylamine=100:1) to give 850mg of brown solid. The yield thereof was found to be 64%. LC-MS: M/z: [ M+1 ]] ⁺ ＝381。

And a second step of:

3- (6-bromo-3, 4-dihydroisoquinolin-2 (1H) -yl) pyrrolidine-1-carboxylic acid tert-butyl ester (850 mg,2.2 mmol) (compound of formula I-114-b) and 5ml trifluoroacetic acid were added sequentially to 5ml dichloromethane and stirred overnight at room temperature. After the reaction solution was concentrated, 50ml of methylene chloride and 5ml of methanol were added, and the mixture was washed with 10ml of a saturated sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated to obtain 600mg of a crude brown oil, which was used directly in the next step. The yield thereof was found to be 95%. LC-MS: M/z: [ M+1 ] ] ⁺ ＝281。

And a third step of:

6-bromo-2- (pyrrolidin-3-yl) -1,2,3, 4-tetrahydroisoquinoline (600 mg,2.1 mmol) (compound represented by formula I-114-c), 37% aqueous formaldehyde (1 ml) and sodium borohydride acetate (900 mg,4.24 mmol) were added to 35ml of methanol and stirred at room temperature overnight. After the reaction solution was concentrated, 20ml of methylene chloride and 2ml of methanol were added, and the mixture was washed with 5ml of a saturated sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated to give 530mg of a brown oil. The yield thereof was found to be 84%. LC-MS: M/z: [ M+1 ]] ⁺ ＝295。

Fourth step:

6-bromo-2- (1-methylpyrrolidin-3-yl) -1,2,3, 4-tetrahydroisoquinoline (530 mg 1.8 mmol) (compound represented by formula I-114-d), benzophenone imine 360mg (2 mmol), sodium tert-butoxide 260mg (2.7 mmol), pd ₂ (dba) ₃ 65mg (0.07 mmol) of BINAP (115 mg,0.185 mmol) was added to 35ml of toluene, purged three times with argon, and then heated to 110℃overnight. The reaction solution was concentrated, and the crude product was purified by column chromatography [7M methanolic ammonia (dichloromethane: ethyl acetate=2:1) =0-10%]540mg of brown oil was obtained in 76% yield. LC-MS: M/z: [ M+1 ]] ⁺ ＝396。

Fifth step:

n- (2- (1-methylpyrrolidin-3-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -1, 1-benzophenone imine (540 mg,1.365 mmol) (a compound represented by formula I-114-e) was dissolved in 40ml of methanol, then sodium acetate 0.56g (6.83 mmol) and hydroxylamine hydrochloride (190 mg,2.73 mmol) were added and the reaction was heated to 60℃overnight. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (7M methanolic ammonia: dichloromethane=0-15%) to obtain 260mg of brown oil, yield 82%. LC-MS: m/z: [M+1] ⁺ ＝232。

Sixth step:

to a solution of 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) (compound of formula 1A) in 15ml of toluene was added m-chloroperoxybenzoic acid (106 mg,0.47 mmol), and the resulting solution was stirred at room temperature for 2 hours.

The reaction solution was concentrated, and then 2- (1-methylpyrrolidin-3-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (130 mg,0.56 mmol) (as the compound represented by the formula I-114-f), 0.2ml of trifluoroacetic acid and 5ml of dimethyl sulfoxide were added thereto, followed by stirring at 60℃for 24 hours. To the above reaction solution, 10ml of saturated aqueous sodium carbonate solution and 15ml of water were added, extraction was performed three times (3 x 20 ml) with methylene chloride, the organic phases were combined, washed with 20ml of water and 20ml of saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, and the obtained crude product was separated twice by a thin layer chromatography plate {7M methanolic ammonia (methylene chloride: ethyl acetate=2:1) =1:9 }, to obtain 160mg of white solid in a yield of 68%. LC-MS: M/z (M+H) ⁺ ＝541,1H NMR(400MHz,MeOD)δ8.84(s,1H),8.02(t,J＝7.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.68(d,J＝7.7Hz,1H),7.63(s,1H),7.36(d,J＝8.2Hz,1H),7.03(d,J＝8.4Hz,1H),5.73(ddt,J＝16.4,10.3,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.90-4.94(d,J＝17.0,1.2Hz,,1H),4.84(d,J＝6.1Hz,2H),3.72–3.60(m,2H),3.12(m,2H),2.97–2.83(m,4H),2.74(m,1H),2.55(dd,J＝16.5,9.1Hz,1H),2.50–2.39(m,4H),2.18(m,1H),1.92(m,1H),1.60(s,6H).

Example 117

The first step:

ethyl 2- (6-acetamido-1, 2,3, 4-tetrahydronaphthalen-2-yl) 4-methylbenzenesulfonate (1.03 mmol) (a compound represented by formula I-117-a) was dissolved in acetonitrile (10 mL), and morpholine (3.10 mmol) and potassium carbonate (4.13 mmol) were added to the reaction solution, which was heated to 50℃and stirred for 16 hours. Filtering the reaction solution, evaporating the filtrate to dryness to obtain a crude product, and purifying the crude product by column chromatography (petroleum ether/ethyl acetate) Ethyl acetate=100/0-50/50) to give the target compound N- (6- (2-morpholinoethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (230 mg, 73.7%) as a white solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝303。

And a second step of:

n- (6- (2-morpholinoethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) acetamide (0.76 mmol) (as shown in formula I-117-b) was dissolved in ethanol (10 mL), sodium hydroxide (10 mL,10 mol/L) was added to the reaction solution, and the reaction solution was heated to reflux and stirred for 18 hours. The reaction solution was separated by water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was evaporated to dryness to give the crude target compound 6- (2-morpholinoethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (152 mg, 76.7%) as a gray solid. LC-MS: M/z: [ M+1 ]] ⁺ ＝261。

And a third step of:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-D]Pyrimidine-3-one (0.28 mmol) (compound of formula 1A) was dissolved in toluene (15 mL), 3-chloroperoxybenzoic acid (0.31 mmol) was added, the reaction solution was stirred at room temperature for 0.5 hours, the reaction solution was evaporated to dryness, the obtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10 mL), 6- (2-morpholinoethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-amine (compound of formula I-117-c) (0.31 mmol) and trifluoroacetic acid (0.5 mL) were added, and the reaction solution was heated to 60℃and stirred for 16 hours. The reaction solution was adjusted to ph=9 with saturated sodium carbonate solution, water (50 mL) ethyl acetate (50 mL) was added, the layers were separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the liquid phase was prepared and purified to give the objective compound 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (6- (2-morpholinoethyl) -5-,6-,7-, 8-tetrahydronaphthalen-2-yl) amino-1, 2-dihydro-3H-pyrazolo [3,4-D ]Pyrimidin-3-one (68 mg, 42.6%) as a white solid. LC-MS: M/z: [ M+H ]] ⁺ ＝570。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.93-7.80(m,2H),7.49-7.35(m,2H),7.26(d,J＝2.2Hz,1H),7.05(d,J＝8.3Hz,1H),5.72(d,J＝6.7Hz,1H),5.01(ddd,J＝18.2,13.6,1.0Hz,2H),4.78(d,J＝6.2Hz,2H),3.80(s,2H),2.85(dd,J＝8.4,4.4Hz,2H),2.70-2.39(m,4H),2.00(d,J＝12.2Hz,1H),1.83(s,1H),1.64(d,J＝19.4Hz,4H),1.54-1.42(m,1H).

Example 119

The first step:

6-bromo-3, 4-dihydronaphthalen-2 (1H) -one (200 mg,0.89 mmol) (compound of formula I-119-a) was dissolved in 10mL of methylene chloride, and benzylamine (0.14 mL,1.33 mmol) and sodium triacetylborohydride (753 mg,3.55 mmol) were added thereto and the reaction was stirred at room temperature for 16H. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and extraction was performed twice with 30ml of methylene chloride each time. The combined organic layers were concentrated and the resulting crude product was purified by column (ethyl acetate: petroleum ether=0-33%) to give a brown oil (140 mg,0.44 mmol) in 50% yield. LC-MS: M/z (M+H) ⁺ ＝316.0，318.0。

And a second step of:

n-benzyl-6-bromo-1, 2,3, 4-tetrahydronaphthalen-2-amine (140 mg,0.44 mmol) (compound represented by formula I-119-b) was dissolved in 10ml of methanol, then acetaldehyde (0.1 ml) and sodium cyanoborohydride (140 mg,2.22 mmol) were added, and the reaction was stirred at room temperature for 18 hours. After concentrating the reaction solution under reduced pressure, 30ml of water was added, and extraction was performed twice with 30ml of methylene chloride each time. The combined organic layers were concentrated and the resulting crude product was purified by column (ethyl acetate: petroleum ether=0-33%) to give a brown oil (102 mg,0.30 mmol) in 67% yield. LC-MS: M/z (M+H) ⁺ ＝344.1,346.1。

And a third step of:

N-benzyl-6-bromo-N-ethyl-1, 2,3, 4-tetrahydronaphthalen-2-amine (102 mg,0.30 mmol) (compound of formula I-119-c), benzophenone imine (58 mg,0.32 mmol), sodium t-butoxide (56 mg,0.60 mmol), pd ₂ (dba) ₃ (13 mg,0.015 mmol) and BINAP (18 mg,0.03 mmol) were added to 10ml toluene, purged three times with argon, and then heated to 100deg.C for 16h. The reaction solution was concentrated, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 10%) to obtain a brown oil (72 mg,0.16 mmol) in 54% yield. LC-MS: M/z (M+H) ⁺ ＝445.3。

Fourth step:

n-benzyl-6- ((benzhydryl) amino) -N-ethyl1,2,3, 4-tetrahydronaphthalen-2-amine (72 mg,0.16 mmol) (compound of formula I-119-d) was dissolved in 10ml of methanol, followed by addition of sodium acetate trihydrate (66 mg,0.48 mmol) and hydroxylamine hydrochloride (25 mg,0.36 mmol) and heating to 60℃for reaction for 6 hours. The reaction solution was concentrated by filtration, and the obtained crude product was purified by column chromatography (methanol: dichloromethane=0 to 20%) to obtain a brown oil (45 mg,0.16 mmol) in 99% yield. LC-MS: M/z (M+H) ⁺ ＝281.2。

Fifth step:

2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (53 mg,0.15 mmol) (compound represented by formula 1A) to a solution of 15ml of methylene chloride was added m-chloroperoxybenzoic acid (37 mg,0.16 mmol), and the resulting solution was stirred at room temperature for 1 hour, and the solvent was distilled off to give 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] ]Dichloromethane solution of pyrimidin-3-one. DIPEA (0.08 ml) and N2-benzyl-N2-ethyl-1, 2,3, 4-tetrahydronaphthalene-2, 6-dimethylamine (compound of formula I-119-e) (44 mg,0.19 mmol) were added to the above-obtained solution, and stirred at 60℃for 24 hours. The crude product was purified by thin layer chromatography (7M methanolic ammonia: dichloromethane=0-10%) to give the title compound 51mg as a yellow solid in 58% yield. 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＝8.0Hz,1H),7.67(d,J＝7.7Hz,1H),7.52(s,1H),7.40(d,J＝7.1Hz,2H),7.35–7.20(m,4H),7.02(d,J＝8.3Hz,1H),5.80–5.65(m,1H),5.04(dd,J＝10.2,1.1Hz,1H),4.92(dd,J＝17.1,1.3Hz,1H),4.83(d,J＝6.0Hz,2H),3.77(s,2H),3.08(s,1H),2.84(dt,J＝11.9,10.6Hz,4H),2.77–2.65(m,2H),2.14(d,J＝10.0Hz,1H),1.71(dd,J＝11.9,5.5Hz,1H),1.60(s,6H),1.09(t,J＝7.1Hz,3H)。

Referring to the above examples, the compounds shown in table 1 were prepared, and their structural characterization is as follows:

table 1 list of examples

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Effect example 1

1. In vitro inhibitory action of Compounds on WEE1 kinase

The testing method comprises the following steps:

test compounds were screened on WEE1 kinase using ELISA at ATP concentration of Km. Screening of 3 compounds on WEE1 kinase was performed to evaluate the kinase inhibitory activity of the test compounds. In the detection process, the initial concentration of the tested compound is 100nM, 6 gradient dilution concentrations are selected for each compound, the gradient dilution multiple is 4 times, and detection is carried out by 2 compound wells per concentration, and MK-1775 is used as a standard control.

WEE1, available from Carna biosciences, inc., cat: 05-177; dimethyl sulfoxide, available from Sigma-Aldrich under the designation: d8418; ATP, purchased from Sigma-Aldrich, cat#: a7699; DTT solution, purchased from Sigma-Aldrich, cat number: 43816; protein Tyrosine Kinase (PTK) substrate (poly-Glu-Tyr), available from Sigma-Aldrich under the designation: p4476; P-Tyr (PY 99), available from Santa Cruz, cat: sc-7020; anti-mouse IgG HRP-linked Anti-body, available from Santa Cruz, cat: 7076S; TMB liquid Substrate System from Sigma-Aldrich, cat: t0440; costar Stripwell Microplate No Lid 1X 8Flat Bottom,Certified High Binding, from Sigma-Aldrich, cat: 42592; 96-well compound plate, purchased from Thermo Scientific, cat: 267245.

The testing steps are as follows:

1. coating a substrate: 1) An appropriate volume of substrate stock Protein Tyrosine Kinase (PTK) substrate (poly-Glu-Tyr) was taken, diluted 10-fold with PBS, and the concentration was diluted from 250mg/mL to 25mg/mL. Add to high adsorption 96 well plates, 125 μl per well. The mixture was placed in an incubator at 37℃overnight for coating. 2) After 24 hours, the 96-well plate is taken out, the liquid in the 96-well plate is poured out, the 96-well plate is washed 3 times by using a washing buffer, and the incubator at 37 ℃ is inverted and dried for 2 hours.

2. Preparation and transfer of the compound: 1) Compound dilution: taking 10mM of test compound stock solution, diluting the compound in multiple steps by using DMSO in a 96-well compound plate to obtain a compound with an initial concentration of 100X, and then taking the compound with the concentration as the first concentration, and carrying out 4-time gradient dilution by using DMSO for 6 concentrations; then respectively taking 2 mu L of gradient diluent and adding the gradient diluent into 48 mu L of 1 Xreaction buffer solution to prepare 4 Xcompounds for later use; 2) Transfer of 4 x compound: transferring 10 μl of 4×compound from the 96-well compound plate prepared in the above step into a dried high adsorption 96-well plate; 10 μl of the following liquids were added to the compound-free control wells and ATP-control wells: mu.L of DMSO was added to 48. Mu.L of 1 Xreaction buffer.

3. Enzyme reaction stage: 1) WEE1 kinase and ATP were prepared as a 2X enzyme solution and a 4X ATP solution in a 1X reaction buffer, respectively. Wherein in this screen, the final concentration of WEE1 kinase is: 0.15 ng/. Mu.L, final ATP concentration: 12. Mu.M; 2) 20. Mu.L of 2 enzyme solution was added to the high adsorption 96 well plate; 3) To the high adsorption 96-well plate, 10. Mu.L of 4 XATP solution was added, and 10. Mu.L of 1 Xreaction buffer was added to the ATP-control blank; 4) After centrifugation at 2000rpm for 20s in a HERAEUS Multifuge X R centrifuge, the plates were left to react at room temperature for 60min.

4. Reaction termination stage: 1) Pouring out the reaction liquid in the plate, adding 200 mu L of washing buffer into each hole, and washing for 5 times; primary antibody P-Tyr (PY 99) (dilution ratio 1:2000) was added at 100 μl per well for 30min at room temperature. 2) The primary antibody in the plate was removed, 200. Mu.L of washing buffer was added to each well, and the plate was washed 5 times; secondary Antibody-mouse IgG HRP-linked Antibody (dilution ratio 1:2000) was added at 100. Mu.L per well for 30min at room temperature. 3) The secondary antibody in the plate is poured out, washed 5 times by a washing buffer, TMB is added, and the color development is carried out for 10-30 min according to the color depth at each hole of 100 mu L. The reaction was quenched with 1N sulfuric acid prior to reading.

5. Detection and data processing: 1) Light absorption at wavelength 450nM is read on ThermoScientific MultiScan GO while background is read at 650 nM. 2) The corresponding IC50 was calculated using a Graphpad Prism 5.0 curve fit to the data at Log (inhibitor) vs. response-Variable slope (four parameters) (half maximal inhibitory concentration).

2. In vitro inhibition of COLO 205 cell lines by Compounds

The testing method comprises the following steps:

the inhibition of proliferation of the p 53-deleted cell line COLO 205 by the compounds was examined using the Luminescence ATP Detection method. 4 compounds were screened on cell lines to evaluate the inhibitory activity of the test compounds on proliferation of the cell lines in vitro. In the detection process, the initial concentration of the tested compound is 10 mu M, 9 gradient dilution concentrations are selected, the gradient dilution multiple is 3 times, and detection is carried out by 2 compound wells per concentration, and MK-1775 is used as a standard control.

COLO 205, human colon cancer cells, purchased from the cell bank of the chinese academy, catalog number: TCHu102; ATPlite 1step Single Addition Luminescence ATP Detection Assay system, available from perkinelmer, cat: 6016739; RPMI 1640, available from GIBCO, cat#: a10491-01; strep/pen, available from GIBCO, cat: 15240-062; fetal bovine serum FBS, purchased from GIBCO, cat No.: 10099-141;96 well black bottom permeabilized cell culture plates, available from Corning under the designation: 3603; 96-well compound plate, purchased from Thermo Scientific, cat: 267245.

the testing steps are as follows:

1. cell culture and inoculation: taking normal cultured cells, digesting and dispersing in the exponential growth state, and regulating cell density to 8.8X10 ³ cells/mL，90 μl per well was inoculated into 96 well cell culture plates; after inoculation, the microplate was placed at 37℃with 5% CO ₂ Is cultured under the condition of (2);

2. drug addition treatment of cells: the microwell plates were removed from the incubator and 10 μl of each compound was added to each well in the microwell plate, 2 multiplex wells per dosing concentration, 9 dosing concentrations per compound. According to different cell lines, the initial concentration of each compound is different, and after completion, the microplate is placed at 37 ℃ with 5% CO ₂ Is cultured for 72 hours under the condition of (2);

3. and (3) collecting data: the microplate was removed from the incubator and equilibrated at room temperature for 30min. Adding 100 mu.l of ATPlaite reaction solution after room temperature equilibration into each well, vibrating for 2min at 1300rpm at room temperature, and then placing the microplates into a HERAEUS Multifuge X R centrifuge for centrifugation at 2000rpm for 1min; after equilibration at room temperature for 10min, the fluorescence signal values were determined on an envision (tm).

4. The in vitro inhibitory activity of the compounds was calculated according to the following formula:

cell proliferation inhibition rate: inhibition (%) = (signal value control-signal value administration)/signal value control×100%. And based on the inhibition ratios of the respective concentrations, 50% inhibition concentrations (50%inhibitory concentration,IC) ₅₀ ). Cell viability calculation: cell availability (%) = signal value dosing/signal value control x 100%. Corresponding IC was calculated by performing Log (inhibitor) vs. response-Variable slope (four parameters) curve fitting using Graphpad Prism 5.0 on the fluorescence signal values at each concentration ₅₀ (half maximal inhibitory concentration)。

3. In vitro inhibition of 5-FU treated COLO 205 cell lines by Compounds

The testing method comprises the following steps:

the present report uses the Luminescence ATP Detection method to examine the inhibitory effect of compounds on proliferation of 5-FU treated p 53-deleted cell line COLO 205. 4 compounds were screened on the cell line to evaluate the inhibitory activity of the test compounds on proliferation of the cell line in vitro after combination with 5-FU. In the detection process, the initial concentration of 5-FU is selected to be 100 mu M, 9 gradient dilution concentrations are selected, the gradient dilution multiple is 3 times, 2 compound holes are used for detection at each concentration, and the tested compound adopts the combined action of 5-FU with the concentration of 300nM and 100nM respectively at 9 concentrations. MK-1775 served as a standard control.

COLO 205, human colon cancer cells, purchased from the cell bank of the chinese academy, catalog number: TCHu102; ATPlite 1step Single Addition Luminescence ATP Detection Assay system, available from perkinelmer, cat: 6016739; RPMI 1640, available from GIBCO, cat#: a10491-01; strep/pen, available from GIBCO, cat: 15240-062; fetal bovine serum FBS, purchased from GIBCO, cat No.: 10099-141;96 well black bottom permeabilized cell culture plates, available from Corning under the designation: 3603; 96-well compound plate, purchased from Thermo Scientific, cat: 267245;

The testing steps are as follows:

1. cell culture and inoculation: taking normal cultured cells, digesting and dispersing in the exponential growth state, and regulating cell density to 8.8X10 ³ cells/mL, 90. Mu.L per well was inoculated in 96 well cell culture plates; after inoculation, the microplate was placed at 37℃with 5% CO ₂ Is cultured under the condition of (2);

2. drug addition treatment of cells: taking out the microplate from the incubator, adding 10×5-FU into each well of the microplate, adding 10 μl of each well, wherein each administration concentration is 2 multiple wells, adding 9 administration concentration controls of each compound into culture medium containing DMSO at the same ratio, and placing the microplate at 37deg.C and 5% CO ₂ Is cultured for 72 hours under the condition of (2);

3. drug addition treatment of cells: the microwell plates were removed from the incubator, 3300nM or 1100nM compound (11 Xcompound) was added to each of 9 gradient 5-FU treated cells in the microwell plates and control wells, 10. Mu.L of each well was added, and after completion the microwell plates were placed at 37℃with 5% CO ₂ Is cultured for 72 hours under the condition of (2);

4. and (3) collecting data: the microplate was removed from the incubator and equilibrated at room temperature for 30min. Adding 100 mu L of ATPlaite reaction solution after room temperature equilibration into each hole, vibrating for 2min at 1300rpm at room temperature, and then placing the microplates into a HERAEUS Multifuge X R centrifuge for centrifugation at 2000rpm for 1min; after equilibration at room temperature for 10min, the fluorescence signal values were determined on an envision (tm).

5. The in vitro inhibitory activity of the compounds was calculated according to the following formula:

4. And testing result 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 shown in Table 3.

TABLE 3WEE1 enzyme inhibitory Activity and cytostatic Activity test results

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Claims

1. Pyrazolopyrimidine compound shown as formula I or pharmaceutically acceptable salt thereof is characterized in that,

wherein X is 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, 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, unsubstituted or R ^1-17 Substituted C ₂ ～C ₇ Alkenyl, unsubstituted or R ^1-18 Substituted C ₂ ～C ₈ Alkynyl, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ", or unsubstituted or R ^1-24 Substituted C ₁ ～C ₇ An alkoxy group;

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ Alkyl or C ₃ ～C ₇ Cycloalkyl;

all R ^1-4 And R is ^1-7 Independently C ₁ ～C ₇ Alkyl, halogen substituted C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, 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 is ^1-4-2 Independently hydrogen or C ₁ ～C ₇ An alkyl group;

all R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 And R is ^1-24 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkylsilyl, unsubstituted or R ^1-16-7 Substituted C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, C ₁ ～C ₇ Alkoxy, -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 Independently is hydroxy, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms being one or more of oxygen, sulfur and nitrogen, C having 1-4 hetero atoms ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of oxygen, sulfur and nitrogen, C having 1-4 heteroatom 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 is ^1-16-5-5 Independently is hydrogen, unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ Alkyl orC ₂ ～C ₇ Alkynyl;

all R ^1-16-5-1-1 Independently is hydroxy or C ₃ ～C ₇ Cycloalkyl;

z is 0.

2. Pyrazolopyrimidine compound I or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R ¹ Is R ^1-16 Substituted C ₁ ～C ₇ In the case of alkyl, said R ^1-16 Is one or more, when there are a plurality of R ^1-16 When said R is ^1-16 The same or different;

and/or when R ¹ Is unsubstituted or R ^1-16 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An alkyl group;

and/or when R ¹ Is R ^1-17 Substituted C ₂ ～C ₇ In the case of alkenyl, said R ^1-17 Is one or more, when there are a plurality of R ^1-17 When said R is ^1-17 The same or different;

and/or when R ¹ Is unsubstituted or R ^1-17 Substituted C ₂ ～C ₇ In the case of alkenyl, said C ₂ ～C ₇ Alkenyl group is C ₂ ～C ₄ Alkenyl groups;

and/or when R ¹ Is R ^1-18 Substituted C ₂ ～C ₈ In the case of alkynyl, R is as follows ^1-18 Is one or more, when there are a plurality of R ^1-18 When said R is ^1-18 The same or different;

and/or when R ¹ Is unsubstituted or R ^1-18 Substituted C ₂ ～C ₈ In the case of alkynyl, said C ₂ ～C ₈ Alkynyl is C ₂ ～C ₄ Alkynyl;

and/or when R ¹ Is R ^1-20 Substituted C ₃ ～C ₇ In the case of cycloalkyl, said R ^1-20 Is one or more, when there are a plurality of R ^1-20 When said R is ^1-20 The same or different;

and/or when R ¹ Is unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ In the case of cycloalkyl, said C ₃ ～C ₇ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R ¹ Is R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When heterocycloalkyl ", said R ^1-21 Is one or more, when there are a plurality of R ^1-21 When said R is ^1-21 The same or different;

and/or when R ¹ Is unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "is" heteroatom is nitrogen and/or oxygen, C having 1-2 heteroatoms ₃ ～C ₅ Heterocycloalkyl ";

and/or when R ¹ Is R ^1-24 Substituted C ₁ ～C ₇ In the case of alkoxy, said R ^1-24 Is one or more, when there are a plurality of R ^1-24 When said R is ^1-24 The same or different;

and/or when R ^1-1 、R ^1-2 Or R is ^1-3 Is unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An alkyl group;

and/or when R ^1-4 Or R is ^1-7 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An alkyl group;

and/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ In the case of alkyl groups, the number of halogens is one or more, whenWhen a plurality of halogens exist, the halogens are the same or different;

and/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ In the case of alkyl groups, the "halogen" is independently fluorine, chlorine, bromine or iodine;

and/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An alkyl group;

and/or when R ^1-4 Or R is ^1-7 Is C ₂ ～C ₇ In the case of alkynyl, said C ₂ ～C ₇ Alkynyl is C ₂ ～C ₄ Alkynyl;

and/or when R ^1-4 Or R is ^1-7 Is C ₁ ～C ₇ In the case of alkoxy, said C ₁ ～C ₇ Alkoxy is C ₁ ～C ₄ An alkoxy group;

and/or when R ^1-4-1 Or R is ^1-4-2 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An alkyl group;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 When halogen, the halogen is fluorine, chlorine, bromine or iodine;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is C ₁ ～C ₇ In the case of the silyl group, the C ₁ ～C ₇ The alkyl silicon group is trimethyl silicon group;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When heterocycloalkyl ", said R ^1-16-6 Is one or more, when there are a plurality of R ^1-16-6 When said R is ^1-16-6 The same or different;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "is" heteroatom is nitrogen and/or oxygen, C having 1-2 heteroatoms 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 is ^1-16-7 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An alkyl group;

and/or when R ^1-16-5 Is "hetero atom is one or more of oxygen, sulfur and nitrogen, C with hetero atom number of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclyl "is" heteroatom is one or more of oxygen, sulfur and nitrogen, C with 1-4 heteroatom number ₃ ～C ₇ Heterocycloalkyl, and which is attached "to the carbonyl group through a nitrogen atom;

and/or when R ^1-16-5 The hetero atom being halogenated is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When a plurality of halogens exist, the halogens are the same or different;

and/or when R ^1-16-5 The hetero atom being halogenated is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl group is, the halogen is independently fluorine, chlorine or bromine;

And/or when R ^1-16-5 Is halogenated "hetero atom is oxygenOne or more of sulfur and nitrogen, C having 1-4 hetero atoms ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl is "heteroatom is nitrogen and the number of heteroatoms is 1-2C ₃ ～C ₇ Heterocycloalkyl, and which is attached "to the 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 is ^1-16-5-5 Is R ^1-16-5-1-1 Substituted C ₁ ～C ₇ In the case of alkyl, said R ^1-16-5-1-1 Is one or more, when there are a plurality of R ^1-16-5-1-1 When said R is ^1-16-5-1-1 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 is ^1-16-5-5 Is unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is C ₁ ～C ₄ An 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 is ^1-16-5-5 Is C ₂ ～C ₇ In the case of alkynyl, said C ₂ ～C ₇ Alkynyl is C ₂ ～C ₄ Alkynyl groups.

3. Pyrazolopyrimidine compound I or a pharmaceutically acceptable salt thereof according to claim 2, wherein when R ¹ Is R ^1-16 Substituted C ₁ ～C ₇ Alkyl, and R is as described ^1-16 When the number of the (B) is more than 2, 3 or 4;

and/or when R ¹ Is unsubstituted or R ^1-16 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or when R ¹ Is R ^1-17 Substituted C ₂ ～C ₇ Alkenyl, and R is as described ^1-17 When the number of the (B) is more than 2, 3 or 4;

and/or when R ¹ Is unsubstituted or R ^1-17 Substituted C ₂ ～C ₇ In the case of alkenyl, said C ₂ ～C ₇ Alkenyl is 2-propenyl;

and/or when R ¹ Is R ^1-18 Substituted C ₂ ～C ₈ Alkynyl, and R is as described ^1-18 When the number of the (B) is more than 2, 3 or 4;

and/or when R ¹ Is unsubstituted or R ^1-18 Substituted C ₂ ～C ₈ In the case of alkynyl, said C ₂ ～C ₈ Alkynyl is 2-propynyl;

and/or when R ¹ Is R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl, and R is as described ^1-20 When the number of the (B) is more than 2, 3 or 4;

and/or when R ¹ Is unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ In the case of cycloalkyl, said C ₃ ～C ₇ Cycloalkyl is cyclobutyl;

and/or when R ¹ Is R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ", and R is said ^1-21 When the number of the (B) is more than 2, 3 or 4;

and/or when R ¹ Is unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl is "heteroatom is nitrogen and the number of heteroatoms is 1-2C ₃ ～C ₅ The heterocycloalkyl group "or" heteroatom "is oxygen,c having 1 to 2 hetero atoms ₃ ～C ₅ Heterocycloalkyl ";

and/or when R ¹ Is R ^1-24 Substituted C ₁ ～C ₇ Alkoxy, and R is as described ^1-24 When the number of the (B) is more than 2, 3 or 4;

and/or when R ^1-1 、R ^1-2 Or R is ^1-3 Is unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ^1-4 Or R is ^1-7 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ When the number of the halogen is more than 2, 3 or 4, the halogen is alkyl;

and/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ^1-4 Or R is ^1-7 Is C ₂ ～C ₇ In the case of alkynyl, said C ₂ ～C ₇ Alkynyl is 2-propynyl or 1-propynyl;

and/or when R ^1-4 Or R is ^1-7 Is C ₁ ～C ₇ In the case of alkoxy, said C ₁ ～C ₇ Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy；

And/or when R ^1-4-1 Or R is ^1-4-2 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl 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 ^1-20 、R ^1-21 Or R is ^1-24 When halogen, the halogen is fluorine;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ", and R is said ^1-16-6 When the number of the (B) is more than 2, 3 or 4;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl is "heteroatom is nitrogen and the number of heteroatoms is 1-2C ₃ ～C ₅ Heterocycloalkyl, C having 1 to 2 hetero atoms, in which the hetero atoms are oxygen 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 is ^1-16-7 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ^1-16-5 Is "hetero atom is one or more of oxygen, sulfur and nitrogen, C with hetero atom number of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "is

And/or when R ^1-16-5 The hetero atom being halogenated is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ", and R is said ^1-16-5 When the number of the (B) is more than 2, 3 or 4;

and/or when R ^1-16-5 The hetero atom being halogenated is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl group is, the 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 is ^1-16-5-5 Is R ^1-16-5-1-1 Substituted C ₁ ～C ₇ Alkyl, and R is as described ^1-16-5-1-1 When the number of the (B) is more than 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 is ^1-16-5-5 Is unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-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 is ^1-16-5-5 Is C ₂ ～C ₇ In the case of alkynyl, said C ₂ ～C ₇ Alkynyl is 2-propynyl or 1-propynyl.

4. Pyrazolopyrimidine compound I or a pharmaceutically acceptable salt thereof according to claim 3, wherein when R ¹ Is unsubstituted or R ^1-16 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when R ¹ Is unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ In the case of heterocycloalkyl, the heteroatom is nitrogen and the number of heteroatoms is C1-2 ₃ ～C ₅ Heterocyclylalkyl is "heteroatom is nitrogen and the number of heteroatoms is 1-2C ₃ ～C ₅ A heterocycloalkyl group wherein the heterocycloalkyl group is linked to Y through a nitrogen atom or a heteroatom is nitrogen, and the number of heteroatoms is 1 to 2C ₃ ～C ₅ Heterocycloalkyl, and the heterocycloalkyl is attached to Y through a carbon atom ";

and/or when R ¹ Is unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ In the case of heterocycloalkyl, the heteroatom is oxygen and the number of heteroatoms is C1-2 ₃ ～C ₅ Heterocyclylalkyl "is

And/or when R ^1-1 、R ^1-2 Or R is ^1-3 Is unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when R ^1-4 Or R is ^1-7 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl;

and/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl isA methyl group;

and/or when R ^1-4 Or R is ^1-7 Is C ₁ ～C ₇ In the case of alkoxy, said C ₁ ～C ₇ Alkoxy is methoxy;

and/or when R ^1-4-1 Or R is ^1-4-2 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ The hetero atom in the case of the heterocycloalkyl group is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "is

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 is ^1-16-7 Is C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl is methyl;

and/or when R ^1-16-5 The hetero atom being halogenated is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the halogenated heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclylalkyl "is

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 is ^1-16-5-5 Is unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ In the case of alkyl, said C ₁ ～C ₇ Alkyl groupIs methyl or ethyl.

5. Pyrazolopyrimidine compound I or a pharmaceutically acceptable salt thereof according to claim 4, wherein when R ¹ Is unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl, where the heterocycloalkyl is attached to Y through a nitrogen atom

And/or when R ¹ Is unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ The hetero atom in the case of the heterocycloalkyl group is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl, where the heterocycloalkyl is attached to Y through a carbon atom

And/or when R ^1-4 Or R is ^1-7 C substituted by halogen ₁ ～C ₇ In the case of alkyl, said halogen substituted C ₁ ～C ₇ Alkyl is trifluoromethyl;

and/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl, where the heterocycloalkyl is linked to other radicals through nitrogen atoms "is

And/or when R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 Or R is ^1-24 Is unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ When the heterocyclic alkyl is, the heteroatom is one or more of oxygen, sulfur and nitrogen, and the heteroatom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl, where the heterocycloalkyl is attached to other radicals through carbon atoms "is

6. Pyrazolopyrimidine compound I or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ¹ Is any one 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-trifluoroethyl, methoxyacyl, methylsulfonyl, 2-trifluoroacetyl, cyclobutyl, cyclopropylmethyl, cyclopropyl, diethylamino, di-n-propylamino, dimethylaminomethyl, methoxy, hydroxy, carboxymethyl,

7. Pyrazolopyrimidine compound I according to claim 1, or a pharmaceutically acceptable salt 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 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

and/or all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or R ^1-1-3 Substituted C ₁ ～C ₇ An alkyl group; all R ^1-1-1 、R ^1-1-2 And R is ^1-1-3 Independently C ₁ ～C ₇ Alkyl or C ₆ ～C ₁₀ An aryl group;

and/or all R ^1-4 And R is ^1-7 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 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-4-1 And R is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

and/or all R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, unsubstituted or R ^1-16-7 Substituted C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^1-16-1 R ^1-16-2 、-OR ^1-16-3 、-SR ^1-16-4 Or- (c=o) R ^1-16-5 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-1 、R ¹ ^-16-2 、R ^1-16-3 、R ^1-16-4 、R ^1-16-6 And R is ^1-16-7 Independently hydrogen or C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of oxygen, sulfur and nitrogen, and heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of oxygen, sulfur and nitrogen, C having 1-4 heteroatom ₃ ～C ₇ Heterocycloalkyl ",-NR ^1-16-5-1 R ^1-16-5-2 OR-OR ^1-16-5-3 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-5-1 、R ^1-16-5-2 、R ^1-16-5-3 、R ^1-16-5-4 And R is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl groups.

8. Pyrazolopyrimidine compound I according to claim 7, or a pharmaceutically acceptable salt thereof, wherein m and n are independently 0, 1, 2 or 3, and m+n is 3;

and/or Y is N, and R ¹ Wherein the atom attached to Y 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 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

and/or all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, -C (=o) NR ^1-1-1 R ^1-1-2 Or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group; all R ^1-1-1 And R is ^1-1-2 Independently C ₁ ～C ₇ An alkyl group;

and/or all R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ¹ ^-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^1-16-1 R ^1-16-2 、-OR ^1-16-3 、-SR ^1-16-4 Or- (c=o) R ^1-16-5 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-1 、R ^1-16-2 、R ^1-16-3 、R ^1-16-4 And R is ¹ ^-16-6 Independently hydrogen or C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of oxygen, sulfur and nitrogen, and heteroatom number is C of 1-4 ₃ ～C ₇ Heterocyclyl ", halogenated" heteroatom is one or more of oxygen, sulfur and nitrogen, C having 1-4 heteroatom ₃ ～C ₇ Heterocycloalkyl ",-NR ^1-16-5-1 R ^1-16-5-2 OR-OR ^1-16-5-3 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-5-1 、R ^1-16-5-2 、R ^1-16-5-3 、R ^1-16-5-4 And R is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl groups.

9. Pyrazolopyrimidine compound I according to claim 8, or a pharmaceutically acceptable salt thereof, wherein m and n are independently 1 or 2 and m+n is 3;

and/or all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group;

and/or all R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ¹ ^-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^1-16-1 R ^1-16-2 、-SR ^1-16-4 Or- (c=o) R ^1-16-5 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-1 、R ^1-16-2 、R ^1-16-4 And R is ^1-16-6 Independently hydrogen or C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of oxygen, sulfur and nitrogen, and heteroatom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ",or-NR ^1-16-5-1 R ^1-16-5-2 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-5-1 、R ^1-16-5-2 、R ¹ ^-16-5-4 And R is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl groups.

10. Pyrazolopyrimidine compound I according to claim 9, or a pharmaceutically acceptable salt thereof, wherein "m is 2, n is 1" or "m is 1, n is 2";

and/or all R ^1-1 And R is ^1-2 Independently hydrogen, or, unsubstituted or C ₆ ～C ₁₀ Aryl substituted C ₁ ～C ₇ An alkyl group;

and/or all R ^1-16 And R is ^1-21 Independently C ₁ ～C ₇ Alkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "or- (c=o) R ^1-16-5 The method comprises the steps of carrying out a first treatment on the surface of the All R ^1-16-6 Independently C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently isAll R ^1-16-5-4 And R is ^1-16-5-5 Independently C ₁ ～C ₇ An alkyl group.

11. Pyrazolopyrimidine compound I according to claim 1, or a pharmaceutically acceptable salt 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 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

All R ^1-4-1 And R is ^1-4-2 Independently C ₁ ～C ₇ An alkyl group;

all R ^1-16 And R is ^1-21 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ', NR', a ^1-16- ¹ R ^1-16-2 、-SR ^1-16-4 Or- (c=o) R ^1-16-5 ；

all R ^1-16-5 Independently is hydroxyl, heteroatom is one or more of oxygen, sulfur and nitrogen, and heteroatom number is C of 1-4 ₃ ～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 is ^1-16-5-5 C independently is hydrogen, unsubstituted or hydroxy ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl;

z is 0.

12. Pyrazolopyrimidine compound I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH;

m is 2, 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 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl ";

all R ^1-16 And R is ^1-21 Independently C ₁ ～C ₇ Alkyl, unsubstituted or R ^1-16-6 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "or- (c=o) R ^1-16-5 ；

All R ^1-16-6 Independently C ₁ ～C ₇ An alkyl group; all R ^1-16-5 Independently isAll R ¹ ^-16-5-4 And R is ^1-16-5-5 Independently C ₁ ～C ₇ An alkyl group;

z is 0.

13. Pyrazolopyrimidine compound I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is 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, 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, unsubstituted or R ^1-17 Substituted C ₂ ～C ₇ Alkenyl, unsubstituted or R ^1-18 Substituted C ₂ ～C ₈ Alkynyl, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl, unsubstituted or R ^1-21 The substituted hetero atom is one or more of oxygen, sulfur and nitrogen, and the hetero atom number is C of 1-4 ₃ ～C ₇ Heterocycloalkyl "or, optionally, R ^1-24 Substituted C ₁ ～C ₇ An alkoxy group;

all R ^1-1 、R ^1-2 And R is ^1-3 Independently hydrogen, C ₁ ～C ₇ Alkyl or C ₃ ～C ₇ Cycloalkyl;

all R ^1-4 And R ^1-7 Independently C ₁ ～C ₇ Alkyl, halogen substituted C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkoxy or NR ^1-4-1 R ^1-4-2 ；

all R ^1-16 、R ^1-17 、R ^1-18 、R ^1-20 、R ^1-21 And R is ^1-24 Independently halogen, cyano, C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, C ₁ ～C ₇ Alkyl silicon group, C ₃ ～C ₇ Cycloalkyl radicals, the hetero atoms being one or more of oxygen, sulfur and nitrogen, C having 1-4 hetero atoms ₃ ～C ₇ Heterocycloalkyl ", C ₆ ～C ₁₀ Aryl, C ₁ ～C ₇ Alkoxy, -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 Independently hydroxy, halogenated "heteroatom is one or more of oxygen, sulfur and nitrogen, C with 1-4 heteroatoms ₃ ～C ₇ Heterocycloalkyl ', NR', a ^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 is ^1-16-5-3 Independently is hydrogen, unsubstituted or R ^1-16-5-1-1 Substituted C ₁ ～C ₇ Alkyl, or C ₂ ～C ₇ Alkynyl;

all R ^1-16-5-1-1 Independently is hydroxy or C ₃ ～C ₇ Cycloalkyl groups.

14. Pyrazolopyrimidine compound I according to claim 1, or a pharmaceutically acceptable salt 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, cyano, -NR ^1-1 R ^1-2 、-OR ^1-3 、-C(＝O)R ^1-4 、-S(＝O) ₂ R ^1-7 、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 ^1-20 Substituted or unsubstituted C ₃ ～C ₇ Cycloalkyl, or, R ^1-24 Substituted or unsubstituted C ₁ ～C ₇ An alkoxy group;

R ^1-1 、R ^1-2 and R is ^1-3 Independently hydrogen, C ₁ ～C ₇ Alkyl or C ₃ ～C ₇ Cycloalkyl;

R ^1-4 and R is ^1-7 Independently C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl, or NR ^1-4-1 R ^1-4-2 ；

all R ^1-16-5 Independently a hydroxyl group.

15. Pyrazolopyrimidine compound I according to claim 1, or a pharmaceutically acceptable salt 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 is ^1-2 Independently C ₁ ～C ₇ An alkyl group;

R ^1-4 independently C ₁ ～C ₇ Alkyl or C ₂ ～C ₇ Alkynyl;

all R ^1-16 Independently cyano, -NR ^1-16-1 R ^1-16-2 OR-OR ^1-16-3 ；

z is 0.

16. Pyrazolopyrimidine compound or pharmaceutically acceptable salt thereof, wherein the pyrazolopyrimidine compound is any one of the following compounds:

/>

17. a process for the preparation of a compound I according to any one of claims 1 to 16, characterized in that it is any one of the following processes:

the method comprises the following steps:

wherein PG is an amino protecting group;

The second method is as follows:

and a third method:

when R is 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 ～C ₈ Alkynyl, or, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ When cycloalkyl, it comprises the steps of: in an organic solvent, in the presence of a reducing agent, the compounds 1E and R ¹ Performing reductive amination reaction on CHO to obtain a compound I;

wherein Y is N, said R ^1’ -CH ₂ -is equivalent to R ¹ ；

The method four:

when R is 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 ～C ₈ Alkynyl, unsubstituted or R ^1-20 Substituted C ₃ ～C ₇ Cycloalkyl, cyano or acetyl, comprising the steps of: in an organic solvent, in the presence of a base, the compounds 1E and R ¹ -X ¹ Carrying out substitution reaction to obtain a compound I;

wherein, X is ¹ Is halogen; y is N;

and a fifth method:

when R is ¹ is-C (=O) R ^1-4 And R is ^1-4 Is C ₁ ～C ₇ Alkyl, C ₂ ～C ₇ Alkenyl, C ₂ ～C ₇ Alkynyl or C ₃ ～C ₇ When cycloalkyl, it comprises the steps of: in an organic solvent, in the presence of a condensing agent, the compound 1E is mixed withPerforming condensation reaction to obtain a compound I;

Wherein Y is N.

18. A compound of formula 1D:

therein, PG, m, n, z, Y, R ¹ And R is ² Is as defined in any one of claims 1 to 17.

19. Use of a compound I as claimed in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of diseases which are associated with WEE1 kinase.

20. Use of a compound I as claimed in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of cancer.

21. A pharmaceutical composition comprising compound I as defined in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.