WO2025067466A1 - Heterocyclic compound, and composition and use thereof - Google Patents

Abstract

Provided in the invention are a heterocyclic compound, and a composition and use thereof. Specifically provided is a compound as shown in formula II or a pharmaceutically acceptable salt thereof. The compound of the present invention has one or more of the following advantages: a novel structure, can efficiently and selectively degrade IKZF2, can inhibit the function of regulatory T cells, and can apply to the treatment of tumors or diseases, and having huge clinical development value.

Description

A heterocyclic compound, its composition and application

This application claims the priority of Chinese patent application No. 2023112756095 filed on September 28, 2023. This application cites the entire text of the above Chinese patent application.

Technical Field

The invention relates to a heterocyclic compound, a composition and application thereof.

Background Art

The Ikaros protein family includes Ikaros (Ikzf1), Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4), and Pegasus (Ikzf5), which are hematopoietic-specific transcription factors involved in regulating the development of lymphocytes. IKZF2 forms homo- or heterodimers with other Ikaros family members and is believed to play a major role in hematopoietic development.

In regulatory T cells (Tregs), IKZF2 is highly expressed at the mRNA and protein levels; by binding to the promoter of FoxP3, the main transcriptional regulator of regulatory T cells, it affects the expression of FoxP3, thereby affecting the development and function of regulatory T cells. The function of IKZF2 in regulatory T cells is to maintain the inhibitory properties of regulatory T cells. Knocking out IKZF2 in regulatory T cells in mice causes activated regulatory T cells to lose their inhibitory properties and express effector T cell factors to exert effector T cell functions.

Regulatory T cells play a vital role in maintaining autoimmune tolerance, but the accumulation of regulatory T cells in the tumor microenvironment (TME) will inhibit anti-tumor immunity. Targeting regulatory T cells is an important direction for the development of tumor immunomodulators. Several clinical candidate drugs have entered the clinical development stage and made clinical progress, such as anti-TIGIT antibodies, anti-CCR4 antibodies, and anti-CTL4 antibodies targeting Tregs, which are used to enhance anti-tumor immune responses.

Immunomodulatory drugs (IMiDs) such as pomalidomide and lenalidomide induce degradation of IKZF1 and IKZF3 transcription factors. IMiDs do not bind IKZF1/3 by themselves, but by binding to CRBN E3 ligase, they form protein-small molecule complexes and generate complex surfaces. These newly formed complex surfaces recruit new substrates. IKZF1 and 3 are recruited to IMiD-bound CRBN and then labeled with ubiquitin, leading to proteasome degradation of IKZF1 and 3. Other proteins such as GSPT1 and IKZF2 can also be degraded by a similar approach.

Protein degraders targeting IKZF2 can inhibit Treg cell activity by degrading IKZF2, thereby inhibiting Treg cell-mediated immunosuppression and increasing the anti-tumor activity of tumor immunotherapy. Therefore, the development of protein degraders targeting Helios (IKZF2) has potential clinical application value.

Summary of the invention

The present invention provides a heterocyclic compound, a composition and an application thereof. The compound of the present invention has one or more of the following advantages: novel structure, can degrade IKZF2 efficiently and selectively, inhibit the function of regulatory T cells, can be used to treat tumors or diseases, and has great clinical development value.

The present invention provides a compound as shown in Formula II or a pharmaceutically acceptable salt thereof;

Where q is 0, 1, 2 or 3;

^R3 is H, -OH or halogen;

^Y1 is CR ^Y1 or N;

^Y2 is CR ^Y2 or N;

^Y3 is CR ^Y3 or N;

R ^Y1 , R ^Y2 and R ^Y3 are each independently H, NR ^a R ^b , OR ^a or halogen;

Q is CR ^Q1 R ^Q2 ;

R ^Q1 and R ^Q2 are independently H, deuterium or C ₁ -C ₆ alkyl;

^RX is H or deuterium;

Each R ¹ is independently C ₁ -C ₆ alkyl or halogen;

Ring A is a 3-12-membered heterocycloalkylene group or a 3-12-membered heterocycloalkenylene group; in the 3-12-membered heterocycloalkylene group and the 3-12-membered heterocycloalkenylene group, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N;

^R2 is _C3 - _C10 monocyclic cycloalkyl, _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3- _C10 monocyclic cycloalkyl substituted by one or more ^R2-1 , _C1 - _C6 alkyl substituted by one or more ^R2-2 , _3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or C5 _{-C10 polycyclic} cycloalkyl substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

Each R ^2-1 is independently OR ^a , -CONR ^a R ^b , CN, C ₃ -C ₁₀ cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl substituted ^{by one or more R 2-1-1 ,} C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each R ^2-4 is independently OR ^a , -CONR ^a R ^b , CN, C ₃ -C ₁₀ cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl substituted by one or more ^{R 2-1-1 ,} C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3. are independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each R ^2-1-1 is independently halogen, cyano, OR ^a , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens;

Each R ^2-1-2 is independently halogen, OR ^a , C ₃ -C ₁₀ cycloalkyl, 3-12 heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-12 membered heteroaryl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-1-3 is independently halogen, cyano, OR ^a , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens;

Each R ^2-2 is independently halogen, OR ^a , C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^2-2-1 , C ₅ -C ₁₀ polycyclic cycloalkyl substituted by one or more R ^2-2-2 , or 3-12 membered heterocycloalkyl substituted by one or more R ^2-2-3 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each R ^2-2-1 is independently halogen, OR ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₁ -C ₆ alkyl; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-2-2 is independently halogen, OR ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-2-3 is independently halogen, OR ^a , Oxo, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-3 is independently oxo (=O), -C(=O)OR ^a , -C(=O)R ^a , -CONR ^a R ^b , Halogen, OR ^a , CN, C ₃ -C ₁₀ cycloalkyl, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, 5-12 membered heteroaryl substituted by one or more ^Ra , C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 , or C ₁ -C ₆ alkyl substituted by one or more R ^2-3-2 ; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each R ^2-3-1 is independently halogen, cyano, OR ^a , or C ₁ -C ₆ alkyl substituted by one or more halogens;

Each R ^2-3-2 is independently halogen, OR ^a , C ₃ -C ₁₀ cycloalkyl, 3-12 heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-12 membered heteroaryl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each ^Ra is independently hydrogen, _C1 - _C6 alkyl, _C1 - _C6 alkyl substituted by one or more halogens, C3- _C10 cycloalkyl or _3-12 membered heterocycloalkyl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by one or more halogens, C ₃ -C ₁₀ cycloalkyl or 3-12 membered heterocycloalkyl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Alternatively, ^Ra , ^Rb and the atoms to which they are connected together form a 3-12 membered heterocycloalkyl group; in the 3-12 membered heterocycloalkyl group, the heteroatoms are selected from one, two or three of N, O and S, and the number of the heteroatoms is one, two or three.

In certain preferred embodiments of the present invention, certain groups in the compound of Formula II or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in some embodiments"),

In R ³ , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ^Y1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ^Y3 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ¹ , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In some embodiments, in R ¹ , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in ring A, the heteroatoms of the 3-12 membered heterocycloalkylene are independently one or two of N, O and S, and at least one heteroatom is N; the number of heteroatoms of the 3-12 membered heterocycloalkylene is preferably 1 or 2; The 12-membered heterocycloalkylene group is more preferably a 4-10-membered heterocycloalkylene group; further preferably a 4-7-membered monocyclic heterocycloalkylene group or a 7-10-membered bridged heterocycloalkylene group; for example For example

In some embodiments, in ring A, the heteroatoms of the 3-12-membered heterocycloalkenylene group are independently N, or N and O; the number of heteroatoms of the 3-12-membered heterocycloalkenylene group is preferably 1 or 2; the 3-12-membered heterocycloalkenylene group is more preferably a 6-10-membered heterocycloalkenylene group; further preferably a 6-membered monocyclic heterocycloalkenylene group or a 9-membered bridging heterocycloalkenylene group; for example For example

In some embodiments, in R ² , the C ₃ -C ₁₀ monocyclic cycloalkyl groups are independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, in R ² , the C ₅ -C ₁₀ polycyclic cycloalkyl groups are each independently For example

In some embodiments, in ^R2 , the heteroatoms of the 3-12 membered heterocycloalkyl are independently one or two of N, O and S; the number of heteroatoms of the 3-12 membered heterocycloalkyl is preferably one or two; the 3-12 membered heterocycloalkyl is more preferably a 4-10 membered heterocycloalkyl; further preferably a 4-7 membered monocyclic heterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl, a 7-10 membered bridged heterocycloalkyl or a 7-10 membered cyclic heterocycloalkyl; for example For example (For example and/or ),

In some embodiments, in R ² , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In some embodiments, in R ^2-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ^2-1 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl.

In some embodiments, in R ^2-1 , the heteroatoms of the 5-12 membered heteroaryl are independently N and/or O; the number of heteroatoms of the 5-12 membered heteroaryl is preferably 1 or 2; the 5-12 membered heteroaryl is more preferably a 6-9 membered heteroaryl; further preferably a 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl; for example For example

In some embodiments, in R ^2-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In some embodiments, in R ^2-4 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ^2-1-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In some embodiments, in R ^2-1-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ^2-1-2 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl.

In some embodiments, in R ^2-1-3 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in R ^2-2 , the C ₃ -C ₁₀ monocyclic cycloalkyl groups are independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, in R ^2-2-1 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl.

In some embodiments, in R ^2-3 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl.

In some embodiments, in R ^2-3 , the heteroatoms of the 5-12 membered heteroaryl are independently N and/or O; the number of heteroatoms of the 5-12 membered heteroaryl is preferably 1 or 2; the 5-12 membered heteroaryl is more preferably a 6-9 membered heteroaryl; and further preferably a 6-membered monocyclic heteroaryl; for example For example

In some embodiments, in R ^2-3-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, in ^Ra , the _C1 - _C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, isobutyl or tert-butyl.

In some embodiments, the C ₁ -C ₆ alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, isobutyl or tert-butyl.

In some embodiments, the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, the C ₃ -C ₁₀ monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, the C ₅ -C ₁₀ polycyclic cycloalkyl groups are each independently For example

In some embodiments, the heteroatoms of the 3-12 membered heterocycloalkyl are independently one or two of N, O and S; the number of heteroatoms of the 3-12 membered heterocycloalkyl is preferably one or two; the 3-12 membered heterocycloalkyl is more preferably a 4-10 membered heterocycloalkyl; further preferably a 4-7 membered monocyclic heterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl, a 7-10 membered bridged heterocycloalkyl or a 7-10 membered cyclic heterocycloalkyl; for example For example (For example and/or

In some embodiments, the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl.

In some embodiments, the heteroatoms of the 5-12 membered heteroaryl are independently N and/or O; the number of heteroatoms of the 5-12 membered heteroaryl is preferably 1 or 2; the 5-12 membered heteroaryl is more preferably a 6-9 membered heteroaryl; further preferably a 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl; for example For example

In some embodiments, the halogen in the C ₁ -C ₆ alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, the C ₁ -C ₆ alkyl groups in the C ₁ -C ₆ alkyl groups substituted by one or more halogens are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments, the C ₁ -C ₆ alkyl substituted by one or more halogens is preferably -CF ₃ .

In some embodiments, q is 0, 1 or 2; preferably 0 or 1; more preferably 0.

In some embodiments, ^R3 is H.

In some embodiments, ^Y1 is CR ^Y1 .

In some embodiments, ^Y2 is CR ^Y2 .

In some embodiments, ^Y3 is CR ^Y3 .

In some embodiments, R ^Y1 and R ^Y2 are independently H or halogen; preferably H.

In some embodiments, R ^Y3 is independently H or halogen.

In some embodiments, R ^Q1 and R ^Q2 are independently H or deuterium; preferably hydrogen.

In some embodiments, ^RX is H.

In some embodiments, each R ¹ is independently C ₁ -C ₆ alkyl or halogen; preferably C ₁ -C ₆ alkyl.

In some embodiments, ring A is a 3-12 membered heterocycloalkylene or a 3-12 membered heterocycloalkenylene; preferably a 3-12 membered heterocycloalkylene; in the 3-12 membered heterocycloalkylene and the 3-12 membered heterocycloalkenylene, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N; more preferably a 4-7 membered monocyclic heterocycloalkylene or a 7-10 membered bridged heterocycloalkylene; for example, a 4-7 membered monocyclic heterocycloalkylene, in the 4-7 membered monocyclic heterocycloalkylene and the 7-10 membered bridged heterocycloalkylene, the number of heteroatoms is independently 1 or 2, and the heteroatoms are independently selected from 1 or 2 of N, O and S, and at least one heteroatom is N.

In some embodiments, ^R2 is _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3- _C10 monocyclic cycloalkyl substituted by one or more ^R2-1 , _C1 - _C6 alkyl substituted by one or more ^R2-2 , _3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or C5-C10 polycyclic cycloalkyl substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 _or 3; preferably _C5 - _C10 polycyclic cycloalkyl, _7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl, or C5- _C10 substituted by one or more ^R2-4. ₁₀ -membered polycyclic cycloalkyl; in the 7-10-membered spirocyclic heterocycloalkyl and 7-10-membered bridged heterocycloalkyl, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently one or two.

In some embodiments, each R ^2-1 is independently -OH, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^2-1-1 , C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; preferably C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

In some embodiments, each R ^2-1-1 is independently C ₁ -C ₆ alkyl substituted with one or more halogens.

In some embodiments, each R ^2-1-2 is independently C ₆ -C ₁₀ aryl.

In some embodiments, each R ^2-1-3 is independently halogen.

In some embodiments, each R ^2-4 is independently halogen, OR ^a , or CN; preferably halogen.

In some embodiments, each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 .

In some embodiments, each R ^2-2-1 is independently C ₆ -C ₁₀ aryl.

In some embodiments, each R ^2-3 is independently oxo (=O), -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; preferably -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; more preferably C ₆ -C ₁₀ aryl or -C(＝O)OR ^a ; In the 5-12 membered heteroaryl group, the heteroatoms are selected from one, two or three of N, O and S, and the number of the heteroatoms is one, two, three or four.

In some embodiments, each R ^2-3-1 is independently halogen or OR ^a ; preferably halogen.

In some embodiments, each ^Ra is independently _C1 - _C6 alkyl or H.

In some embodiments, the pharmaceutically acceptable salt of the compound of Formula II may be a formate salt.

In some embodiments, q is 0, 1 or 2;

^R3 is H, -OH or halogen;

^Y1 is CR ^Y1 ;

^Y2 is CR ^Y2 ;

^Y3 is CR ^Y3 ;

R ^Y1 , R ^Y2 and R ^Y3 are each independently H or halogen;

Q is CR ^Q1 R ^Q2 ;

R ^Q1 and R ^Q2 are independently H;

^RX is H;

Each R ¹ is independently C ₁ -C ₆ alkyl or halogen;

Ring A is a 3-12-membered heterocycloalkylene group or a 3-12-membered heterocycloalkenylene group; in the 3-12-membered heterocycloalkylene group and the 3-12-membered heterocycloalkenylene group, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N;

R ² is C ₅ -C ₁₀ polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^2-1 , C ₁ -C ₆ alkyl substituted by one or more R ^2-2 , 3-12 membered heterocycloalkyl substituted by one or more R ^2-3 , or C ₅ -C ₁₀ polycyclic cycloalkyl substituted by one or more R ^2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each R ^2-1 is independently -OH, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^2-1-1 , C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-1-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more halogens;

Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group;

Each R ^2-1-3 is independently halogen;

each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 ;

Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group;

Each R ^2-3 is independently oxo (=O), -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-3-1 is independently halogen or OR ^a ;

Each R ^2-4 is independently halogen, OR ^a , or CN; preferably halogen;

Each ^Ra is independently _C1 - _C6 alkyl or H.

In some embodiments, q is 0 or 1;

^R3 is H, -OH or halogen;

^Y1 is CR ^Y1 ;

^Y2 is CR ^Y2 ;

^Y3 is CR ^Y3 ;

R ^Y1 and R ^Y2 are each independently H;

^RY3 is H or halogen;

Q is CR ^Q1 R ^Q2 ;

R ^Q1 and R ^Q2 are independently H;

^RX is H;

Each R ¹ is independently C ₁ -C ₆ alkyl;

Ring A is a 3-12 membered heterocycloalkylene group; in the 3-12 membered heterocycloalkylene group, the number of heteroatoms is independently 1, 2 or 3, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N;

^R2 is _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3-C10 monocyclic cycloalkyl substituted by one or _more ^R2-1 , C1- _C6 alkyl substituted by one or more ^R2-2 , 3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or _{C5 -C10 polycyclic cycloalkyl} substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

Each R ^2-1 is independently a C ₆ -C ₁₀ aryl group or a C ₁ -C ₆ alkyl group substituted by one or more R ^2-1-2 ;

Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group;

each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 ;

Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group;

Each R ^2-3 is independently -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Each R ^2-3-1 is independently halogen;

Each R ^2-4 is independently halogen, OR ^a , or CN; preferably halogen;

Each ^Ra is independently _C1 - _C6 alkyl or H.

In some embodiments, the compound represented by Formula II is a compound represented by the following Formula II-1:

in,

R ³ is H, -OH or halogen; preferably H;

^Y3 is CR ^Y3 ;

R ^Y3 is independently H or halogen;

^RX is H;

Ring A is a 4-7 membered monocyclic heterocycloalkylene group or a 7-10 membered bridged heterocycloalkylene group; in the 4-7 membered monocyclic heterocycloalkylene group and the 7-10 membered bridged heterocycloalkylene group, the number of heteroatoms is independently 1 or 2, the heteroatoms are independently 1 or 2 of N, O and S, and at least one heteroatom is N; preferably a 4-7 membered monocyclic heterocycloalkylene group; in the 4-7 membered monocyclic heterocycloalkylene group, the number of heteroatoms is independently 1 or 2, the heteroatoms are independently 1 or 2 of N, O and S, and at least one heteroatom is N;

^R2 is _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3-C10 monocyclic cycloalkyl substituted by one or _more ^R2-1 , C1- _C6 alkyl substituted by one or more ^R2-2 , 3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or _{C5 -C10 polycyclic cycloalkyl} substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably _C5 - _C10 polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl, or _C5 -C10 substituted by one or more ^R2-4 . ₁₀ -membered polycyclic cycloalkyl; in the 7-10-membered spirocyclic heterocycloalkyl and 7-10-membered bridged heterocycloalkyl, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently one or two;

Each R ^2-1 is independently a C ₆ -C ₁₀ aryl group or a C ₁ -C ₆ alkyl group substituted by one or more R ^2-1-2 ;

Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group;

Each R ^2-4 is independently halogen;

each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 ;

Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group;

Each R ^2-3 is independently C ₆ -C ₁₀ aryl or -C(═O)OR ^a ;

Each ^Ra is independently a _C1 - _C6 alkyl group.

In some embodiments, ^R2 is

In some embodiments, for

In some embodiments, for

In some embodiments, ^Rx is H.

In some embodiments, the compound shown in Formula II is any of the following structures:

In some embodiments, IKZF2 degradation (Hibit) DC ₅₀ is ≥50nM; the maximum degradation rate at 1μM is ≥50%; or, IKZF2 degradation (Hibit) DC ₅₀ is <50nM; the maximum degradation rate at 1μM is ≥50%; the IKZF2 degradation (WB) and IKZF2 degradation (Hibit) are measured under the test conditions of Effect Examples 1 and 2.

In some embodiments, the pharmaceutically acceptable salt of the compound shown in Formula II is any of the following structures:

In some embodiments, IKZF2 degradation (WB) DC ₅₀ is <100nM; the maximum degradation rate at 1μM is ≥75%; or, IKZF2 degradation (Hibit) DC ₅₀ is <50nM; the maximum degradation rate at 1μM is ≥50%; the IKZF2 degradation (WB) and IKZF2 degradation (Hibit) are measured under the test conditions of Effect Examples 1 and 2.

The present invention also provides a compound as shown in Formula III or a pharmaceutically acceptable salt thereof;

wherein q, R ¹ , Ring A, R ³ , Y ¹ , Y ² , Y ³ , Q and ^RX are as defined above;

R ⁵ is H, -C(=O)-OR ^5-1 or a C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^5-2 ;

R ^5-1 is C ₁ -C ₆ alkyl;

Each R ^5-2 is independently a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₀ aryl group substituted by one or more R ^2-5-1 ;

Each R ^2-5-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more halogens.

In some embodiments, R ⁵ is H,

In some embodiments, the compound shown in Formula III is any of the following structures:

The present invention also provides a compound as shown in formula IV:

q, R ¹ , Ring A and R ⁵ are as defined above;

R ⁶ is oxo (=O) or

In some embodiments, the compound as shown in Formula IV is any of the following structures:

The present invention also provides the following compounds

The present invention also provides a pharmaceutical composition, which comprises a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

The present invention also provides a use of a substance Z in the preparation of a protein degradation agent targeting IKZF2 or a drug for treating and/or preventing diseases related to IKZF2, wherein the substance Z is a compound as shown in formula II or a pharmaceutically acceptable salt thereof.

The present invention also provides a use of a substance Z or the above-mentioned pharmaceutical composition in the preparation of a protein degradation agent targeting IKZF2 or a drug for treating and/or preventing diseases related to IKZF2, wherein the substance Z is a compound as shown in formula II or a pharmaceutically acceptable salt thereof.

In some embodiments, the IKZF2-related disease is one or more of a tumor, a disease caused by infection with a virus, bacteria or other pathogen, or a disease associated with human aging; the tumor is preferably one or more of head and neck cancer, cervical cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer, rectal cancer, hepatocellular carcinoma, glioma, kidney cancer, neuroblastoma, sarcoma, lung cancer, ovarian cancer, bladder cancer, pancreatic cancer, melanoma, breast cancer, triple-negative breast cancer, nasopharyngeal cancer, bone cancer, brain cancer, spinal cord cancer, melanoma, meningioma, prostate cancer, uterine cancer, lymphoma and myeloid leukemia.

The present invention also provides a method for treating and/or preventing diseases related to IKZF2, comprising administering an effective amount of substance Z to a patient, wherein the substance Z is a compound as shown in formula II or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating and/or preventing diseases related to IKZF2, comprising administering an effective amount of substance Z or the above-mentioned pharmaceutical composition to a patient, wherein substance Z is a compound as shown in formula II or a pharmaceutically acceptable salt thereof.

The present invention also provides an application of a substance Z in the preparation of a medicine, wherein the substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

The present invention also provides a use of a substance Z or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

In some embodiments, the drug is used to treat one or more of tumors, diseases caused by infection with viruses, bacteria or other pathogens, or diseases associated with human aging; the tumor is preferably head and neck cancer, cervical cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer, One or more of cancer, colorectal cancer, hepatocellular carcinoma, glioma, renal cancer, neuroblastoma, sarcoma, lung cancer, ovarian cancer, bladder cancer, pancreatic cancer, melanoma, breast cancer, triple-negative breast cancer, nasopharyngeal cancer, bone cancer, brain cancer, spinal cord cancer, melanoma, meningioma, prostate cancer, uterine cancer, lymphoma and myeloid leukemia.

Terminology

Unless otherwise specified, the terms used in the present invention have the following meanings:

In the present invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

In the present invention, the structural fragment It means that the structural fragment is connected to the rest of the molecule through this bond. For example, It refers to pyridyl.

In the present invention, the term "one or more" refers to 1, 2, 3, 4 or 5, such as 1, 2 or 3.

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

The term "oxo" refers to =0, where an oxygen atom replaces two hydrogen or sulfur lone pairs of electrons on the same carbon atom, i.e., a carbonyl group replaces a methylene group or a Sulfur replacement.

In the present invention, the term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₁ -C ₆ ). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

In the present invention, the term "alkoxy" refers to the group R ^Y -O-, and R ^Y is defined the same as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like.

In the present invention, the term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group with a specified number of carbon atoms (e.g., C ₃ -C ₆ ), which is a monocyclic or polycyclic group (e.g., polycyclic groups are 2 or 3 rings). When the "cycloalkyl" is polycyclic, it is a spirocyclic cycloalkyl, a paracyclic cycloalkyl, or a bridged cycloalkyl, etc., preferably a spirocyclic cycloalkyl, wherein the monocyclic groups share one carbon atom. Cycloalkyl groups include, but are not limited to: wait.

In the present invention, the term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 3-12, 4-10, 5, 6, 7, 8 or 9 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S), which is a monocyclic or polycyclic group (e.g., a polycyclic group having 2 or 3 rings). When the "heterocycloalkyl" is polycyclic, it is preferably a cycloheterocycloalkyl, a spirocycloheterocycloalkyl or a bridged-ring heterocycloalkyl; more preferably, a spirocycloheterocycloalkyl and a bridged-ring heterocycloalkyl. The monocyclic rings of the spirocycloheterocycloalkyl share one carbon atom; the monocyclic rings of the bridged-ring heterocycloalkyl share two or more carbon atoms and/or heteroatoms. The spirocycloheterocycloalkyl and the bridged-ring heterocycloalkyl are separated by a ring having a heteroatom or a ring without a heteroatom. The heterocycloalkyl group is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl groups include but are not limited to: wait.

In the present invention, the term "heterocycloalkylene" refers to a cyclic, saturated divalent group having a specified number of ring atoms (e.g., 3-12, 4-10, 5, 6, 7, 8 or 9), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), which is a monocyclic or polycyclic ring (e.g., a polycyclic ring is 2 or 3 rings). When the "heterocycloalkylene" is polycyclic, it is preferably a sub-cycloheterocycloalkylene, a sub-spirocycloheterocycloalkylene or a sub-bridged ring heterocycloalkylene; more preferably a sub-bridged ring heterocycloalkylene. The monocyclic rings of the sub-spirocycloheterocycloalkylene share one carbon atom; the monocyclic rings of the sub-bridged ring heterocycloalkylene share two or more carbon atoms and/or heteroatoms. The sub-spirocycloheterocycloalkylene and the sub-bridged ring heterocycloalkylene are connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the sub-heterocycloalkylene is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkylene includes, but is not limited to: wait.

In the present invention, the term "aryl" refers to a cyclic, unsaturated hydrocarbon group with a specified number of carbon atoms (e.g., C ₆ -C ₁₀ ), which is monocyclic or polycyclic (e.g., polycyclic is 2 or 3 rings). When it is polycyclic, the monocyclics share two atoms and one bond, and each ring has aromaticity. Aryl includes, but is not limited to, phenyl, naphthyl, etc.

In the present invention, the term "heteroaryl" refers to a cyclic, unsaturated group having a specified number of ring atoms (e.g., 5-12 members, 5-6 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S), which is monocyclic or polycyclic (e.g., polycyclic is 2 or 3 rings). When it is polycyclic, the monocyclic rings share two atoms and a bond, and at least one ring is aromatic. The heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties. Heteroaryl groups include but are not limited to wait.

In the present invention, the term "heterocycloalkenyl" refers to a ring having a specified number of ring atoms (eg, 3-12, 6-10, 6 or 9), A cyclic, unsaturated, monovalent hydrocarbon group with a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), having one or more (e.g., 1, 2, or 3) carbon-carbon ^sp2 double bonds, being monocyclic or polycyclic (e.g., polycyclic is 2 or 3 rings), and not aromatic. When the "heterocycloalkenyl" is polycyclic, it is preferably a cyclic heterocycloalkyl, a spirocyclic heterocycloalkyl, or a bridged heterocycloalkenyl, etc.; more preferably a bridged heterocycloalkenyl. The monocyclic rings of the bridged heterocycloalkenyl share two or more carbon atoms and/or heteroatoms, and the bridged heterocycloalkenyl is connected to the rest of the molecule through a ring with a double bond or a ring without a double bond; the bridged heterocycloalkenyl is connected to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom; the heterocycloalkenyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyl includes, but is not limited to: wait.

In the present invention, the term "heterocycloalkenylene" refers to a cyclic, unsaturated divalent hydrocarbon group having a specified number of ring atoms (e.g., 3-12, 6-10, 6 or 9), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), which has one or more (e.g., 1, 2 or 3) carbon-carbon ^sp2 double bonds, is monocyclic or polycyclic (e.g., polycyclic is 2 or 3 rings), and is not aromatic. When the "heterocycloalkenylene" is polycyclic, it is preferably a sub-heterocycloalkylene, a sub-spirocycloalkylene or a sub-bridged heterocycloalkenylene, etc.; more preferably a sub-bridged heterocycloalkenylene. The monocyclic rings of the sub-bridged heterocycloalkenyl group share two or more carbon atoms and/or heteroatoms; the sub-bridged heterocycloalkenyl group is connected to the rest of the molecule through a ring with a double bond or a ring without a double bond; the sub-bridged heterocycloalkenyl group is connected to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom; the sub-bridged heterocycloalkenyl group is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyl groups include but are not limited to wait.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

The positive progressive effect of the present invention is that the compounds of the present application can degrade IKZF2 efficiently and highly selectively, and are expected to inhibit the function of regulatory T cells by degrading the level of IKZF2, so that the immune system can more effectively attack tumors or diseases, and can be used to treat tumors or diseases, and have great clinical development value.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

Synthesis Examples of Intermediates

Synthesis of M1

Under nitrogen atmosphere, M1-1 (1.0 g, 3.1 mmol) and diboronic acid pinacol ester (0.9 g, 3.7 mmol) were added to DMF (N,N-dihydropyridine). KOAc (potassium acetate, 0.9 g, 9.3 mmol) and Pd(dppf)Cl ₂ ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 0.33 g, 0.45 mmol) were added to a solution of methylformamide (10 mL), and the mixture was reacted at 100°C for 16 hours. The mixture was returned to room temperature, diluted with 50 mL of water, extracted with EA (ethyl acetate, 100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography [DCM (dichloromethane)/MeOH (methanol)] to obtain a white solid M1 (1 g, yield 87%), LCMS m/z＝371.1[M+H] ⁺ .

Synthesis of M2

Under nitrogen atmosphere, NBS (N-bromosuccinimide, 10.95 g, 62 mmol) was added to a solution of M2-1 (7.0 g, 56 mmol) in ACN (acetonitrile, 70 mL), and the mixture was reacted at room temperature for 1 hour. 100 mL of water was added for dilution, and the mixture was extracted with DCM (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE (petroleum ether)/EA) to give a white solid M2-2 (4.2 g, yield 37%), LCMS m/z=204.0 [M+H] ⁺ .

Under nitrogen atmosphere, cuprous cyanide (6.88 g, 73.52 mmol) was added to a DMF (80 mL) solution of M2-2 (5.0 g, 24.51 mmol), and the mixture was reacted at 140° C. for 16 hours. The mixture was returned to room temperature, diluted with 100 mL of water, extracted with DCM (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE/EA) to give a white solid M2-3 (2.0 g, yield 54%), LCMS m/z=151.1[M+H] ⁺ .

Under nitrogen atmosphere, copper bromide (5.94 g, 26.64 mmol) and tert-butyl nitrite (2.74 g, 26.64 mmol) were added to a solution of M2-3 (2.0 g, 13.32 mmol) in ACN (30 mL), and the mixture was reacted at 65° C. for 16 hours. The mixture was returned to room temperature, diluted with 100 mL of water, extracted with DCM (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give a red solid M2-4 (1.6 g, yield 56%), LCMS m/z=214.0 [M+H] ⁺ .

Under nitrogen atmosphere, sodium hydroxide (1.81 g, 45.33 mmol) was added to a solution of M2-4 (1.6 g, 7.48 mmol) in water (55 mL) and MeOH (40 mL), and the mixture was reacted at 100°C for 16 hours. The mixture was returned to room temperature, diluted with 30 mL of water, and the pH value of the system was adjusted to 2 with 2M hydrochloric acid, extracted with DCM (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid M2-5 (1.1 g, yield 63%), LCMS m/z=232.8[M+H] ⁺ .

Under nitrogen atmosphere, concentrated sulfuric acid (0.2 g, 4.72 mmol) was added to a solution of M2-5 (1.1 g, 4.72 mmol) in MeOH (15 mL), and the mixture was reacted at 70°C for 16 hours. The mixture was returned to room temperature, diluted with 30 mL of water, and then extracted with DCM (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oil M2-6 (1.1 g, yield 93%), LCMS m/z=247.0 [M+H] ⁺ .

Under nitrogen atmosphere, AIBN (azobisisobutyronitrile, 166 mg, 1.01 mmol) and NBS (396 mg, 2.23 mmol) were added to a CCl ₄ (carbon tetrachloride, 5 mL) solution of M2-6 (500 mg, 2.02 mmol) and reacted at 80° C. for 16 hours. The mixture was returned to room temperature, diluted with 20 mL of water, extracted with DCM (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a white solid M2-7 (540 mg, yield 82%), LCMS m/z=326.9 [M+H] ⁺ .

Under nitrogen atmosphere, DIPEA (N,N-diisopropylethylamine, 595 mg, 4.60 mmol) was added to a DMF (6 mL) solution of M2-7 (0.5 g, 1.53 mmol) and 3-amino-2,6-piperidinedione (295 mg, 2.30 mmol), and the mixture was reacted at 80°C for 16 hours. The mixture was returned to room temperature, diluted with 20 mL of water, extracted with DCM (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM/MeOH) to give a brown solid M2 (340 mg, yield 50%), LCMS m/z=340.8[M+H] ⁺ .

Synthesis of M3

Under nitrogen atmosphere, to a solution of M2 (200 mg, 586 μmol) in 1,4-dioxane (10 mL) were added pinacol borate (179 mg, 704 μmol), Pd(dppf)Cl ₂ (43 mg, 59 μmol) and KOAc (115 mg, 1.17 mmol), and the mixture was reacted at 100° C. for 3 hours. The mixture was returned to room temperature, diluted with 20 mL of water, extracted with DCM (20 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM/MeOH) to give a white solid M3 (200 mg, yield 88%), LCMS m/z=389.2[M+H] ⁺ .

Synthesis of M4

Under nitrogen atmosphere, TEA (triethylamine, 2.2 g, 21.7 mmol), Pd ₂ (dba) ₃ (tris(dibenzylideneacetone)dipalladium, 551 mg, 0.61 mmol) and S-phos (2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 495 mg, 1.21 mmol) were added to a solution of M4-1 (4.1 g, 12.1 mmol) in 1.4-dioxane (80 mL), and then triethylsilane (9.9 g, 60.3 mmol) was added to react at 100° C. for 1 hour. The mixture was returned to room temperature, added to 50 mL of water and extracted with DCM (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give a yellow solid M4-2 (2.64 g, yield 83%), LCMS m/z=262.3 [M+H] ⁺ .

Under nitrogen atmosphere, bis(2-methoxyethyl)aminosulfur trifluoride (4.23 g, 19.16 mmol) was added dropwise to a solution of M4-2 (1 g, 3.83 mmol) in chloroform (30 mL), and stirred at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give a yellow solid M4-3 (420 mg, yield 39%), LCMS m/z=284.3[M+H] ⁺ .

To a solution of M4-3 (420 mg, 1.48 mmol) in DCM (3 mL) was added TFA (trifluoroacetic acid, 3 mL) dropwise at 0°C, and the mixture was reacted for 1 hour at 0°C. The mixture was concentrated under reduced pressure, and the residue was purified by C18 column (acetonitrile/water/0.01% TFA) to give a white solid M4 (270 mg, yield 61%), LCMS m/z=184.2 [M+H] ⁺ .

Synthesis of M5

Under nitrogen atmosphere, (t-Bu ₃ P) ₂ Pd [di(tri-tert-butylphosphine)palladium, 1.58 g, 3.09 mmol] and DIEA (20 g, 154.7 mmol) were added to a solution of M1-1 (5 g, 15.47 mmol) and M5-1 (14.35 g, 46.41 mmol) in 1,4-dioxane (100 mL) and water (20 mL), and the mixture was reacted at 110° C. for 4 hours. The mixture was returned to room temperature, diluted with 300 mL of DCM, filtered and concentrated under reduced pressure, the residue was slurried with methyl tert-butyl ether, filtered, and the filter cake was dried under vacuum to obtain a white solid M5-2 (6.5 g, yield 98%), LCMS m/z=426.2 [M+H] ⁺ .

Under hydrogen atmosphere, Pd/C (palladium carbon, purity 10%, 1 g) was added to a solution of M5-2 (1 g, 2.35 mmol) in DMF (60 mL), and the mixture was reacted at room temperature for 16 hours. The mixture was filtered through diatomaceous earth, 60 mL of water was added, and the mixture was extracted with DCM (100 mL×3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether to obtain a white solid M5-3 (0.9 g, yield 90%), LCMS m/z=428.2[M+H] ⁺ .

Under nitrogen atmosphere, 10 mL 4M hydrochloric acid (1,4-dioxane) was added to a 10 mL DCM solution of M5-3 (200 mg, 0.468 mmol), and the mixture was reacted at room temperature for 1 hour. The mixture was filtered, the filter cake was washed with DCM, and vacuum dried to obtain a white solid M5 (150 mg, yield 98%), LCMS m/z=328.2 [M+H] ⁺ .

Synthesis of M6

Under oxygen atmosphere, PhSiH 3 (phenylsilane, 509 mg, 4.7 mmol) was added to a solution of M5-2 (1 g, 2.35 mmol) and Mn(dpm) ₃ (tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese, 284 mg, 0.47 mmol) in DCM (20 mL) and i-PrOH (isopropanol, 150 mL) and reacted at room temperature for 16 hours. 200 mL _of water was added for dilution, extracted with DCM (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (ethyl acetate) to obtain a white solid M6-1 (600 mg, yield 58%), LCMS m/z=388.2[M-56] ⁺ .

Under nitrogen atmosphere, 10 mL of 4M hydrochloric acid (1,4-dioxane) was added to a 10 mL DCM solution of M6-1 (200 mg, 0.45 mmol) and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was washed three times with ether and dried in vacuo to obtain a white solid M6 (150 mg, yield 97%), LCMS m/z=344.2 [M+H] ⁺ .

Synthesis of M7

Under nitrogen atmosphere, a solution of M6-1 (300 mg, 0.7 mmol) in DCM (10 mL) was cooled to -78°C, and DAST (diethylaminosulfur trifluoride, 218 mg, 1.4 mmol) was added dropwise, and the mixture was heated to room temperature for 4 hours. The mixture was quenched with a cold saturated sodium bicarbonate solution, extracted with DCM (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM/MeOH) to obtain a white solid product M7-1 (200 mg, yield 54%), LCMS m/z=390.1[M-56] ⁺ .

To a 2 mL DCM solution of M7-1 (200 mg, 0.45 mmol) was added 2 mL 4 M hydrochloric acid (1,4-dioxane) at 0°C, and the mixture was reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the solid was washed three times with ether and dried in vacuo to obtain a white solid M7 (180 mg, yield 89%), LCMS m/z=346.1 [M+H] ⁺ .

Synthesis of M8

M2-5 was replaced with 4-bromo-2-fluoro-6-methyl-benzoic acid, and the synthetic method of M2 was used to obtain M8: brown solid, LCMS m/z=340.8 [M+H] ⁺ .

Synthesis of M9

M1-1 was replaced by M8, and the synthetic method of M5 was used to obtain M9: white solid, LCMS m/z=346.0 [M+H] ⁺ .

Synthesis of M10

M2-1 was replaced with 4-bromo-5-fluoro-2-methylbenzoic acid, and the synthetic method of M2 was used to obtain M10: brown solid, LCMS m/z=340.8 [M+H] ⁺ .

Synthesis of M11

M1-1 was replaced by M10, and the synthetic method of M5 was used to obtain M9: white solid, LCMS m/z=346.0 [M+H] ⁺ .

Synthesis of M12

M1-1 was replaced by M2, and the synthetic method of M5 was used to obtain M12: white solid, LCMS m/z=346.0 [M+H] ⁺ .

Synthesis of M13

M1-1 was replaced by M10, and the synthetic method of M6 was used to obtain M13: white solid, LCMS m/z=362.1 [M+H] ⁺ .

Synthesis of M14

M5-1 was replaced with N-tert-butyloxycarbonyl-nortropinone, and the synthetic method of M6 was used to obtain M14: white solid, LCMS m/z=370.2 [M+H] ⁺ .

Synthesis of M15

Under nitrogen atmosphere, NaBH ₄ (sodium borohydride, 261 mg, 6.89 mmol) was added to a solution of M15-1 (0.6 g, 2.30 mmol) in MeOH (10 mL), and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with DCM (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid M15-2 (540 mg, yield 89%), LCMS m/z=271.1 [M+Na] ⁺ .

Under nitrogen atmosphere, TFA (390 mg, 3.42 mmol) was added to a DCM (10 mL) solution of M15-2 (0.3 g, 1.14 mmol), and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to obtain a yellow oil M15 (300 mg, yield 90%), LCMS m/z=164.0 [M+H] ⁺ .

Synthesis of M16

M5-1 was replaced with (S)-1-BOC-2-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, and the synthetic method of M5 was used to obtain M16: white solid, LCMS m/z=342.2 [M+H] ⁺ .

Synthesis of Example 1

Under nitrogen atmosphere, 1-2 (793 mg, 2.95 mmol) and K ₂ CO ₃ (potassium carbonate, 61 mg, 442 μmol) were added to a solution of 1-1 (500 mg, 2.95 mmol) in EtOH (ethanol, 10 mL), and the mixture was reacted at 80° C. for 3 hours. The mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE/EA) to give a yellow solid 1-3 (260 mg, yield 26%), LCMS m/z=216.0 [M+H] ⁺ .

NaBH ₄ (57.6 mg, 929 μmol) was added to a solution of 1-3 (0.1 g, 465 μmol) in MeOH (5 mL) at 0°C, and the reaction was continued at 0°C for 1 hour. The reaction system was concentrated under reduced pressure, diluted with 2 mL of water, extracted with DCM (20 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a white solid 1-4 (90 mg, yield 89%), LCMS m/z=217.9 [M+H] ⁺ .

To a solution of 1-4 (80 mg, 368 μmol) in Py (pyridine, 5 mL) was added TsCl (p-toluenesulfonyl chloride, 105 mg, 552 μmol), and the mixture was reacted at 25° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give a white solid 1-5 (90 mg, yield 81%), LCMS m/z=372.3 [M+H] ⁺ .

Under nitrogen atmosphere, 4-ethylpyridine (10 mg, 93 μmol), ethylene glycol dimethyl ether nickel bromide (3 mg, 9 μmol), Mn (manganese, 10 mg, 186 μmol), KI (potassium iodide, 16 mg, 98 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (2.5 mg, 9 μmol) were added to a solution of 1-5 (30 mg, 93 μmol) and M1-1 (35 mg, 93 μmol) in DMA (3 mL), and the mixture was reacted at 80 °C for 5 hours. The mixture was returned to room temperature, diluted with 10 mL of water, and extracted with DCM (20 mL×3). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a white solid 1 (1.1 mg, yield 3%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.66(d,J＝8.0Hz,1H),7.38(s,1H),7.34–7.28(m,6H),5.10(dd,J＝13.3,5.2Hz,1H),4.48–4.34(m,2H),3.19–3.11(m,2H),2.92– 2.83(m,1H),2.78–2.72(m,1H),2.51–2.36(m,2H),2.23–2.10(m,3H),1.83–1.70(m,4H),0.99–0.94(m,2H),0.83–0.80(m,2H), LCMS m/z=443.9[M+H] ⁺ .

Synthesis of Example 2

Replace 1-1 with 1-phenylcyclobutylamine hydrochloride and use the synthesis method of Example 1 to Example 2: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.46(s,1H),7.70(d,J＝8.0Hz,1H),7.59–7.51(m,2H),7.50–7.42(m,3H),7.40(s,1H),7.34(d,J＝8.4Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H ),4.49–4.37(m,2H),3.46–3.32(m,1H),2.93–2.82(m,1H),2.79–2.73 (m,3H),2.65–2.56(m,3H),2.51–2.40(m,1H),2.19–2.09(m,3H),2.03 –1.84(m,6H),1.68–1.57(m,1H), LCMS m/z=457.9[M+H] ⁺ .

Synthesis of Example 3

Replace 1-1 with 3-phenyl-3-oxetanamine hydrochloride, and adopt the synthesis method of Example 1 to Example 3: white solid, ¹ HNMR (400 MHz, Methanol-d ₄ )δ7.68(d, J＝8.0 Hz, 1H), 7.42–7.30(m, 5H), 7.19–7.15(m, 2H), 5.11(dd, J＝13.3, 5.0 Hz, 1H), 4.96–4.90(m, 4H), 4.47–4.37(m, 2H), 3.01–2.96(m, 2H), 2.92–2.83(m, 1H), 2.78–2.72(m, 1H), 2.51–2.38(m, 2H), 2.19–2.10(m, 1H), 1.89–1.73(m, 6H), LCMS m/z＝459.9[M+H] ⁺ .

Synthesis of Example 4

Under nitrogen atmosphere, a solution of 1-3 (250 mg, 1.16 mmol) in THF (tetrahydrofuran, 10 mL) was cooled to -78°C, and LiHMDS (lithium bistrimethylsilylamide, 1 M THF solution, 1.174 mL, 1.74 mmol) was added dropwise, stirred for 1 hour, and then N-phenylbis(trifluoromethanesulfonyl)imide (621 mg, 1.74 mmol) was added, and the reaction was continued at -78°C for 16 hours. The mixture was quenched with 20 mL of saturated ammonium chloride solution, extracted with DCM (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to obtain a white solid 26-1 (240 mg, yield 53%), LCMS m/z=348.2[M+H] ⁺ .

Under nitrogen atmosphere, Pd(dppf)Cl ₂ ·DCM ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 16 mg, 20 μmol) and K ₃ PO ₄ (potassium phosphate, 65 mg, 309 μmol) were added to a DMF (1 mL) solution of 4-1 (76 mg, 206 μmol) and M1 (71 mg, 206 μmol), and the mixture was reacted at 110°C for 3 hours. The mixture was returned to room temperature, diluted with 10 mL of water, extracted with DCM (10 mL×3), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM\MeOH) to obtain a white solid 13 (60 mg, yield 54%), ¹ HNMR (500 MHz, DMSO-d ₄ )δ10.99(s,1H),7.64(d,J＝8.0Hz,1H),7.57(s,1H),7.51(d,J＝7.9Hz,1H),7.37–7.34(m,4H),7. 30–7.28(m,1H),6.25–6.22(m,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.2Hz,1H),4.29(d ,J＝17.2Hz,1H),3.19–3.16(m,2H),2.93–2.87(m,1H),2.76–2.71(m,2H),2.61–2.57(m,1H),2.4 8–2.46(m,2H),2.40–2.36(m,1H),1.99–1.96(m,1H),0.96–0.93(m,2H),0.82–0.80(m,2H), LCMS m/z=442.5[M+H] ⁺ .

Under oxygen atmosphere, i-PrOH (5 mL), DMF (1 mL), Mn(dpm) ₃ (41 mg, 68 μmol) and PhSiH ₃ (29 mg, 272 μmol) were added to a DCM (5 mL) solution of 13 (60 mg, 136 μmol) and reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give a white solid 4 (4 mg, yield 6%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.71(d,J＝8.0Hz,1H),7.65(s,1H),7.59(dd,J＝8.4,1.2Hz,1H),7.39–7.26 (m,5H),5.12(dd,J＝13.3,5.1Hz,1H),4.49–4.39(m,2H),3.01–2.94(m,2H),2 .93–2.83(m,1H),2.78–2.72(m,1H),2.70–2.64(m,2H),2.52–2.42(m,1H),2. 17–2.05(m,3H),1.73–1.65(m,2H),1.05–1.03(m,2H),0.90–0.87(m,2H), LCMS m/z＝459.9[M+H] ⁺ .

Synthesis of Example 5

Under nitrogen atmosphere, compound 1-2 (1.74 g, 6.46 mmol) and K ₂ CO ₃ (61 mg, 442 μmol) were added to a mixed solution of 5-1 (1 g, 4.97 mmol) in EtOH (10 mL) and water (10 mL), and the mixture was reacted at 80° C. for 3 hours. The mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE/EA) to obtain 5-2 (1.1 g, yield 78%) as a yellow solid, LCMS m/z=284.2 [M+H] ⁺ .

Under nitrogen atmosphere, a solution of 5-2 (360 mg, 1.27 mmol) in THF (10 mL) was cooled to -78°C, and LiHMDS (1M THF solution, 1.27 mL, 1.27 mmol) was added dropwise, stirred for 1 hour, and then N-phenylbis(trifluoromethanesulfonyl)imide (681 mg, 1.91 mmol) was added, and the reaction was continued at -78°C for 16 hours. The mixture was quenched with 20 mL of saturated ammonium chloride solution, extracted with DCM (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to obtain a light yellow solid 5-3 (320 mg, yield 61%), LCMS m/z＝416.3[M+H] ⁺ .

Under nitrogen atmosphere, Pd(dppf)Cl ₂ (40 mg, 54 μmol) and Na ₂ CO 3 (172 mg, 1.62 mmol) were added to a mixed solution of M1 (200 mg, 540 μmol) and _5-3 (269 mg, 648 μmol) in 1,4-dioxane (4 mL) and water (1 mL), and the mixture was reacted at 60° C. for 3 hours. The mixture was returned to room temperature, diluted with 10 mL of water, extracted with EA (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM\MeOH) to obtain a light yellow solid 5-4 (105 mg, yield 38%), LCMS m/z＝510.2[M+H] ⁺ .

Under hydrogen atmosphere, Pd/C (purity 10%, 10 mg) was added to a DMF (0.5 mL) solution of 5-4 (10 mg, 19.63 μmol) and reacted at room temperature for 16 hours. The reaction system was filtered through diatomaceous earth, the filter cake was washed with water and DCM, the filtrate was extracted with DCM (20 mL × 3), washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a white solid 5 (5 mg, yield 49%), ¹ H NMR (500 MHz, DMSO-d ₆ )δ11.04(s,1H),7.79(d,J＝8.0Hz,2H),7.67(d,J＝7.9Hz,1H),7.60(d,J＝7.9Hz,2H), 7.49(s,1H),7.39(d,J＝7.9Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝67.2,1 7.3Hz,3H),3.22–3.13(m,2H),2.99–2.93(m,1H),2.73–2.61(m,2H),2.13–2.03(m,4 H),1.82–1.77(m,2H),1.73–1.67(m,2H),1.04–1.01(m,2H),0.91–0.88(m,2H), LCMS m/z=512.6[M+H] ⁺ .

Synthesis of Example 6

Replace 1-1 with 1-phenylcyclobutylamine hydrochloride and use the synthesis method of Example 4 to Example 6: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.52(s,1H),7.74(d,J＝8.4Hz,1H),7.67(s,1H),7.60(d,J＝8.0Hz,1H), 7.52–7.37(m,5H),5.13(dd,J＝13.3,5.2Hz,1H),4.50–4.40(m,2H),3.14–3 .00(m,2H),2.93–2.84(m,1H),2.78–2.69(m,3H),2.60–2.38(m,5H),2.26– 2.13(m,3H),2.00–1.92(m,1H),1.83–1.74(m,2H),1.69–1.57(m,1H), LCMS m/z＝473.9[M+H] ⁺ .

Synthesis of Example 7

Replace 5-1 with 1-pyridin-3-ylcyclopropylamine, and adopt the synthesis method of Example 5 to Example 7: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 7.72-7.68 (m, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.42 (s, 1H), 7.41-7.37 (m, 1H), 7.34-7.30 (m, 1H), 5.08 (dd, J = 13.4, 5.1 Hz, 1H), 4.39 (d, J = 17.3, 1.6 Hz, 1H). z,1H),4.26(d,J＝17.2Hz,1H),3.12–3.08(m,2H),2.93–2.86(m,1H),2.62–2.55(m,1H),2.37–2.34(m,1 LCMS m/z=445.6[M+H] ⁺ .

Synthesis of Example 8

Replace 5-1 with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropylamine, and use the synthesis method of Example 5 to Example 8: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ))δ10.97(s,1H),7.60(d,J＝7.9Hz,1H),7.42(s,1H),7.38(d,J＝8.3Hz,2H),7.32(d,J＝7.8Hz,1H),7.15(dd,J＝8.3,1.2Hz,1H),5.0 9(dd,J＝13.3,5.0Hz,1H),4.39(d,J＝17.2Hz,1H),4.25(d,J＝17.3Hz,1H),3.11–3.05(m,2H),2.94–2.86(m,1H),2.65–2.56(m,1H), 2.42–2.35(m,2H),2.07–2.00(m,2H),2.00–1.94(m,1H),1.75–1.69(m,2H),1.65–1.56(m,2H),0.93–0.88(m,2H),0.83–0.78(m,2H), LCMS m/z=524.5[M+H] ⁺ .

Synthesis of Example 9

Replace 1-1 with 3-phenyl-3-oxetanamine hydrochloride, and adopt the synthesis method of Example 4 to Example 9: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.96(s,1H),7.70–7.58(m,3H),7.46(d,J＝7.2Hz,2H),7.39–7.33(m,2H),7.32–7.26(m,1H),5.10(dd,J＝13.4,4.9Hz,1H),5.00(s,1H),4.42(d,J＝17.2Hz,1H),4.28(d,J＝17.6Hz,1H),3.16(d,J＝1 3.6Hz,1H),3.02(d,J＝5.4Hz,1H),2.96–2.86(m,1H),2.83–2.74(m,2H),2.71(d,J＝5.4Hz,1H),2.64 (d,J＝13.6Hz,2H),2.59–2.55(m,1H),2.48–2.32(m,2H),2.00–1.80(m,3H),1.63–1.49(m,2H), LCMS m/z=476.1[M+H] ⁺ .

Synthesis of Example 10

5-1 was replaced by 1-1, M1 was replaced by M3, and the synthesis method of Example 4 was used to prepare Example 10: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.55(d,J＝8.0Hz,1H),7.46–7.40(m,1H),7.39–7.30(m,4H),7.29–7.19(m,1H),5.10(dd,J＝13.4,4.9Hz,1H),4.54–4.42(m,2H),3.21–3 .12(m,2H),2.93–2.81(m,1H),2.80–2.62(m,2H),2.52–2.42(m,1H),2.25–2.10(m,3H),1.88–1.70(m,4H),0.98(s,2H),0.83(s,2H), LCMS m/z=461.9[M+H] ⁺ .

Synthesis of Example 11

The synthesis method of 13 was used to prepare Example 11 by replacing M1 with M3: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.96(s,1H),7.47(d,J＝8.0Hz,1H),7.43–7.37(m,1H),7.34–7.29(m,4 H),7.28–7.24(m,1H),5.98(s,1H),5.06(dd,J＝12.0,4.0Hz,1H),4.55–4. 26(m,2H),2.92–2.82(m,1H),2.71–2.66(m,2H),2.65–2.52(m,2H),2.43– 2.36(m,3H),2.01–1.89(m,2H),0.95–0.90(m,2H),0.78–0.74(m,2H), LCMS m/z＝459.9[M+H] ⁺ .

Synthesis of Example 12

Replace 5-1 with 3-phenyl-3-oxetanamine hydrochloride, replace M1 with M3, and adopt the synthesis method of Example 5 to Example 12: white solid, LCMS m/z=478.0 [M+H] ⁺ .

Synthesis of Example 14

5-1 was replaced with M4, and the synthesis method of Example 5 was used to obtain Example 14: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ ) δ7.67 (d, J=7.6 Hz, 1H), 7.41-7.26 (m, 7H), 5.10 (dd, J=13.4, 5.1 Hz, 1H), 4.46-4.36 (m, 2H), 3.12-3.03 (m, 4H), 2.95-2.83 (m, 3H), 2.78-2.72 (m, 1H), 2.51-2.35 (m, 2H), 2.16-2.11 (m, 1H), 1.82-1.69 (m, 6H), LCMS m/z=494.0 [M+H] ⁺ .

Synthesis of Example 15

Replacing 5-1 with 1-phenylcyclopentylamine, and adopting the synthesis method of Example 5 to obtain Example 15: white solid, LCMS m/z=472.2 [M+H] ⁺ .

Synthesis of Example 16

5-1 was replaced with (1-benzylcyclopropyl)amine, and the synthesis method of Example 5 was used to prepare Example 16: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.96(s,1H),8.34(s,1H),7.61(d,J＝7.8Hz,1H),7.46(s,1H),7.36(d,J ＝7.9Hz,1H),7.30–7.14(m,5H),5.09(dd,J＝13.2,4.8Hz,1H),4.44–4.23(m ,2H),2.95–2.85(m,5H),2.69–2.54(m,5H),2.41–2.31(m,1H),2.05–1.94( m,1H),1.80–1.66(m,2H),1.60–1.49(m,2H),0.46(s,2H),0.33(s,2H), LCMS m/z＝458.1[M+H] ⁺ .

Synthesis of Example 17 and Example 19

To a solution of 17-1 (2 g, 12.89 mmol) in acetone (15 mL) was added dropwise a solution of iodomethane (1.83 g, 12.9 mmol) in acetone (5 mL) at 0°C, and the temperature was raised to room temperature for 16 hours. A large amount of solid precipitated, which was filtered, and the filter cake was washed with DCM and dried in vacuo to obtain a yellow solid 17-2 (2.2 g, yield 57%), LCMS m/z=170.0 [M+H] ⁺ .

Under nitrogen atmosphere, K ₂ CO ₃ (622 mg, 4.50 mmol) was added to a solution of 17-2 (1 g, 5.87 mmol) and 1-1 (664 mg, 3.92 mmol) in EtOH (10 mL) and water (3 mL), and the mixture was reacted at 80° C. for 3 h. After the mixture was returned to room temperature, 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE/EA) to obtain a red oil 17-3 (630 mg, yield 44%), LCMS m/z=257.9 [M+H] ⁺ .

Under nitrogen atmosphere, a solution of 17-3 (300 mg, 1.17 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (625 mg, 1.75 mmol) in THF (2 mL) was cooled to -78 °C, and LiHMDS (1 M THF solution, 1.75 mL, 1.75 mmol) was added dropwise, and the reaction was continued at -78 °C for 16 hours. The mixture was quenched with 20 mL of saturated ammonium chloride. The mixture was then extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a light yellow solid 17-4 (120 mg, yield 23%), LCMS m/z = 389.9 [M+H] ⁺ .

Under nitrogen atmosphere, Pd(dppf)Cl ₂ (24 mg, 32 μmol) and Na ₂ CO 3 (100 mg, 924 μmol) were added to a solution of 17-4 (120 mg, 308 μmol) and intermediate _M1 (172 mg, 464 μmol) in 1,4-dioxane (8 mL) and water (4 mL), and the mixture was reacted at 55° C. for 3 hours. The mixture was returned to room temperature, filtered, and the filter cake was washed with DCM/isopropanol. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a white solid 17 (68 mg, yield 45%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.55(dd,J＝8.0,0.5Hz,1H),7.43–7.43(m,1H),7.41–7.40(m,1H),7.12–6.95(m,5H),6.1 6–6.12(m,1H),5.10(dd,J＝12.0,4.0Hz,1H),4.42–4.32(m,2H),3.79–3.73(m,1H),3.73–3.6 9(m,2H),3.67–3.63(m,1H),3.54–3.50(m,1H),3.46–3.43(m,1H),2.93–2.83(m,1H),2.81–2 .71(m,1H),2.48–2.41(m,2H),2.17–2.09(m,2H),1.09–1.03(m,2H),0.89–0.73(m,2H), LCMS m/z=483.9[M+H] ⁺ .

Under hydrogen atmosphere, Pd(OH) ₂ /C (palladium hydroxide supported on carbon, purity 15%, 25 mg) was added to a solution of 17 (49 mg, 101 μmol) in DMF (5 mL), and the mixture was reacted at 50° C. for 16 hours. The mixture was returned to room temperature, filtered through celite, and the filter cake was washed with DCM/isopropanol. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a white solid 19 (17 mg, yield 10%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.61(d,J＝8.0Hz,1H),7.51–7.47(m,2H),7.39–7.35(m,1H),7.34–7.30(m,2H),7.27 (s,1H),7.14(dd,J＝7.9,1.1Hz,1H),5.10(dd,J＝13.4,5.1Hz,1H),4.46–4.31(m,2H),3 .76–3.68(m,1H),3.44–3.39(m,2H),2.95–2.83(m,1H),2.79–2.73(m,1H),2.52–2.40( m,1H),2.20–1.87(m,5H),1.67–1.54(m,3H),1.07–1.03(m,2H),0.93–0.85(m,3H), LCMS m/z=486.0[M+H] ⁺ .

Synthesis of Example 18

Replace 5-1 with 1-phenylcyclopropylmethylamine, and adopt the synthesis method of Example 5 to Example 18: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.96 (s, 1H), 8.22 (s, 1H), 7.61 (d, J＝7.6 Hz, 1H), 7.45 (s, 1H), 7.38–7.32 (m, 3H), 7.31–7.24 (m, 2H), 7.18–7.13 (m, 1H), 5.09 (dd, J＝13.2, 5.3 Hz, 1H), 4.45–4.22 (m, 2H), 3.11–3.70 (m, 3H). 3.05(m,2H),2.94–2.85(m,1H),2.69–2.58(m,4H),2.44–2.35(m,1H),2.34–2.30(m,1H) ,2.08–1.93(m,3H),1.77–1.67(m,2H),1.64–1.50(m,2H),0.82(s,2H),0.74(s,2H), LCMS m/z=458.2[M+H] ⁺ .

Synthesis of Example 20

Replace 17-1 with (S)-1,2-dimethylpiperidin-4-one, replace 1-1 with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropylamine, and adopt the synthesis method of Example 19 to Example 20: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.67(d, J＝7.9 Hz, 1H), 7.39(s, 1H), 7.33(d, J＝7.9 Hz, 1H), 7.28(d, J＝1.5 Hz, 1H), 7.25(dd, J＝8.3, 1.6 Hz, 1H), 7.15(d, J＝8.2 Hz, 1H), 5.10(dd, J＝13.4, 5.2 Hz, 1H), 4.46-4.35(m, 2H), 2.94-2.82(m, 1H ),2.80–2.70(m,1H),2.54–2.42(m,2H),2.42–2.34(m,1H),2.33–2.25(m,1H),2.20–2.09(m,2H),1. 87–1.65(m,3H),1.52–1.43(m,1H),1.41(d,J＝5.8Hz,3H),1.24–1.08(m,2H),0.86–0.72(m,2H), LCMS m/z=537.8[M+H] ⁺ .

Synthesis of Example 21

5-1 was replaced with 1-phenylcyclopropylmethylamine, and the synthesis method of Example 5 was used to obtain Example 21: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.99(s,1H),7.73–7.65(m,3H),7.61–7.53(m,3H),7.40(s,1H),7.33( d,J＝8.9Hz,1H),5.10(dd,J＝13.1,5.4Hz,1H),4.49–4.24(m,2H),3.89–3. 75(m,2H),2.70–2.65(m,2H),2.65–2.61(m,1H),2.02–1.92(m,6H),1.84– 1.74(m,4H),1.62–1.44(m,2H),1.32–1.16(m,3H),1.15–0.99(m,3H), LCMS m/z＝486.3[M+H] ⁺ .

Synthesis of Example 22 and Example 23

Replace 5-1 with M15 and use the synthesis method of Example 5 to Example 22 and Example 23:

Example 22 or 23, white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.68(d,J＝7.9Hz,1H),7.39(s,1H),7.37–7.29(m,3H),7.27–7.21(m,1H),7.19–7.13(m,2H),5.11(dd,J＝13.3,5.2Hz,1H),4.51–4.34(m,3 H),3.27–3.23(m,2H),3.04–2.92(m,2H),2.90–2.80(m,1H),2.79–2.6 5(m,1H),2.51–2.37(m,2H),2.28–2.08(m,3H),1.87–1.72(m,6H), LCMS m/z=474.0[M+H] ⁺ .

Example 22 or 23, white solid, ¹ H NMR (400 MHz, Methanol-d ₄ ) δ7.68 (d, J=8.0 Hz, 1H), 7.47-7.28 (m, 7H), 5.11 (dd, J=13.4, 5.2 Hz, 1H), 4.51-4.33 (m, 2H), 3.78-3.66 (m, 1H), 3.20-3.03 (m, 3H), 2.99-2.81 (m, 1H), 2.79-2.68 (m, 1H), 2.53-2.37 (m, 2H), 2.35-2.25 (m, 2H), 2.25-2.00 (m, 2H), 1.98-1.73 (m, 6H), LCMS m/z=474.0 [M+H] ⁺ .

Synthesis of Example 24

5-1 was replaced with 4-phenyltetrahydropyran-4-amine, and the synthesis method of Example 5 was used to obtain Example 24: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.71(d,J＝7.9Hz,1H),7.64–7.50(m,5H),7.41(s,1H),7.35(dd,J＝7.9 ,1.3Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.61–4.53(m,4H),4.50–4.36 (m,2H),4.03–3.94(m,2H),3.85–3.65(m,1H),2.96–2.84(m,2H),2.80–2 .67(m,2H),2.52–2.39(m,2H),2.19–2.12(m,4H),2.07–1.90(m,4H), LCMS m/z=476.9[M+H] ⁺ .

Synthesis of Example 25

To a solution of M5 (120 mg, 367 μmol) and 25-1 (51 mg, 367 μmol) in DMF (5 mL) was added STAB (

Sodium triacetoxyborohydride, 233 mg, 1.101 mmol), react at room temperature for 16 hours. Add 10 mL of water to dilute and extract with EA (30 mL×3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, the residue is purified by preparative HPLC to give a white solid 25 (19 mg, yield 12%), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.98 (s, 1H), 7.65 (d, J＝7.7 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J＝7.7 Hz, 1H), 5.09 (dd, J＝13.2, 4.7 Hz, 1H), 4.48–4.22 (m, 2H), 3.46–3.40 (m, 4H), 3.04–2.96 (m, 2H),2.93–2.79(m,2H),2.71–2.57(m,2H),2.45–2.31(m,1H),2.07–1.8 9(m,5H),1.85–1.60(m,6H),1.59–1.50(m,2H),1.49–1.40(m,2H), LCMS m/z=452.7[M+H] ⁺ .

Synthesis of Example 26

M5 was replaced by M6, and the synthesis method of Example 25 was used to prepare Example 26: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.97(s,1H),8.24(s,1H),7.71(s,1H),7.69–7.59(m,2H),5.10(dd, J＝13.2,5.0Hz,1H),4.49–4.26(m,2H),3.45–3.44(m,4H),2.98–2.82(m ,3H),2.80–2.66(m,3H),2.64–2.55(m,2H),2.46–2.25(m,3H),2.09–1. 93(m,5H),1.72–1.60(m,4H),1.58–1.52(m,2H),1.51–1.42(m,2H), LCMS m/z=468.2[M+H] ⁺ .

Synthesis of Example 27

M5 was replaced by M7, and the synthesis method of Example 25 was used to prepare Example 27: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.98 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.52-4.29 (m, 2H), 3.55-3.51 (m, 2H), 3.46-3.44 (m, 2H), 2.98-2 .85(m,1H),2.81–2.72(m,3H),2.65–2.57(m,1H),2.47–2.31(m,1H),2.21–2.12(m,1 H),2.10–1.98(m,6H),1.96–1.86(m,2H),1.61–1.53(m,4H),1.49–1.42(m,2H), LCMS m/z=470.2[M+H] ⁺ .

Synthesis of Example 28

A solution of 28-1 (2.0 g, 9.3 mmol) in MeOH (40 mL) was cooled to 0°C, and NaBH ₄ (1.14 g, 18.58 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with 100 mL of saturated ammonium chloride solution, extracted with DCM (60 mL×3), washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to obtain a colorless oil 28-2 (1.9 g, yield 94%), LCMS m/z=171.9[M-56] ⁺ .

TsCl (2.31 g, 12.1 mmol) was added to a solution of 28-2 (1.1 g, 4.84 mmol) in Py (10 mL), and the mixture was reacted at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with 30 mL of water, extracted with DCM (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to obtain a white solid 28-3 (1.2 g, yield 59%), LCMS m/z=403.9 [M+Na] ⁺ .

Under nitrogen atmosphere, 4-ethylpyridine (99 mg, 928 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (25 mg, 93 μmol), ethylene glycol dimethyl ether nickel bromide (29 mg, 93 μmol), Mn (33 mg, 1.86 mmol), KI (154 mg, 928 μmol) were added to M1-1 (0.3 g, 928 μmol) and 28-3 (531 mg, 1.39 mmol) in DMA (3 mL), and the mixture was reacted at 100° C. for 5 hours. The mixture was returned to room temperature, diluted with 10 mL of water, and then extracted with DCM (10 mL×3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give 28-4 as a white solid (240 mg, yield 48%), LCMS m/z=397.9[M-56] ⁺ .

2 mL of 4M hydrochloric acid (1,4-dioxane) was added to a DCM (2 mL) solution of 28-4 (240 mg, 529 μmol) and reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the solid was washed three times with ether and dried in vacuo to obtain a white solid 28-5 (180 mg, yield 96%), LCMS m/z=354.2 [M+H] ⁺ .

Under nitrogen atmosphere, STAB (180 mg, 849 μmol) was added to a DMF (5 mL) solution of 28-5 (100 mg, 283 μmol) and 25-1 (119 mg, 849 μmol), and the mixture was reacted at room temperature for 16 hours. 10 mL of water was added to dilute the mixture and the mixture was extracted with DCM (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain a white solid 28 (3 mg, yield 2%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.52(s,1H),7.76(d,J＝8.0Hz,1H),7.53(s,1H),7.48(d,J＝8.4Hz,1H),5.13(dd,J＝ 13.3,5.1Hz,1H),4.55(s,2H),4.51–4.40(m,2H),3.95(s,2H),3.67–3.62(m,2H),3.6 1–3.56(m,2H),3.41–3.32(m,1H),2.94–2.84(m,1H),2.80–2.72(m,1H),2.54–2.42(m ,1H),2.40–2.27(m,4H),2.20–2.13(m,4H),2.08–2.00(m,4H),1.70–1.64(m,4H), LCMS m/z=478.0[M+H] ⁺ .

Synthesis of Example 29

Replace 25-1 with spiro[2.3]hexan-5-one, and adopt the synthetic method of Example 25 to Example 29: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ ) 7.75 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.52-4.39 (m, 2H), 3.80-3.69 (m, 1H), 3.54-3.45 (m, 2H), 3.03-2.92 (m, 1H),2.91–2.82(m,1H),2.82–2.72(m,3H),2.53-2.42(m,3H),2.31–2.22(m,2H), 2.21–2.07(m,3H),2.01-1.90(m,2H),0.61–0.57(m,2H),0.52–0.48(m,2H), LCMS m/z=408.0[M+H] ⁺ .

Synthesis of Example 30

Replace 25-1 with spiro[2.3]hexan-5-one and use the synthesis method of Example 25 to Example 30: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.74(d,J＝8.0Hz,1H),7.48(s,1H),7.42(d,J＝7.2Hz,1H),5.12(dd,J＝13.3,5.2 Hz,1H),4.73(s,2H),4.62(s,2H),4.51–4.42(m,2H),3.45–3.38(m,2H),3.35–3.28 (m,1H),2.97–2.84(m,2H),2.79–2.73(m,1H),2.70–2.62(m,4H),2.52–2.41(m,1H ),2.38–2.33(m,2H),2.17–2.12(m,1H),2.11–2.03(m,2H),1.97–1.90(m,2H), LCMS m/z=424.0[M+H] ⁺ .

Synthesis of Example 31

TFA (5 mL) was added dropwise to a DCM (5 mL) solution of 31-1 (2 g, 8.36 mmol) at 0°C, and the mixture was heated to room temperature for 1 hour. The mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to adjust the pH to pH>7, and the mixture was extracted with DCM:MeOH=10:1, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was added with water and freeze-dried to obtain a white solid 31-2 (1.03 g, yield 88%), LCMS m/z=140.1 [M+H] ⁺ .

A solution of 31-2 (600 mg, 4.31 mmol) and DIPEA (1.11 g, 8.62 mmol) in DCM (10 mL) was cooled to 0°C, acetyl chloride (406 mg, 5.17 mmol) was added, and the temperature was raised to room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM/MeOH) to give a yellow oil 31-3 (762 mg, yield 97%), LCMS m/z=182.1[M+H] ⁺ .

STAB (453 mg, 2.14 mmol) was added to a solution of M5 (58 mg, 321 μmol) and 31-3 (70 mg, 214 μmol) in DMF (3 mL) and the mixture was stirred at room temperature for 16 hours. The reaction solution was directly purified by C18 column (acetonitrile/water) to obtain a white solid 31 (10 mg, yield ⁹ %). NMR (500MHz, DMSO) δ10.98(s,1H),7.65(d,J＝7.8Hz,1H),7.49(s,1H),7.40(d,J＝8.0Hz,1H),5.10(dd,J＝13.3,5.1Hz, 1H),4.43(d,J＝17.3Hz,1H),4.29(d,J＝17.2Hz,1H),3.28–3.26(m,2H),3.01–2.94(m,2H),2.93–2.87(m,1H),2.86–2.7 7(m,1H),2.70–2.65(m,1H),2.65–2.56(m,2H),2.44–2.35(m,1H),2.03–2.00(m,2H),1.99–1.95(m,4H),1.90(s,3H), 1.82–1.77(m,2H),1.77–1.69(m,2H),1.69–1.61(m,2H),1.58–1.54(m,1H),1.50–1.45(m,2H),1.40–1.37(m,1H), LCMS m/z=493.5[M+H] ⁺ .

Synthesis of Example 32

Replace 25-1 with 2-oxaspiro[3.5]nonan-7-one, and adopt the synthesis method of Example 25 to Example 32: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.43(s,1H),7.75(d,J＝8.4Hz,1H),7.49(s,1H),7.43(d,J＝8.4Hz,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.52-4.43(m,4H),4.35(s,2H),3.60-3.53(m,2H),3.22-3.12(m,3H),3 .05–2.99(m,1H),2.93–2.84(m,1H),2.79–2.73(m,1H),2.52–2.41(m,1H),2.36–2.29( m,2H),2.18–2.12(m,3H),2.10–2.04(m,3H),2.01–1.98(m,1H),1.62–1.48(m,4H), LCMS m/z=451.9[M+H] ⁺ .

Synthesis of Examples 33, 45 and 46

Replace 25-1 with 3-oxabicyclo[3.2.1]octan-8-one, and adopt the synthetic method of Example 25 to Example 33: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.49(s,1H),7.75(d,J＝7.6Hz,1H),7.48(s,1H),7.43(d,J＝7.5Hz,1H),5.13(dd,J＝13.2,4.8Hz,1H),4.59-4.39(m,5H),3.63-3.52(m,2H),3.00-2.72(m,5H),2.62-2.39(m,2H),2.19-2.06(m,3H),2.05-1.87(m,6H),1.84-1.76(m,3H),LCMS m/z＝438.0[M+H] ⁺ . Example 33 was separated by preparative HPLC to obtain Example 45 and Example 46. Example 45 or 46: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.53(s,1H),7.76(d,J＝7.9Hz,1H),7.51(s,1H),7.44(d,J＝8.0Hz,1H),5 .15(dd,J＝13.3,5.1Hz,1H),4.58–4.41(m,4H),3.63(d,J＝12.3Hz,2H),3.29 –3.21(m,1H),3.03–2.85(m,4H),2.83–2.73(m,1H),2.68–2.58(m,2H),2.56 –2.42(m,1H),2.22–1.92(m,7H),1.83–1.74(m,2H),1.55–1.44(m,2H), LCMS m/z＝438.0[M+H] ⁺ .

Example 46 or 45: White solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.53(s,1H),7.77(d,J＝8.0Hz,1H),7.51(s,1H),7.45(dd,J＝7.9,1.1H z,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.56–4.42(m,4H),3.60(d,J＝12.2H z,2H),3.50–3.39(m,1H),3.02–2.86(m,4H),2.83–2.74(m,1H),2.56–2. 43(m,1H),2.21–2.08(m,3H),2.04–1.91(m,6H),1.88–1.77(m,4H), LCMS m/z=438.0[M+H] ⁺ .

Synthesis of Example 34

M5 was replaced by M9, and the synthesis method of Example 25 was used to obtain Example 34: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ ) δ8.47 (s, 1H), 7.30 (s, 1H), 7.11 (d, J=10.6 Hz, 1H), 5.09 (dd, J=13.4, 5.2 Hz, 1H), 4.55-4.40 (m, 2H), 3.69-3.61 (m, 2H), 3.61-3.54 (m, 2H), 3.49-3.39 (m, 3H), 2.99-2. 83(m,2H),2.80–2.70(m,1H),2.70–2.59(m,2H),2.53–2.38(m,1H),2.35–2.24(m,2 H),2.19–2.05(m,3H),1.98–1.85(m,4H),1.70–1.64(m,2H),1.63–1.54(m,2H), LCMS m/z=470.0[M+H] ⁺ .

Synthesis of Example 35

M5 was replaced by M11, and the synthesis method of Example 25 was used to obtain Example 35: white solid, 1H NMR (400 MHz, DMSO-d ₆ ) δ7.54 (d, J=8 Hz, 1H), 7.47 (d, J=12 Hz, 1H), 5.12 (dd, J=12, 4 Hz, 1H), 4.50-4.40 (m, 2H), 3.67-3.61 (m, 2H), 3.60-3.54 (m, 2H), 3.48-3.37 (m, 3H), 3.25-3.14 (m, 1 H),2.93–2.84(m,1H),2.79–2.73(m,1H),2.69–2.62(m,2H),2.52–2.41(m,1H), 2.32–2.27(m,2H),2.11–1.87(m,7H),1.68–1.65(m,2H),1.61–1.59(m,2H), LCMS m/z=469.9[M+H] ⁺ .

Synthesis of Example 36

M5 was replaced by M12, and the synthesis method of Example 25 was used to obtain Example 36: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.33(s,1H),7.63(d,J＝8.0Hz,1H),7.53–7.46(m,1H),5.14(dd,J＝13.3,5.2Hz,1H),4.60–4.48(m,2H),3.66–3.55(m,7H),3.36–3.30(m,1 H),2.92–2.85(m,3H),2.82–2.71(m,1H),2.54–2.47(m,1H),2.39–2.3 4(m,2H),2.19–1.96(m,7H),1.69–1.67(m,2H),1.63–1.61(m,2H), LCMS m/z=469.9[M+H] ⁺ .

Synthesis of Example 37

To a DCM (5 mL) solution of 67-1 (5 g, 20.9 mmol) was added 5 mL of 4 M hydrochloric acid (1,4-dioxane) at 0°C and reacted at room temperature for 2 hours. The filter cake was filtered, washed with ether, and dried in vacuo to obtain a brown solid 37-2 (2 g, yield 69%), LCMS m/z = 140.1 [M+H] ⁺ .

Under oxygen atmosphere, compound 37-2 (1 g, 7.2 mmol) was added to a DMF (10 mL) solution of phenylboronic acid (1.8 g, 14.4 mmol), Cu(OAc) ₂ (copper acetate, 144 mg, 0.72 mmol), DIEA (3.7 g, 28.8 mmol), and pyridine (2.3 g, 28.8 mmol), and the mixture was reacted at room temperature for 16 hours. 10 mL of water was added, and the mixture was extracted with DCM (30 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain a yellow oil 37-3 (80 mg, yield 5%), LCMS m/z=216.3[M+H] ⁺ .

STAB (236 mg, 1.12 mmol) was added to a DMF (2 mL) solution of 37-3 (80 mg, 0.37 mmol) and M5 (121 mg, 0.37 mmol) and reacted at room temperature for 16 hours. Purification by C18 column chromatography (acetonitrile/water) was performed to obtain 37 as a yellow solid. (15 mg, yield 10%), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.22-7.13 (m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 5.10 (dd, J = 13.4, 5.0 Hz, 1H), 4.42 (d, J = 17.4 Hz, 1H), 4.2 8(d,J＝17.2Hz,1H),3.15–3.09(m,2H),3.09–3.01(m,2H),2.99–2.85(m,3H),2.77–2.54(m,3H),2 .42–2.32(m,1H),2.06–1.94(m,3H),1.86–1.73(m,4H),1.71–1.63(m,4H),1.62–1.50(m,4H), LCMS m/z=527.7[M+H] ⁺ .

Synthesis of Example 38

Replace 25-1 with 2-oxaspiro[4.5]decan-8-one, and adopt the synthesis method of Example 25 to Example 38: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 8.15 (s, 1H), 7.61 (d, J＝8.0 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J＝8.8 Hz, 1H), 5.07 (dd, J＝13.3, 5.1 Hz, 1H), 4.41-4.21 (m, 2H), 3.67 (m, 3H), 3.44 (s, 1H), 3.06-2.99 (m, 2 H),2.92–2.83(m,1H),2.68–2.52(m,2H),2.42–2.30(m,4H),1.97–1.92(m,1H),1.83–1.7 5(m,2H),1.73–1.69(m,3H),1.67–1.61(m,3H),1.59–1.54(m,2H),1.44–1.21(m,5H), LCMS m/z=466.4[M+H] ⁺ .

Synthesis of Example 39

M5 was replaced by M6, 25-1 was replaced by 2-oxaspiro[3.5]nonan-7-one, and the synthesis method of Example 25 was used to obtain Example 39: white solid, ¹ H NMR (500 MHz, Methanol-d ₄ ) δ7.77 (d, J=8.1 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.52-4.43 (m, 4H), 4.35 (s, 2H), 2.94-2.87 (m, 1H), 2.86-2.78 (m, 4H ),2.55–2.47(m,1H),2.46–2.38(m,1H),2.27–2.21(m,2H),2.19–2.11(m,3H),1 .98–1.90(m,2H),1.81–1.74(m,2H),1.55–1.48(m,2H),1.37–1.27(m,3H), LCMS m/z=468.2[M+H] ⁺ .

Synthesis of Example 40

M5 was replaced by M6, 25-1 was replaced by 2-oxaspiro[3.3]heptane-6-one, and the synthesis method of Example 25 was used to Example 40: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.99(s,1H),7.75–7.59(m,3H),5.11(dd,J＝13.2,5.0Hz,1H),5.02(s,1H),4.60(s,2H),4.46(s,2H),4.43–4.22(m,2H LCMS m/z=440.3[M+H] ⁺ .

Synthesis of Example 41

M5 was replaced by M13, 25-1 was replaced by 2-oxaspiro[3.5]nonan-7-one, and the synthesis method of Example 25 was used to Example 41: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.89(d,J＝6.8Hz,1H),7.48(d,J＝10.8Hz,1H),5.16–5.11(m,1H),4.49– 4.45(m,4H),4.34(s,2H),3.36–3.33(m,2H),3.04–3.00(m,1H),2.93–2.8 4(m,1H),2.79–2.73(m,1H),2.63–2.55(m,2H),2.53–2.41(m,1H),2.34–2 .27(m,2H),2.19–2.00(m,4H),1.95–1.87(m,2H),1.60–1.48(m,5H), LCMS m/z＝485.9[M+H] ⁺ .

Synthesis of Example 42

M5 was replaced by M14, 25-1 was replaced by 2-oxaspiro[3.5]nonan-7-one, and the synthesis method of Example 25 was used to Example 42: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.97(s,1H),7.68–7.53(m,3H),5.10(dd,J＝13.2,5.0Hz,1H),4.90(s ,1H),4.47–4.30(m,2H),4.28(s,2H),4.23(s,2H),3.48(s,2H),2.97–2.8 5(m,1H),2.65–2.55(m,1H),2.42–2.32(m,2H),2.21–2.05(m,4H),2.02–1 .98(m,3H),1.77–1.63(m,6H),1.54–1.42(m,2H),1.14–1.12(m,2H), LCMS m/z=494.2[M+H] ⁺ .

Synthesis of Example 43

M5 was replaced by M13, 25-1 was replaced by 3-oxabicyclo[3.2.1]octan-8-one, and the synthesis method of Example 25 was used to Example 43: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.93(d,J＝6.8Hz,1H),7.53(d,J＝2.4Hz,1H),5.17–5.10(m,1H),4.48–4.40(m,2H),3.62–3.59(m,1H),3.52–3.30(m,2H) LCMS m/z=471.9[M+H] ⁺ .

Synthesis of Example 44

M5 was replaced by M12, 25-1 was replaced by 3-oxabicyclo[3.2.1]octan-8-one, and the synthesis method of Example 25 was used to obtain Example 44: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.45(s,1H),7.63-7.60(m,1H),7.54-7.47(m, 1H),5.13(dd,J＝13.3,5.2Hz,1H),4.60–4.47(m,4H),3.71–3.55(m,2H),3.25–3.15(m,1H),3.03–2.83(m,3H),2.7 9–2.73(m,1H),2.65–2.52(m,1H),2.51–2.43(m,1H),2.17–1.96(m,9H),1.83–1.77(m,3H),1.51–1.43(m,1H), LCMS m/z=455.9[M+H] ⁺ .

Synthesis of Example 47

Replace 37-1 with N-tert-butyloxycarbonyl-nortropinone, and use the synthesis method of Example 37 to Example 47: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.97(s,1H),7.61(d,J＝7.8Hz,1H),7.44(s,1H),7.35(d,J＝7.8Hz,1H) ,7.18(dd,J＝8.3,7.4Hz,2H),6.80(d,J＝8.0Hz,2H),6.62(t,J＝7.2Hz,1H), 5.09(dd,J＝13.3,5.1Hz,1H),4.46–4.21(m,4H),2.96–2.79(m,4H),2.69– 2.58(m,2H),2.43–2.31(m,1H)2.11–1.93(m,5H),1.82–1.53(m,10H), LCMS m/z=513.2[M+H] ⁺ .

Synthesis of Example 48

Replace 37-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, and adopt the synthetic method of Example 37 to Example 48: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) 10.99 (s, 1H), 8.24 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.21-7.07 (m, 2H), 6.70-6.61 (m, 1H), 6.40 (d, J=7.4 Hz, 2H), 5.24-4.98 (m, 1H) ,4.58–4.22(m,2H),3.82(s,2H),3.70(s,2H),2.99–2.86(m,3H),2.71–2.56(m,4H ),2.43–2.29(m,3H),2.09–1.95(m,3H),1.87–1.77(m,4H),1.71–1.66(m,2H), LCMS m/z=499.1[M+H] ⁺ .

Synthesis of Example 49

M5 was replaced by M14, 25-1 was replaced by 3-oxabicyclo[3.2.1]octan-8-one, and the synthesis method of Example 25 was used to obtain Example 49: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ ) δ8.51 (s, 1H), 7.81 (dd, J=8.1, 1.6 Hz, 1H), 7.77 (s, 1H), 7.68 (dd, J=8.1, 1.2 Hz, 1H), 5.16 (dd, J=13.3, 5.1 Hz, 1H), 4.57-4.45 (m, 4H), 3.69-3.55 (m, 1H), 3.56-3.43 (m, 2H), 3 .37–3.33(m,1H),3.28–3.21(m,1H),2.98–2.87(m,1H),2.83–2.74(m,1H),2.70–2.61( m,1H),2.56–2.44(m,1H),2.38–2.27(m,2H),2.21–1.96(m,7H),1.88–1.76(m,3H), LCMS m/z=453.9[M+H] ⁺ .

Synthesis of Example 50

Replace 37-1 with tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate, and adopt the synthesis method of Example 37 to Example 50: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.28 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.63 (t, J = 7.4 Hz, 1H), 6.40 (d, J = 7.8 Hz, 2H), 5.12-5.10 (dd, J = 13.4, 6.0 Hz, 1H),4.46–4.25(m,2H),3.53(s,2H),3.46(s,2H),3.00–2.84(m,3H),2.71–2.55(m,2H),2.45– 2.26(m,5H),2.01–1.90(m,3H),1.82–1.61(m,6H),1.58–1.47(m,2H),1.39–1.33(m,2H), LCMS m/z=527.1[M+H] ⁺ .

Synthesis of Example 51

Replace 37-1 with 8-oxo-2-azaspiro[4-]decane-2-carboxylic acid tert-butyl ester, and adopt the synthesis method of Example 37 to Example 51: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.25 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.18-7.10 (m, 2H), 6.59-6.51 (m, 2H), 6.47 (d, J = 7.4 Hz, 1H), 5.10 (d, J = 8.2 Hz, 1H), 4.42 (d, J = 17.4 Hz, 1H), 4.28(d,J＝17.2Hz,1H),3.26–3.21(m,2H),3.11(s,1H),3.06–2.95(m,3H),2.94–2.82(m,1H),2.6 8–2.64(m,2H),2.45–2.28(m,5H),2.05–1.95(m,1H),1.90–1.61(m,10H),1.52–1.33(m,4H), LCMS m/z=541.2[M+H] ⁺ .

Synthesis of Example 52

Under nitrogen atmosphere, a solution of 52-1 (1.0 g, 4.25 mmol) in DCM (10 mL) was cooled to -78 °C, trifluoromethanesulfonic anhydride (1.44 g, 5.10 mmol) and TEA (2.58 g, 25.51 mmol) were added, and the temperature was slowly raised to room temperature for 16 hours. The mixture was quenched with 20 mL of saturated sodium bicarbonate solution, extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give a white solid 52-2 (320 mg, yield 21%), ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 6.54 (s, 1H), 4.32–4.17 (m, 2H), 4.00 (t, J＝10.9 Hz, 2H), 1.46 (s, 9H).

Under nitrogen atmosphere, 52-2 (0.15 g, 408 μmol) and M1 (152 mg, 408.4 μmol) in 1,4-dioxane (4 mL) were added. Na ₂ CO ₃ (65 mg, 612.6 μmol) and Pd(dppf)Cl ₂ (66 mg, 82 μmol) were added to the solution of 1 mL of water, and the mixture was reacted at 60° C. for 3 hours. After the mixture was returned to room temperature, 10 mL of water was added, and the mixture was extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM/MeOH) to give a white solid 52-3 (140 mg, yield 55%), LCMS m/z=461.9 [M+H] ⁺ .

Under hydrogen atmosphere, Pd(OH) ₂ /C (15% purity, 60 mg, 64.3 μmol) was added to a DMF (10 mL) solution of 52-3 (0.14 g, 303.4 μmol), and the mixture was reacted at 40°C for 16 hours. The mixture was filtered through Celite pad, and the filter cake was washed with DMF. 10 mL of water was added, and the mixture was extracted with DCM (30 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a black solid 52-4 (120.00 mg, yield 85%), LCMS m/z=407.9 [M-55] ⁺ .

Under nitrogen atmosphere, TFA (89 mg, 778 mmol) was added to a DCM (10 mL) solution of 52-4 (120 mg, 259 μmol), and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried in vacuo to obtain a black solid 52-5 (90 mg, yield 95%), LCMS m/z=362.2 [M+H] ⁺ .

Under nitrogen atmosphere, STAB (158 mg, 743 μmol) was added to a DMF (10 mL) solution of 52-5 (90 mg, 248 μmol) and 25-1 (35 mg, 248 μmol), and the mixture was reacted at 40°C for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 52 (5.5 mg, yield 5%) as a white solid. ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.75(d,J＝7.6Hz,1H),7.56(s,1H),7.48(d,J＝8.0Hz,1H),5.13(dd,J＝13.3,5. 2Hz,1H),4.53–4.43(m,2H),3.66–3.60(m,2H),3.58–3.53(m,2H),3.19–3.14(m, 1H),3.08–3.00(m,1H),2.95–2.83(m,2H),2.79–2.73(m,1H),2.53–2.42(m,1H), 2.29–1.89(m,8H),1.77–1.72(m,1H),1.69–1.62(m,3H),1.58–1.55(m,2H), LCMS m/z=488.0[M+H] ⁺ .

Synthesis of Example 53

The tert-butyl group of 2-oxo-6-azanaphtho[3.4]6-carboxylate was replaced by 37-1, and the synthesis method of Example 37 was used to obtain Example 53: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.73(d,J＝8.0Hz,1H),7.48(s,1H),7.42(dd,J＝8.0,1.0Hz,1H),7.17– 7.08(m,2H),6.62–6.46(m,3H),5.13(dd,J＝12.0,4.0Hz,1H),4.52–4.39 (m,2H),3.34–3.22(m,3H),3.24–3.18(m,3H),2.94–2.72(m,3H),2.52–2 .42(m,1H),2.31–2.22(m,4H),2.18–1.93(m,8H),1.90–1.83(m,2H), LCMS m/z=513.0[M+H] ⁺ .

Synthesis of Example 54

Replace 37-1 with tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2-carboxylate, and adopt the synthesis method of Example 37 to Example 54: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.72(d, J＝8.0 Hz, 1H),7.39(s, 1H),7.35(d, J＝7.9 Hz, 1H),7.21-7.14(m, 2H),6.74-6.70(m, 3H),5.12(dd, J＝12.0,4.0 Hz, 1H),4.50-4.37(m, 2H),3.62-3.49 (m,2H),3.42–3.35(m,2H),3.19–3.07(m,3H),2.92–2.69(m,7H),2.51–2.44(m,3H ),2.19–2.10(m,1H),2.10–1.97(m,2H),1.95–1.79(m,2H),1.71–1.56(m,2H), LCMS m/z=513.0[M+H] ⁺ .

Synthesis of Example 55

Under nitrogen atmosphere, Selectfluor (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt, 0.85 g, 2.4 mmol) was added to a solution of M5-2 (0.85 g, 2 mmol) in ACN (10 mL) and water (3 mL), and the mixture was reacted at room temperature for 0.5 hours, and Selectfluor (0.35 g, 1 mmol) was added, and the mixture was reacted at 50°C for 1 hour. The mixture was returned to room temperature, quenched with 20 mL of saturated sodium bicarbonate solution, extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (DCM/MeOH) to give 55-1 as a white solid (140 mg, yield 15%), LCMS m/z=406.2[M-55] ⁺ .

Under nitrogen atmosphere, TFA (104 mg, 910 μmol) was added to a solution of 55-1 (0.14 g, 303 μmol) in DCM (10 mL), and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried in vacuo to obtain a black solid 55-2 (35 mg, yield 30%), LCMS m/z=362.3 [M+H] ⁺ .

Under nitrogen atmosphere, STAB (53 mg, 249 μmol) was added to a DMF (10 mL) solution of 55-2 (30 mg, 83 μmol) and 25-1 (12 mg, 83 μmol), and the mixture was reacted at 40°C for 1 hour. The mixture was quenched with 10 mL of saturated sodium bicarbonate solution and extracted with DCM (10 mL×3). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a white solid 55 (26.3 mg, yield 65%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.81–7.78(m,2H),7.71–7.68(m,1H),5.14(dd,J＝13.3,5.1Hz,1H),5.10–4.9 4(m,1H),4.55–4.44(m,2H),3.66–3.53(m,4H),3.17–3.11(m,2H),2.97–2.83(m, 2H),2.80–2.73(m,1H),2.65–2.60(m,1H),2.54–2.42(m,2H),2.22–2.13(m,3H), 2.11–2.03(m,1H),1.92–1.86(m,1H),1.81–1.73(m,2H),1.68–1.54(m,4H), LCMS m/z=485.9[M+H] ⁺ .

Synthesis of Example 56

Under nitrogen atmosphere, Cs ₂ CO ₃ (2 g of cesium carbonate, 6.18 mmol) was added to a solution of 2-fluoropyridine (200 mg, 2.06 mmol) and 37-2 (434 mg, 2.47 mmol) in ACN (3 mL), and the mixture was reacted at room temperature for 3 hours. The mixture was filtered through celite pad, the filter cake was washed with EA, and the mixture was decompressed. The filtrate was concentrated, and the residue was purified by silica gel flash column chromatography (PE/EA) to give white solid 56-1 (280 mg, yield 63%), LCMS m/z=217.1 [M+H] ⁺ .

Under nitrogen atmosphere, STAB (20 mg, 92 μmol) was added to a DMF (1.5 mL) solution of 56-1 (20 mg, 92 μmol), and the mixture was reacted for 15 minutes. Intermediate M5 (34 mg, 92 μmol) was added and the mixture was reacted at room temperature for 16 hours. 5 mL of water was added, and the mixture was extracted with EA (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (DCM/MeOH) to give a white solid 56 (23 mg, yield 47%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ10.98(s,1H),8.08(d,J＝3.5Hz,1H),7.65(d,J＝7.8Hz,1H),7.53–7.46(m,2H),7.41(d,J＝7.8Hz,1H),6.81(d ,J＝8.6Hz,1H),6.58(dd,J＝6.3,5.4Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.43(d,J＝17.2Hz,1H),4.30(d,J＝17. 1Hz,1H),3.52–3.47(m,2H),3.43–3.40(m,2H),2.97–2.88(m,3H),2.76–2.69(m,1H),2.66–2.58(m,2H),2.44–2 .36(m,1H),2.05–1.98(m,3H),1.84–1.75(m,4H),1.73–1.66(m,2H),1.62–1.56(m,4H),1.53–1.48(m,2H), LCMS m/z=528.7[M+H] ⁺ .

Synthesis of Example 57

Replace 37-1 with 5-oxo-2-azaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester, and adopt the synthesis method of Example 37 to Example 57: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.72(d, J＝7.9 Hz, 1H),7.48(s, 1H),7.42(d, J＝8.3 Hz, 1H),7.19-7.12(m, 2H),6.69-6.64(m, 1H),6.45(d, J＝8.5 Hz, 2H),5.14(dd, J＝13.5,5.3 Hz, 1H),4.52-4.40(m, 2H),4.37(d, J＝7.7 Hz, 1H),3.81(d, J＝8. .2Hz,1H),3.73–3.66(m,2H),3.07–2.97(m,1H),2.96–2.86(m,1H),2.76–2.69(m,2H),2.56–2.42(m,1 LCMS m/z=499.0[M+H] ⁺ .

Synthesis of Example 58

Under nitrogen atmosphere, a solution of 55-1 (200 mg, 433 μmol) in DCM (5 mL) was cooled to 0°C, TEA (132 mg, 1.30 mmol) and MsCl (methylsulfonyl chloride, 99 mg, 867 μmol) were added, and the temperature was raised to 25°C for 16 hours. 10 mL of water was added for dilution, extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE/EA) to give a white solid 58-1 (60 mg, yield 31%), LCMS m/z=443.9 [M+H] ⁺ .

Under hydrogen atmosphere, Pd(OH) ₂ /C (purity 15%, 25 mg, 27 μmol) was added to a solution of 58-1 (60 mg, 135 μmol) in DMF (10 mL), and the mixture was reacted at 40° C. for 16 hours. The mixture was filtered through celite and concentrated under reduced pressure. The mixture was extracted with DCM (10 mL×3) and freeze-dried with water to obtain a black solid 58-2 (60 mg, yield 99%). LCMS m/z=445.9 [M+H] ⁺ .

Under nitrogen atmosphere, TFA (46 mg, 404 μmol) was added to a solution of 58-2 (60 mg, 135 μmol) in DCM (10 mL), and the mixture was reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure and dried in vacuo to obtain a black solid 58-3 (45 mg, yield 99%), LCMS m/z=345.9 [M+H] ⁺ .

Under nitrogen atmosphere, STAB (92 mg, 434 μmol) was added to a DMF (10 mL) solution of 58-3 (45 mg, 130 μmol) and 37-1 (20 mg, 145 μmol), and the mixture was reacted at 40°C for 1 hour. 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain a white solid 58 (6.7 mg, yield 10%). ¹ H NMR (400 MHz, Methanol-d ₄ )δ7.75(d,J＝7.6Hz,1H),7.56(s,1H),7.49(d,J＝8.4Hz,1H),5.16–5.11(m,1H),5.03–4.91(m,1H ),4.53–4.42(m,2H),3.66–3.61(m,2H),3.59–3.47(m,3H),3.36–3.30(m,1H),3.26–3.22(m,1H), 3.18–3.05(m,1H),2.93–2.84(m,1H),2.79–2.73(m,1H),2.70–2.57(m,1H),2.52–2.36(m,3H),2. 25–2.13(m,3H),1.97–1.90(m,2H),1.84–1.79(m,1H),1.68–1.63(m,2H),1.62–1.57(m,2H), LCMS m/z=470.1[M+H] ⁺ .

Synthesis of Example 59

Replace 37-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, replace phenylboronic acid with 2-fluorophenylboronic acid. Use the synthesis method of Example 37 to Example 59: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),8.26(s,1H),7.65(d,J＝7.8Hz,1H),7.50(s,1H),7.41(d,J＝7.6Hz,1H),7.09-6.95(m,2H),6.74-6.65(m,1H),6.56-6.47(m,1H),5.11(dd,J＝13.2,5.0Hz,1H) ,4.43(d,J＝17.0Hz,1H),4.29(d,J＝17.2Hz,1H),3.93(s,2H),3.80(s,2H),2.97–2.87( m,3H),2.71–2.57(m,5H),2.45–2.29(m,3H),2.06–1.96(m,3H),1.89–1.61(m,5H), LCMS m/z=517.3[M+H] ⁺ .

Synthesis of Example 60

Replace 37-1 with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, replace phenylboronic acid with 2-methoxyphenylboronic acid. Use the synthesis method of Example 37 to Example 60: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.31 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=7.7 Hz, 1H), 6.84–6.76 (m, 2H), 6.71–6.66 (m, 1H), 6.35 (dd, J=7.7, 1.3 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4. 46–4.25(m,2H),3.84(s,2H),3.73–3.69(m,5H),2.97–2.87(m,3H),2.70–2.57(m,4H),2.45– 2.36(m,1H),2.32–2.23(m,2H),2.05–1.92(m,3H),1.88–1.74(m,4H),1.72–1.60(m,2H), LCMS m/z=529.2[M+H] ⁺ .

Synthesis of Example 61

Replace 25-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, and adopt the synthesis method of Example 25 to Example 61: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.10 (dd, J = 13.2, 5.0 Hz, 1H), 4.42 (d, J = 17.4 Hz, 1H), 4.28 (d, J = 17.4 Hz, 1H), 3.85 (s, 2H) ,3.73(s,2H),2.98–2.83(m,3H),2.64–2.54(m,3H),2.45–2.36(m,1H),2.31–2.20 (m,2H),2.05–1.88(m,3H),1.85–1.73(m,4H),1.70–1.55(m,2H),1.36(s,9H), LCMS m/z=523.2[M+H] ⁺ .

Synthesis of Example 62

Under nitrogen atmosphere, TFA (1.62 g, 14.20 mmol) was added to a solution of 62-1 (1.0 g, 4.73 mmol) in DCM (10 mL), and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to obtain a yellow oil 62-2 (0.5 g, yield 95%), LCMS m/z=112.0 [M+H] ⁺ .

Under nitrogen atmosphere, NaHCO ₃ (sodium bicarbonate, 1.13 g, 13.5 mmol) and methyl chloroformate (850 mg, 9.00 mmol) were added to a solution of compound 62-2 (0.5 g, 4.50 mmol) in THF (10 mL) and water (5 mL), and the mixture was reacted at room temperature for 4 hours. 20 mL of water was added for dilution, and the mixture was extracted with DCM (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil 62-3 (140 mg, yield 18%), LCMS m/z=170.0 [M+H] ⁺ .

STAB (195 mg, 916 μmol) was added to a DMF (2 mL) solution of M5 (0.1 g, 306 μmol) and 62-3 (52 mg, 306 μmol), and the mixture was reacted at 40°C for 1 hour. The reaction system was filtered, and the filtrate was purified by preparative HPLC to obtain a white solid 62 (23 mg, yield 15%). ¹ H NMR (400 MHz, Methanol-d ₄ )7.74(d,J＝8.0Hz,1H),7.47(s,1H),7.42(d,J＝8.0Hz,1H),5.13(dd,J＝13.3, 5.2Hz,1H),4.51–4.40(m,2H),4.03(s,2H),3.92(s,2H),3.62(s,3H),3.36–3. 29(m,2H),3.25–3.21(m,1H),2.93–2.84(m,2H),2.79–2.73(m,1H),2.55–2.41 (m,5H),(m,2H),2.18–2.11(m,1H),2.08–1.99(m,2H),1.93–1.83(m,2H), LCMS m/z＝480.9[M+H] ⁺ .

Synthesis of Example 63

Replace 25-1 with 5-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, and adopt the synthesis method of Example 25 to Example 63: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ10.99 (s, 1H), 7.64 (d, J＝7.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J＝ 8.2Hz,1H),5.10(dd,J＝13.4,5.1Hz,1H),4.42(d,J＝17.3Hz,1H),4.28(d,J＝17.1Hz,1H),4.26–4.19(m,1H),3.75–3.64( LCMS m/z=523.7[M+H] ⁺ .

Synthesis of Example 64

Replace 25-1 with 6-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, and adopt the synthesis method of Example 25 to Example 64: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ )δ10.99(s,1H),7.70–7.61(m,1H),7.48(s,1H),7.39(d,J＝7.6Hz,1H),5.10(dd,J＝13.3,5.0Hz,1H),4.42(d,J＝17.1Hz,1H),4.29(d,J＝17.6 LCMS m/z=551.4[M+H] ⁺ .

Synthesis of Example 65

Replace 25-1 with 2-oxaspiro[3.3]heptane-5-one, and adopt the synthesis method of Example 25 to Example 65: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ10.99 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=7.7 Hz, 1H), 5.10 (dd, J=13.3, 5.0 Hz, 1H), 4.92 (d, J=5.9 Hz, 1H), 4.46 (d, J=7.0 Hz, 1H), 4.45-4.40 (m, 1H ),4.37(d,J＝6.7Hz,1H),4.29(d,J＝16.8Hz,1H),2.94–2.83(m,2H),2.73–2.64(m,2 H),2.63–2.54(m,4H),2.39–2.36(m,1H),2.05–1.97(m,2H),1.94–1.69(m,8H), LCMS m/z=424.3[M+H] ⁺ .

Synthesis of Example 66

M5 was replaced by M16, 25-1 was replaced by 2-oxaspiro[3.3]heptane-6-one, and the synthesis method of Example 25 was used to Example 66: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ )δ10.97(s,1H),7.63(d,J＝7.9Hz,1H),7.48(s,1H),7.38(d,J＝7.5Hz,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.61-4.55(m,2H),4.45-4.44(m,1H),4.43-4.37(m,1H),4.32-4.22(m,1H) ,3.19–3.13(m,1H),3.00–2.82(m,3H),2.64–2.53(m,2H),2.42–2.26(m,4H),2.02–1.96(m ,1H),1.95–1.74(m,4H),1.74–1.66(m,1H),1.63–1.54(m,2H),0.97(d,J＝6.7Hz,3H), LCMS m/z=438.5[M+H] ⁺ .

Synthesis of Example 67

M5 was replaced by M16, 25-1 was replaced by 2-oxaspiro[3.5]nonane-7-one, and the synthesis method of Example 25 was used to Example 67: white solid, ¹ H NMR (400 MHz, Methanol-d ₄ )δ8.51(s,1H),7.69–7.55(m,2H),5.14(dd,J＝13.4,5.1Hz,1H),4.65–4.47(m,2H),4.05–3.92(m,2H),3.53–3.45(m,1H),3.41–3.29(m,7H) ,2.97–2.83(m,1H),2.82–2.72(m,1H),2.55–2.38(m,3H),2.37–2.23(m,2H),2.20–1.84(m,5H),1.79–1.67(m,2H),1.65–1.53(m,2H), LCMS m/z=469.9[M+H] ⁺ .

Synthesis of Example 68

To a solution of compound 63 (270 mg, 0.52 mmol) in DCM (2.7 mL) was added 1.29 mL of 4M hydrochloric acid (1,4-dioxane) at 0°C, and reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to obtain a white solid 68-1 (0.15 g, yield 51%), LCMS m/z=423.3 [M+H] ⁺ .

Under nitrogen atmosphere, triethylamine (61 μL, 437 μmol) was added to a DMF (1 mL) solution of 68-1 (50 mg, 87.5 μmol), the temperature was lowered to 0°C, acetyl chloride (10 mg, 131 μmol) in 1 mL DMF was added dropwise, and the mixture was stirred at room temperature for 1 hour. 10 mL of water was added to the reaction system, and the residue was lyophilized and purified by preparative thin layer chromatography to obtain a white solid 68 (7.9 mg, yield: 19%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ10.99(s,1H),7.64(dd,J＝7.8,4.5Hz,1H),7.51(s,1H),7.41(d,J＝7.8Hz,1H),5.37(dd, J＝27.2,6.0Hz,1H),5.10(dd,J＝13.3,5.0Hz,1H),4.51–4.36(m,2H),4.32–4.25(m,1H),4.1 9(dd,J＝9.4,3.2Hz,1H),3.98–3.89(m,2H),3.72–3.59(m,2H),2.96–2.80(m,3H),2.72–2. 54(m,3H),2.44–2.34(m,2H),2.02–1.95(m,2H),1.90–1.78(m,5H),1.74–1.69(m,3H), LCMS m/z=465.6[M+H] ⁺ .

Synthesis of Example 69

Compound 63 was replaced by compound 64, and the synthesis method of Example 68 was used to prepare Example 69: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.45 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.3 Hz, 1H), 3.91-3.73 (m, 2H), 3.64-3.45 (m ,3H),3.20–3.00(m,3H),3.00–2.85(m,2H),2.63–2.56(m,1H),2.45–2.32(m,2H),2.25–1.92 (m,6H),1.83–1.78(m,1H),1.75(d,J＝3.6Hz,3H),1.71–1.62(m,1H),1.41–1.21(m,4H), LCMS m/z=493.70[M+H] ⁺ .

Synthesis of Example 70

PCC (pyridinium chlorochromate, 489 mg, 2.27 mmol) was added to a solution of 70-1 (200 mg, 1.13 mmol) in DCM (5 mL), and the mixture was reacted at room temperature for 3 hours. The mixture was filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (PE:EA) to give a colorless oil 70-2 (120 mg, yield 60%), ¹ H NMR (500 MHz, CDCl ₃ ) δ9.40 (s, 1H), 7.38–7.33 (m, 2H), 7.30–7.26 (m, 2H), 7.26–7.25 (m, 1H), 2.57–2.49 (m, 2H), 1.94–1.85 (m, 2H), 1.79–1.73 (m, 2H), 1.69–1.62 (m, 2H).

Under nitrogen atmosphere, STAB (1.46 g, 6.89 mmol) was added to a DMF (3 mL) solution of M5 (248 mg, 681 μmol) and 69-2 (120 mg, 688 μmol), and the mixture was reacted at 60°C for 16 hours. The mixture was returned to room temperature, and the pH value of the system was adjusted to 8 with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with EA (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give 70 (15 mg, yield 4%) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ )δ10.99(s,1H),7.61(d,J＝7.9Hz,1H),7.43(s,1H),7.36–7.30(m,3H),7.27(t,J＝7.7Hz,2H),7 .14(t,J＝7.2Hz,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.40(d,J＝17.3Hz,1H),4.27(d,J＝17.2Hz,1H ),2.94–2.86(m,1H),2.64–2.56(m,1H),2.48–2.43(m,1H),2.42(s,2H),2.40–2.31(m,3H),2.1 3–2.01(m,4H),2.01–1.95(m,1H),1.77–1.65(m,4H),1.65–1.59(m,2H),1.58–1.49(m,4H), LCMS m/z=486.8[M+H] ⁺ .

Synthesis of Example 71

Replace 25-1 with 7-oxaspiro[3.5]nonan-1-one, and adopt the synthesis method of Example 25 to Example 71: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ10.99 (s, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J=7.8 Hz, 1H), 5.10 (dd, J=13.2, 4.7 Hz, 1H), 4.41 (d, J=17.2 Hz, 1H), 4.28 (d, J=16.8 Hz, 1H), 3.86-3.72 (m, 1H), 3.70-3.59 (m, 1H), 3.44-3.37 (m, 1H), 3. 20–3.15(m,1H),2.96–2.86(m,2H),2.85–2.75(m,1H),2.66–2.55(m,2H),2.44–2.36(m,2H),2.33–2.26(m ,1H),2.05–1.95(m,2H),1.94–1.82(m,2H),1.79–1.69(m,5H),1.68–1.57(m,3H),1.46–1.32(m,2H), LCMS m/z=452.6[M+H] ⁺ .

Synthesis of Example 72

The acetyl chloride was replaced by 2-methylpropane-1-sulfonyl chloride, and the synthesis method of Example 68 was used to Example 72: white solid, ¹ H NMR(500MHz,DMSO-d ₆ )δ10.98(s,1H),7.64(d,J＝7.9Hz,1H),7.52(s,1H),7.42(d,J＝7.9Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.2Hz,1 H),4.29(d,J＝17.1Hz,1H),4.22(d,J＝7.9Hz,1H),3.81–3.68(m,3H),3.25(d,J＝11.6Hz,1H),2.98–2.92(m,2H),2.92–2.86(m ,1H),2.83(d,J＝10.7Hz,1H),2.72–2.64(m,1H),2.63–2.55(m,2H),2.44–2.37(m,1H),2.11–2.04(m,1H),2.03–1.96(m,2H), 1.91–1.84(m,3H),1.84–1.74(m,4H),1.73–1.65(m,1H),1.51–1.44(m,1H),1.02(d,J＝0.8Hz,3H),1.00(d,J＝0.8Hz,3H), LCMS m/z=543.7[M+H] ⁺ .

Synthesis of Example 73

Acetyl chloride was replaced by isovaleryl chloride, and the synthesis method of Example 68 was used to Example 73: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ10.98 (s, 1H), 7.67–7.61 (m, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.36 (dd, J=23.4, 6.0 Hz, 1H), 5.13–5.07 (m, 1H), 4.50–4.43 (m, 1H), 4.43–4.38 (m, 1H), 4.32–4.26 (m, 1H), 4.26–4.17 (m, 1H), 4.00–3.89 (m, 2H), 3.7 3–3.62(m,2H),2.97–2.89(m,1H),2.89–2.81(m,2H),2.68–2.63(m,1H),2.62–2.56(m,2H),2.41–2.35(m,1H),2.0 2–1.96(m,2H),1.93–1.85(m,4H),1.83–1.76(m,2H),1.75–1.69(m,2H),0.91–0.89(m,1H),0.89–0.82(m,6H), LCMS m/z=543.7[M+H] ⁺ .

Synthesis of Example 75

25-1 was replaced with 1-oxo-7-azaspiro[1-3]nonane-7-carboxylic acid tert-butyl ester, and the synthesis method of Example 25 was used to Example 75: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ )δ10. ¹ H NMR (500 MHz, DMSO-d ₆ )98(s,1H),7.63(d,J＝7.9Hz,1H),7.49(s,1H),7.38(d,J＝8.0Hz,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.41(d ,J＝17.2Hz,1H),4.28(d,J＝17.2Hz,1H),3.94–3.85(m,1H),3.81–3.74(m,1H),2.94–2.87(m,1H),2.83–2.76 (m,2H),2.67–2.54(m,3H),2.54–2.52(m,1H),2.46–2.39(m,1H),2.39–2.29(m,2H),2.01–1.95(m,1H),1.94 LCMS m/z=551.7[M+H] ⁺ .

Synthesis of Example 76

Replace 25-1 with 7-oxaspiro[3.5]nonan-1-one, replace M5 with M12, and use the synthesis method of Example 25 to Example 76: White solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.14 (s, 1H), 7.53–7.47 (m, 1H), 5.08 (dd, J=13.3, 5.1 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 4.33 (d, J=17.3 Hz, 1H), 3.78–3.71 (m, 1H), 3.61 (dd, J=11.2, 4.0 Hz, 1H), 3.39–3.35 (m, 2H), 3.17–3.1 2(m,1H),2.94–2.83(m,3H),2.81–2.74(m,1H),2.62–2.52(m,1H),2.44–2.34(m,1H),2.33–2.24(m,1H LCMS m/z=470.3[M+H] ⁺ .

Synthesis of Example 77

25-1 was replaced by 2-oxaspiro[3.3]heptane-5-one, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 77: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.21 (s, 1H), 7.56–7.49 (m, 2H), 5.15–5.02 (m, 1H), 4.93–4.85 (m, 1H), 4.56–4.30 (m, 5H), 3.00–2.77 (m, 4H), 2.67–2.53 (m, 2H), 2.43–2.29 (m, 1H), 2.08–1.94 (m, 2H), 1.92–1.69 (m, 9H), 1.44–1.33 (m, 1H), LCMS m/z＝441.9[M+H] ⁺ .

Synthesis of Example 81

Replace 25-1 with tert-butyl 1-oxo-7-azaspiro[1-3]nonane-7-carboxylate, replace M5 with M12, and adopt the synthesis method of Example 25 to Example 81: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 7.56–7.44 (m, 2H), 5.08 (dd, J=13.4, 5.1 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 4.33 (d, J=17.2 Hz, 1H), 3.95–3.70 (m, 2H), 2.96–2.83 (m, 2H), 2.83–2.68 (m ,3H),2.60–2.53(m,1H),2.44–2.37(m,1H),2.36–2.28(m,1H),2.01–1.93(m,1H), 1.90–1.78(m,2H),1.77–1.62(m,8H),1.52–1.43(m,2H),1.40–1.31(m,12H), LCMS m/z=569.0[M+H] ⁺ .

Synthesis of Example 82

25-1 was replaced by 6-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 82: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),7.61–7.35(m,2H),5.08(dd,J＝13.3,5.1Hz,1H),4.52(d,J＝17.4Hz,1H),4.34(d,J＝17.3Hz,1H),3.67– 3.42(m,5H),2.96–2.83(m,2H),2.60–2.52(m,1H),2.45–2.30(m,3H),2.02–1.92(m,2H),1.89–1.58(m,6H),1.40–1.30 (m,11H),1.29–1.13(m,5H), LCMS m/z=568.9[M+H] ⁺ .

Synthesis of Example 83

25-1 was replaced by spiro[3.5]nonane-2-one, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 83: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.97(s,1H),7.52–7.49(m,2H),5.07(dd,J＝13.3,5.2Hz,1H),4.51(d,J＝17.4Hz,1H),4.33(d,J＝17.3Hz,1H),2.96–2.83(m ,5H),2.60–2.52(m,1H),2.42–2.33(m,2H),2.01–1.92(m,1H),1.91–1.74(m,5H),1.74–1.67(m,4H),1.49–1.31(m,10H), LCMS m/z=468.0[M+H] ⁺ .

Synthesis of Example 84

Replace 25-1 with spiro[3.5]nonane-1-one, replace M5 with M12, and adopt the synthesis method of Example 25 to Example 84: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.98 (s, 1H), 7.52–7.49 (m, 2H), 5.08 (dd, J=13.2, 5.1 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 4.33 (d, J=17.3 Hz, 1H), 2.94–2.83 (m, 3H), 2.79–2.73 (m, 1H), 2.60–2.53 (m, 1H), 2. 42–2.34(m,1H),2.27–2.19(m,1H),2.01–1.93(m,1H),1.87–1.79(m,2H),1.76–1.65(m ,6H),1.63–1.52(m,4H),1.46–1.37(m,3H),1.32–1.22(m,3H),1.14–1.01(m,2H), LCMS m/z=468.0[M+H] ⁺ .

Synthesis of Example 85

25-1 was replaced by spiro[3.3]heptane-2-one, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 85: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),7.58(d,J＝7.7Hz,1H),7.48–7.40(m,1H),5.09(dd,J＝13.3,5.0Hz,1H),4.53(d,J＝17.4Hz,1H),4.35(d,J＝17.3Hz),3.2, 1H0–3.08(m,1H),2.96–2.79(m,2H),2.62–2.54(m,1H),2.44–2.33(m,1H),2.31–2.12(m,4H),2.10–1.86(m,12H),1.84–1.72(m,3H), LCMS m/z=444.0[M+H] ⁺ .

Synthesis of Example 86

25-1 was replaced by 6,6-difluorospiro[3.3]heptan-2-one, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 86: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),7.56(d,J＝7.7Hz,1H),7.51–7.43(m,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.52(d,J＝17.4Hz,1H),4.35(d,J＝17.4 LCMS m/z=475.9[M+H] ⁺ .

Synthesis of Example 87

25-1 was replaced by spiro[2.3]hexan-5-one, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 87: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.98(s,1H),7.60–7.37(m,2H),5.09(dd,J＝13.3,5.0Hz,1H),4.53(d,J＝17.4Hz,1H),4.35(d,J＝17.3Hz,1H),3.17–3.02( LCMS m/z=425.9[M+H] ⁺ .

Synthesis of Example 88

25-1 was replaced by spiro[3.4]octan-1-one, M5 was replaced by M12, and the synthesis method of Example 25 was used to Example 88: white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.65–7.49 (m, 2H), 5.10 (dd, J=12.9, 5.1 Hz, 1H), 4.54 (d, J=17.2 Hz, 1H), 4.36 (d, J=17.2 Hz, 1H), 2.97–2.86 (m, 2H), 2.69–2.56 (m, 2H), 2.46–2.41 (m, 1H), 2.03–1.97 (m, 1H), 1.94–1.67 (m, 8H), 1.67–1.39 (m, 12H), LCMS m/z＝453.9[M+H] ⁺ .

Synthesis of Example 89

Replace 25-1 with spiro[3.4]octan-1-one, and adopt the synthesis method of Example 25 to Example 89: white solid, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.19 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.41 (d, J=17.2 Hz, 1H), 4.28 (d, J=17.2 Hz, 1H), 4.24 (s, 2H), 4.15 (s,2H),2.97–2.83(m,3H),2.76–2.67(m,1H),2.67–2.55(m,2H),2.44–2.30(m,3H),2.19–2 .08(m,2H),2.04–1.93(m,1H),1.90–1.80(m,2H),1.80–1.71(m,2H),1.70–1.56(m,2H), LCMS m/z=472.3[M+H] ⁺ .

Effect Example 1: Protein Degradation Western Blot Detection Method

1. Reagent Preparation

1) Cell lysis working solution:

To 20 mL of cell lysis buffer (Beyotime Cat#P0013B), add one tablet of protease inhibitor (Roche(Cat#4693132001)) and one tablet of phosphatase inhibitor Roche(Cat#04906837001)) and mix gently until completely dissolved.

2) 4× sample preparation working solution:

Add 200 mM DTT (Sigma Cat#D9779-1G) to 4x sample preparation buffer (Thermo Fisher Cat#NP0007) to prepare 4x sample preparation working solution.

3) Electrophoresis buffer:

Dilute 20x electrophoresis buffer (Thermo Fisher Cat# NP0001) to 1x with ultrapure water.

4) Transfer buffer:

Dilute 20x transfer buffer (Thermo Fisher Cat# NP0006-1) to 1x with ultrapure water and add 20% methanol.

5) TBST buffer:

Dilute 10×TBST (CST Cat#9997S) with ultrapure water to 1xTBST buffer

6) Blocking solution and antibody working solution:

Dissolve 5 g BSA (Solarbio Cat#A8020) in 100 mL 1× TBST and store at 4°C.

7) Primary antibody working solution:

eRF3/GSPT1 antibody (CST Cat#14980), Ikaros (D6N9Y) antibody (CST Cat#14859), and Helios (D8W4X) antibody (CST Cat#42427)) were diluted to the antibody working solution at a ratio of 1:1000.

Dilute GAPDH antibody (CST Cat#5174) 1:10,000 into antibody working solution.

8) Secondary antibody working solution:

Anti-rabbit IgG, HRP-linked (CST (Cat#7074)) antibody was diluted to the antibody working solution at a ratio of 1:5000.

2. Protein Extraction

1) Jurkat cells (ATCC Cat#TIB-152) were seeded into 96-well cell culture plates (Corning Cat#3599), 5×10 ⁴ cells per well, 100 μL culture medium (Invitrogen Cat#A1049101, Gibco Cat#10099141C, Solarbio Cat#P1400), and cultured for 24 hours.

2) The test compound was dissolved in DMSO (Sigma Cat#D8418) to prepare 10 mM as a stock solution. The test drug was diluted 3 times with DMSO. 100 nL was added to each well and centrifuged at 1000 rpm (Eppendorf Cat#5810R) for 1 minute. The cells were cultured in a 37°C 5% CO ₂ incubator for 24 hours.

3) Centrifuge at 4000 rpm in a cell processor (Eppendorf Cat#5810R) for 5 minutes, discard the culture medium in the plate, add 45 μL of cell lysis working solution to each well, shake at 380 rpm for 2 minutes, and incubate on ice for 20 minutes.

4) Add 15 μL 4X sample preparation buffer (Thermo Fisher Cat#NP0007) to each well of the 96-well plate and mix with the protein sample, and heat at 70°C for 10 minutes.

3 Western Blot Detection

1) Load 10 μl of sample into each well of precast gel (Thermo Fisher (Cat# WG1403BOX) and perform electrophoresis at a constant voltage of 120 V for about 60 min (power supply Bio-Rad PowerPac HC 1645052, electrophoresis tank Thermo Fisher XCell4SureLock).

2) Use PVDF membrane (Millipore Cat#IPVH00010) for transfer, constant current 300mA, 1 hour (power supply Bio-Rad PowerPac HC 1645052), transfer instrument Bio-Rad Cat#1704071).

3) After transfer, block with blocking solution at room temperature for 1 hour.

4) Incubate in primary antibody working solution at 4°C overnight.

5) Wash the membrane with 1× TBST buffer for 3×10 min. Incubate with secondary antibody working solution at room temperature for 1 hour.

6) Wash the membrane with 1× TBST buffer for 3×10 min, and then expose and develop the color using color developing solution (Thermo Fisher Cat#32134).

4DC50 Analysis

Image Studio Lite Ver 5.2 software was used to perform semi-quantitative analysis on the gray value of each band. GraphPad 8.0 was used to obtain the DC50 of the compound using a nonlinear fitting formula.

Fitting formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogDC50-X)*HillSlope)); X: log value of compound concentration; Y: compound inhibition percentage.

Effect Example 2: Evaluation of protein degradation of IKZF2 or IKZF1 in cell lines using the Nano-Glo Hibit detection system

The Nano-Glo Hibit assay system was used to evaluate the degradation efficiency of compounds against IKZF2 or IKZF1 in engineered cell lines (293FT-IKZF2-HibiT and K562-IKZF1-HibiT).

1. Experimental Materials

1.1 Cell lines and culture methods

Table 2. Cell lines and culture methods

1.2 Culture medium

Table 3. Culture media and reagents

1.3 Multi-well plate

Greiner CELLSTAR 96-well plate, flat black plate (with lid and clear bottom), #655090.

1.4 Reagents and instruments used in cell viability experiments

(1) Promega HiBiT Lytic Detection System Kit (Promega-N3050)

(2) 2105 EnVision plate reader, PerkinElmer.

2. Experimental methods and steps

2.1 Cell culture

293FT-IKZF2-HibiT or K562-IKZF1-HibiT cell lines were cultured in an incubator at 37°C and 5% CO ₂ according to the culture conditions shown in Table 2. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating.

2.2 Cell plating

(1) Stain cells with trypan blue and count live cells.

(2) Adjust the cell concentration to an appropriate level.

(3) According to the experimental purpose (testing IKZF2 or IKZF1 degradation), 90 μL of the corresponding cell suspension was added to each well of the culture plate, and culture medium without cells was added to the blank control well.

(4) Incubate the culture plate overnight in an incubator at 37°C, 5% CO ₂ , and 100% relative humidity.

2.3 Preparation of compound storage plate

(1) Prepare a 400X compound storage plate: dilute the compound with DMSO from the highest concentration to the lowest concentration.

2.4 Preparation of 10X compound working solution and compound treatment of cells

(1) Preparation of 10X compound working solution: Add 78 μL of cell culture medium to a 96-well plate with a V-bottom. Pipette 2 μL of compound from the 400X compound storage plate and add it to the cell culture medium in the 96-well plate. Add 2 μL of DMSO to the vehicle control and blank control. After adding the compound or DMSO, mix well by pipetting with a dispenser.

(2) Dosing: Take 10 μL of 10X compound working solution and add it to the cell culture plate. Add 10 μL of DMSO-cell culture medium mixture to the vehicle control and blank control. The final DMSO concentration is 0.25%.

(3) Place the 96-well cell plate back into the incubator and culture for 24 hours.

2.5 HiBiT Lytic Detection

The following steps are based on Promega The test was performed according to the instructions of HiBiT Lytic Detection System kit (promega-N3050).

(1) Add 100 μL detection reagent (1 mL lysis buffer + 20 ul lytic substrate + 10 μL LgBiT protein).

(2) Shake at 300 r for 3 minutes and detect the luminescent signal on a 2105 Envision plate reader.

2.6 Data Analysis

The degradation rate (DR) of the test compound was calculated using the following formula: DR (%) = (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%. The degradation rates of the compounds at different concentrations were calculated in Excel, and then the inhibition curves were fitted using GraphPad Prism software using log (inhibitor) vs. response--Variable slope, and related parameters were obtained, including the minimum degradation rate, the maximum degradation rate Dmax and the relative DC ₅₀ .

IKZF2 degradation (WB) DC ₅₀ (nM):

+++,<100nM; ++,≥100nM,<1000nM; +,≥1000nM

IKZF2 degradation (WB) Dmax (%):

+++,≥75%;++,≥50%,<75%;+,≤50%

IKZF2 degradation (Hibit) DC ₅₀ (nM)

+++,<50nM;++,≥50nM,<500nM;+,≥500nM

IKZF2 degradation (Hibit) Dmax (%)

+++,≥75%;++,≥50%,<75%;+,≤50%

IKZF1 degradation (WB) DC ₅₀ (nM)

+, ≤200nM; ++, ≥200nM, <1000nM; +++, ≥1000nM

IKZF1 degradation (Hibit) DC ₅₀ (nM)

+, ≤200nM; ++, ≥200nM, <1000nM; +++, ≥1000nM

GSPT1 degradation (WB) DC ₅₀ (nM)

+, ≤200nM; ++, ≥200nM, <1000nM; +++, ≥1000nM

- stands for not detected.

Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims (14)

A compound of formula II or a pharmaceutically acceptable salt thereof;
Where q is 0, 1, 2 or 3; ^R3 is H, -OH or halogen; ^Y1 is CR ^Y1 or N; ^Y2 is CR ^Y2 or N; ^Y3 is CR ^Y3 or N; R ^Y1 , R ^Y2 and R ^Y3 are each independently H, NR ^a R ^b , OR ^a or halogen; Q is CR ^Q1 R ^Q2 ; R ^Q1 and R ^Q2 are independently H, deuterium or C ₁ -C ₆ alkyl; ^RX is H or deuterium; Each R ¹ is independently C ₁ -C ₆ alkyl or halogen; Ring A is a 3-12-membered heterocycloalkylene group or a 3-12-membered heterocycloalkenylene group; in the 3-12-membered heterocycloalkylene group and the 3-12-membered heterocycloalkenylene group, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N; ^R2 is _C3 - _C10 monocyclic cycloalkyl, _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3- _C10 monocyclic cycloalkyl substituted by one or more ^R2-1 , _C1 - _C6 alkyl substituted by one or more ^R2-2 , _3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or C5 _{-C10 polycyclic} cycloalkyl substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R ^2-1 is independently OR ^a , -CONR ^a R ^b , CN, C ₃ -C ₁₀ cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl substituted ^{by one or more R 2-1-1 ,} C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R ^2-4 is independently OR ^a , -CONR ^a R ^b , CN, C ₃ -C ₁₀ cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl substituted by one or more ^{R 2-1-1 ,} C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R ^2-1-1 is independently halogen, cyano, OR ^a , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens; Each R ^2-1-2 is independently halogen, OR ^a , C ₃ -C ₁₀ cycloalkyl, 3-12 heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-12 membered heteroaryl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R ^2-1-3 is independently halogen, cyano, OR ^a , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens; Each R ^2-2 is independently halogen, OR ^a , C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^2-2-1 , C ₅ -C ₁₀ polycyclic cycloalkyl substituted by one or more R ^2-2-2 , or 3-12 membered heterocycloalkyl substituted by one or more R ^2-2-3 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R ^2-2-1 is independently halogen, OR ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₁ -C ₆ alkyl; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R ^2-2-2 is independently halogen, OR ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R ^2-2-3 is independently halogen, OR ^a , Oxo, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₁ -C ₆ alkyl or one or more halogen-substituted C ₁ -C ₆ alkyl groups; in the 5-12 membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R ^2-3 is independently oxo (=O), -C(=O)OR ^a , -C(=O)R ^a , -CONR ^a R ^b , Halogen, OR ^a , CN, C ₃ -C ₁₀ cycloalkyl, 3-12 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, 5-12 membered heteroaryl substituted by one or more ^Ra , C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 , or C ₁ -C ₆ alkyl substituted by one or more R ^2-3-2 ; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R ^2-3-1 is independently halogen, cyano, OR ^a , or C ₁ -C ₆ alkyl substituted by one or more halogens; Each R ^2-3-2 is independently halogen, OR ^a , C ₃ -C ₁₀ cycloalkyl, 3-12 heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-12 membered heteroaryl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each ^Ra is independently hydrogen, _C1 - _C6 alkyl, _C1 - _C6 alkyl substituted by one or more halogens, C3- _C10 cycloalkyl or _3-12 membered heterocycloalkyl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by one or more halogens, C ₃ -C ₁₀ cycloalkyl or 3-12 membered heterocycloalkyl; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Alternatively, ^Ra , ^Rb and the atoms to which they are connected together form a 3-12 membered heterocycloalkyl group; in the 3-12 membered heterocycloalkyl group, the heteroatoms are selected from one, two or three of N, O and S, and the number of the heteroatoms is one, two or three. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) In R ³ , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (2) In R ^Y1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (3) In R ^Y3 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (4) In ^R1 , the _C1 - _C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably is methyl; (5) In R ¹ , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (6) In ring A, the heteroatoms of the 3-12-membered heterocycloalkylene group are independently one or two of N, O and S; the number of heteroatoms of the 3-12-membered heterocycloalkylene group is preferably one or two; the 3-12-membered heterocycloalkylene group is more preferably a 4-10-membered heterocycloalkylene group; further preferably a 4-7-membered monocyclic heterocycloalkylene group or a 7-10-membered bridged heterocycloalkylene group; for example For example (7) In ring A, the heteroatoms of the 3-12-membered heterocycloalkenylene group are independently N, or N and O; the number of heteroatoms of the 3-12-membered heterocycloalkenylene group is preferably 1 or 2; the 3-12-membered heterocycloalkenylene group is more preferably 6-10-membered heterocycloalkenylene group; further preferably 6-membered monocyclic heterocycloalkenylene group or 9-membered bridging heterocycloalkenylene group; for example For example (8) In R ² , the C ₃ -C ₁₀ monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (9) In R ² , the C ₅ -C ₁₀ polycyclic cycloalkyl groups are each independently For example (10) In ^R2 , the heteroatoms of the 3-12 membered heterocycloalkyl group are independently one or two of N, O and S; the number of heteroatoms of the 3-12 membered heterocycloalkyl group is preferably one or two; the 3-12 membered heterocycloalkyl group is more preferably a 4-10 membered heterocycloalkyl group; further preferably, a 4-7 membered monocyclic heterocycloalkyl group, a 7-10 membered spirocyclic heterocycloalkyl group, a 7-10 membered bridged heterocycloalkyl group or a 7-10 membered cyclic heterocycloalkyl group; for example For example The Preferably and/or (11) In R ² , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (12) In R ^2-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (13) In R ^2-1 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl; (14) In R ^2-1 , the heteroatoms of the 5-12 membered heteroaryl group are independently N and/or O; the number of heteroatoms of the 5-12 membered heteroaryl group is preferably 1 or 2; the 5-12 membered heteroaryl group is more preferably a 6-9 membered heteroaryl group; further preferably a 6-membered monocyclic heteroaryl group or a 9-membered bicyclic heteroaryl group; for example For example (15) In R ^2-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (16) In R ^2-4 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (17) In R ^2-1-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (18) In R ^2-1-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (19) In R ^2-1-2 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl; (20) In R ^2-1-3 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (21) In R ^2-2 , the C ₃ -C ₁₀ monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (22) In R ^2-2-1 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl; (23) In R ^2-3 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl; (24) In R ^2-3 , the heteroatoms of the 5-12 membered heteroaryl group are independently N and/or O; the number of heteroatoms of the 5-12 membered heteroaryl group is preferably 1 or 2; the 5-12 membered heteroaryl group is more preferably a 6-9 membered heteroaryl group; and further preferably a 6-membered monocyclic heteroaryl group; for example For example (25) In R ^2-3-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (26) In ^Ra , the _C1 - _C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, isobutyl or tert-butyl; (27) The C ₁ -C ₆ alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, isobutyl or tert-butyl; (28) The halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (29) The C ₃ -C ₁₀ monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (30) The C ₅ -C ₁₀ polycyclic cycloalkyl groups are each independently For example (31) The heteroatoms of the 3-12 membered heterocycloalkyl group are independently one or two of N, O and S; the number of heteroatoms of the 3-12 membered heterocycloalkyl group is preferably one or two; the 3-12 membered heterocycloalkyl group is more preferably a 4-10 membered heterocycloalkyl group; further preferably a 4-7 membered monocyclic heterocycloalkyl group, a 7-10 membered spirocyclic heterocycloalkyl group, a 7-10 membered bridged heterocycloalkyl group or a 7-10 membered cycloheterocycloalkyl group; for example For example The Preferably and/or (32) The C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, preferably phenyl; (33) The heteroatoms of the 5-12 membered heteroaryl group are independently N and/or O; the number of heteroatoms of the 5-12 membered heteroaryl group is preferably 1 or 2; the 5-12 membered heteroaryl group is more preferably a 6-9 membered heteroaryl group; further preferably a 6-membered monocyclic heteroaryl group or a 9-membered bicyclic heteroaryl group; for example For example (34) The halogen in the C ₁ -C ₆ alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine, preferably fluorine; (35) The C _{1 -C 6} alkyl group substituted by one or more halogens is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert _- butyl; (36) The C ₁ -C ₆ alkyl group substituted by one or more halogens is preferably -CF ₃ . The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) q is 0, 1 or 2; preferably 0 or 1; more preferably 0; (2) R ³ is H; (3) ^Y1 is CR ^Y1 ; (4) ^Y2 is CR ^Y2 ; (5) ^Y3 is CR ^Y3 ; (6) ^RY1 and ^RY2 are independently H or halogen; preferably H; (7) R ^Y3 is independently H or halogen; (8) R ^Q1 and R ^Q2 are independently H or deuterium; preferably hydrogen; (9) ^RX is H; (10) Each R ¹ is independently C ₁ -C ₆ alkyl or halogen; preferably C ₁ -C ₆ alkyl; (11) Ring A is a 3-12-membered heterocycloalkylene group or a 3-12-membered heterocycloalkenylene group; preferably a 3-12-membered heterocycloalkylene group; in the 3-12-membered heterocycloalkylene group and the 3-12-membered heterocycloalkenylene group, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N; more preferably, a 4-7-membered monocyclic heterocycloalkylene group or a 7-10-membered bridging heterocycloalkylene group; for example, a 4-7-membered monocyclic heterocycloalkylene group; in the 4-7-membered monocyclic heterocycloalkylene group and the 7-10-membered bridging heterocycloalkylene group, the number of heteroatoms is independently 1 or 2, and the heteroatoms are independently selected from 1 or 2 of N, O and S, and at least one heteroatom is N; (12) ^R2 is _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, _C3 - _C10 monocyclic cycloalkyl substituted by one or more ^R2-1 , _C1 - _C6 alkyl substituted by one or more ^R2-2 , 3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or _C5 - _C10 polycyclic cycloalkyl substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably _C5 - _C10 polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl, or _C5 -C10 substituted by one or more ^R2-4 ₁₀ -membered polycyclic cycloalkyl; in the 7-10-membered spirocyclic heterocycloalkyl and 7-10-membered bridged heterocycloalkyl, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; (13) Each R ^2-1 is independently -OH, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^2-1-1 , C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; preferably C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; (14) Each R ^2-1-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more halogens; (15) Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group; (16) each R ^2-1-3 is independently halogen; (17) Each R ^2-4 is independently halogen, OR ^a , or CN; preferably halogen; (18) each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^2-2-1 ; (19) Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group; (20) Each R ^2-3 is independently oxo (=O), -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; preferably -C(＝O)OR ^a , -C(＝O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; more preferably C ₆ -C ₁₀ aryl or -C(=O)OR ^a ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; (21) Each R ^2-3-1 is independently halogen or OR ^a ; preferably halogen; (22) Each ^Ra is independently _C1 - _C6 alkyl or H; (23) The pharmaceutically acceptable salt of the compound of Formula II is formate. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is the following scheme a, scheme b or scheme c; Plan A: q is 0, 1, or 2; ^R3 is H, -OH or halogen; ^Y1 is CR ^Y1 ; ^Y2 is CR ^Y2 ; ^Y3 is CR ^Y3 ; R ^Y1 , R ^Y2 and R ^Y3 are each independently H or halogen; Q is CR ^Q1 R ^Q2 ; R ^Q1 and R ^Q2 are independently H; ^RX is H; Each R ¹ is independently C ₁ -C ₆ alkyl or halogen; Ring A is a 3-12-membered heterocycloalkylene group or a 3-12-membered heterocycloalkenylene group; in the 3-12-membered heterocycloalkylene group and the 3-12-membered heterocycloalkenylene group, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N; R ² is C ₅ -C ₁₀ polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^2-1 , C ₁ -C ₆ alkyl substituted by one or more R ^2-2 , 3-12 membered heterocycloalkyl substituted by one or more R ^2-3 , or C ₅ -C ₁₀ polycyclic cycloalkyl substituted by one or more R ^2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R ^2-1 is independently -OH, halogen, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, C ₆ -C ₁₀ aryl substituted by one or more R ^2-1-1 , C ₁ -C ₆ alkyl substituted by one or more R ^2-1-2 , or 5-12 membered heteroaryl substituted by one or more R ^2-1-3 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R ^2-1-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more halogens; Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group; Each R ^2-1-3 is independently halogen; each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 ; Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group; Each R ^2-3 is independently oxo (=O), -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R ^2-3-1 is independently halogen or OR ^a ; Each R ^2-4 is independently halogen, OR ^a , or CN; preferably halogen; Each ^Ra is independently _C1 - _C6 alkyl or H; Option B: q is 0 or 1; ^R3 is H, -OH or halogen; ^Y1 is CR ^Y1 ; ^Y2 is CR ^Y2 ; ^Y3 is CR ^Y3 ; R ^Y1 and R ^Y2 are each independently H; ^RY3 is H or halogen; Q is CR ^Q1 R ^Q2 ; R ^Q1 and R ^Q2 are independently H; ^RX is H; Each R ¹ is independently C ₁ -C ₆ alkyl; Ring A is a 3-12 membered heterocycloalkylene group; in the 3-12 membered heterocycloalkylene group, the number of heteroatoms is independently 1, 2 or 3, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and at least one heteroatom is N; ^R2 is _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3-C10 monocyclic cycloalkyl substituted by one or _more ^R2-1 , C1- _C6 alkyl substituted by one or more ^R2-2 , 3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or _{C5 -C10 polycyclic cycloalkyl} substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R ^2-1 is independently a C ₆ -C ₁₀ aryl group or a C ₁ -C ₆ alkyl group substituted by one or more R ^2-1-2 ; Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group; each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 ; Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group; Each R ^2-3 is independently -C(=O)OR ^a , -C(=O)R ^a , C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl substituted by one or more R ^2-3-1 ; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the heteroatoms are selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, The number of atoms is 1, 2, 3 or 4; Each R ^2-3-1 is independently halogen; Each R ^2-4 is independently halogen, OR ^a , or CN; preferably halogen; Each ^Ra is independently _C1 - _C6 alkyl or H; Option c: In scheme c, the compound shown in formula II is a compound shown in formula II-1 below:
in, R ³ is H, -OH or halogen; preferably H; ^Y3 is CR ^Y3 ; R ^Y3 is independently H or halogen; ^RX is H; Ring A is a 4-7 membered monocyclic heterocycloalkylene group or a 7-10 membered bridged heterocycloalkylene group; in the 4-7 membered monocyclic heterocycloalkylene group and the 7-10 membered bridged heterocycloalkylene group, the number of heteroatoms is independently 1 or 2, the heteroatoms are independently 1 or 2 of N, O and S, and at least one heteroatom is N; preferably a 4-7 membered monocyclic heterocycloalkylene group; in the 4-7 membered monocyclic heterocycloalkylene group, the number of heteroatoms is independently 1 or 2, the heteroatoms are independently 1 or 2 of N, O and S, and at least one heteroatom is N; ^R2 is _C5 - _C10 polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, C3-C10 monocyclic cycloalkyl substituted by one or _more ^R2-1 , C1- _C6 alkyl substituted by one or more ^R2-2 , 3-12 membered heterocycloalkyl substituted by one or more ^R2-3 , or _{C5 -C10 polycyclic cycloalkyl} substituted by one or more ^R2-4 ; in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably _C5 - _C10 polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl, or _C5 -C10 substituted by one or more ^R2-4 . ₁₀ -membered polycyclic cycloalkyl; in the 7-10-membered spirocyclic heterocycloalkyl and 7-10-membered bridged heterocycloalkyl, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; Each R ^2-1 is independently a C ₆ -C ₁₀ aryl group or a C ₁ -C ₆ alkyl group substituted by one or more R ^2-1-2 ; Each R ^2-1-2 is independently a C ₆ -C ₁₀ aryl group; Each R ^2-4 is independently halogen; each R ^2-2 is independently a C ₃ -C ₁₀ monocyclic cycloalkyl substituted with one or more R ^2-2-1 ; Each R ^2-2-1 is independently a C ₆ -C ₁₀ aryl group; Each R ^2-3 is independently C ₆ -C ₁₀ aryl or -C(═O)OR ^a ; Each ^Ra is independently a _C1 - _C6 alkyl group. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that it satisfies one or more of the following conditions: (1) R ² is (2) for (3) for (4) ^Rx is H. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that the compound of formula II The compound shown is any of the following structures:




Preferably, IKZF2 degradation (Hibit) DC ₅₀ is ≥50 nM; the maximum degradation rate at 1 μM is ≥50%; or, IKZF2 degradation (Hibit) DC ₅₀ is <50 nM; the maximum degradation rate at 1 μM is ≥50%. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that the pharmaceutically acceptable salt of the compound of formula II is any of the following structures:

Preferably, IKZF2 degradation (WB) DC ₅₀ was <100 nM; the maximum degradation rate at 1 μM was ≥75%; or, IKZF2 degradation (Hibit) DC ₅₀ was <50 nM; the maximum degradation rate at 1 μM was ≥50%. A compound of formula III or a pharmaceutically acceptable salt thereof, or a compound of formula IV:
wherein q, R ¹ , Ring A, R ³ , Y ¹ , Y ² , Y ³ , Q and ^RX are as defined in any one of claims 1 to 7; R ⁵ is H, -C(=O)-OR ^5-1 or a C ₃ -C ₁₀ monocyclic cycloalkyl substituted by one or more R ^5-2 ; R ^5-1 is C ₁ -C ₆ alkyl; Each R ^5-2 is independently a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₀ aryl group substituted by one or more R ^2-5-1 ; Each R ^2-5-1 is independently a C ₁ -C ₆ alkyl group substituted by one or more halogens; R ⁶ is oxo (=O) or Preferably, R ⁵ is H, The compound of formula III or a pharmaceutically acceptable salt thereof according to claim 8, or the compound of formula IV, characterized in that it satisfies one or two of the following conditions: (1) The compound shown in formula III is any of the following structures:
(2) The compound shown in formula IV is any of the following structures:
A compound as shown below: A pharmaceutical composition comprising a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in formula II as described in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A use of a substance Z or a pharmaceutical composition as claimed in claim 11 in the preparation of a protein degrader targeting IKZF2 or a drug for treating and/or preventing diseases related to IKZF2, wherein the substance Z is a compound as shown in formula II as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. The use according to claim 12, characterized in that the IKZF2-related disease is one or more of a tumor, a disease caused by infection with a virus, bacteria or other pathogen, or a disease associated with human aging; the tumor is preferably one or more of head and neck cancer, cervical cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer, rectal cancer, hepatocellular carcinoma, glioma, kidney cancer, neuroblastoma, sarcoma, lung cancer, ovarian cancer, bladder cancer, pancreatic cancer, melanoma, breast cancer, triple-negative breast cancer, nasopharyngeal cancer, bone cancer, brain cancer, spinal cord cancer, melanoma, meningioma, prostate cancer, uterine cancer, lymphoma and myeloid leukemia. A use of a substance Z or a pharmaceutical composition as claimed in claim 11 in the preparation of a drug, wherein the substance Z is a compound as represented by formula II as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof; The drug is preferably for treating one or more of tumors, diseases caused by infection with viruses, bacteria or other pathogens, or diseases associated with human aging; the tumor is preferably one or more of head and neck cancer, cervical cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer, rectal cancer, hepatocellular carcinoma, glioma, kidney cancer, neuroblastoma, sarcoma, lung cancer, ovarian cancer, bladder cancer, pancreatic cancer, melanoma, breast cancer, triple-negative breast cancer, nasopharyngeal cancer, bone cancer, brain cancer, spinal cord cancer, melanoma, meningioma, prostate cancer, uterine cancer, lymphoma and myeloid leukemia.