Heterocyclic compound, and composition and use thereof

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

[0001] This application claims the benefit of Chinese Patent Application No. 2023112756095, filed September 28, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention relates to a heterocyclic compound, a composition and an application thereof. Background Art

[0003] The Ikaros protein family, which includes Ikaros (Ikzf1), Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4), and Pegasus (Ikzf5), is a hematopoietic-specific transcription factor involved in regulating lymphocyte development. IKZF2 forms homo- and heterodimers with other Ikaros family members and is thought to play a major role in hematopoietic development.

[0004] In regulatory T cells (Tregs), IKZF2 is highly expressed at both the mRNA and protein levels. It binds to the promoter of FoxP3, the primary transcriptional regulator of Tregs, affecting FoxP3 expression, thereby influencing Treg development and function. The function of IKZF2 in Tregs is to maintain their suppressive properties. Knocking out IKZF2 in Tregs in mice causes activated Tregs to lose their suppressive properties and express effector T cell factors, which then function as effector T cells.

[0005] Regulatory T cells play a crucial role in maintaining autoimmune tolerance, but their accumulation within the tumor microenvironment (TME) can suppress anti-tumor immunity. Targeting regulatory T cells is an important area of ​​research for the development of tumor immunomodulators, with several clinical candidates already in clinical development and achieving clinical progress. These include anti-TIGIT antibodies, anti-CCR4 antibodies, and anti-CTL4 antibodies targeting Tregs, which are used to enhance anti-tumor immune responses.

[0006] Immunomodulatory drugs (IMiDs), such as pomalidomide and lenalidomide, induce the degradation of the IKZF1 and IKZF3 transcription factors. IMiDs do not bind to IKZF1 / 3 themselves, but instead bind to the CRBN E3 ligase, forming protein-small molecule complexes and generating 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 their degradation by the proteasome. Other proteins, such as GSPT1 and IKZF2, can also be degraded through similar pathways.

[0007] Protein degraders targeting IKZF2 can inhibit Treg cell activity by degrading IKZF2, thereby suppressing Treg cell-mediated immunosuppression and potentially increasing the anti-tumor activity of tumor immunotherapy. Therefore, the development of protein degraders targeting Helios (IKZF2) has potential clinical application value.

[0008] Summary of the Invention

[0009] The present invention provides a heterocyclic compound, a composition thereof, and its application. The compound of the present invention has one or more of the following advantages: novel structure, efficient and highly selective degradation of IKZF2, inhibition of regulatory T cell function, application in the treatment of tumors or diseases, and great clinical development value.

[0010] The present invention provides a compound as shown in Formula II or a pharmaceutically acceptable salt thereof;

[0011] Where q is 0, 1, 2 or 3;

[0012] R 3 is H, -OH or halogen;

[0013] Y 1 CR Y1 or N;

[0014] Y 2 CR Y2 or N;

[0015] Y 3 CR Y3 or N;

[0016] R Y1 、R Y2 and R Y3 are independently H, NR a R b , OR a or halogen;

[0017] Q is CR Q1 R Q2 ;

[0018] R Q1 and R Q2 are independently H, deuterium or C1-C6 alkyl;

[0019] R X is H or deuterium;

[0020] Each R 1 are independently C1-C6 alkyl or halogen;

[0021] Ring A is a 3-12 membered heterocycloalkylene group or a 3-12 membered heterocycloalkenylene group; the number of heteroatoms in the 3-12 membered heterocycloalkylene group and the 3-12 membered heterocycloalkenylene group 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;

[0022] R 2 C3-C 10 Monocyclic cycloalkyl, C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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;

[0023] Each R 2-1 Independently OR a 、 -CONR a R b 、 CN, C3-C 10 Cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl, 2- 1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 substituted 5-12 membered heteroaryl; 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;

[0024] Each R 2-4 Independently OR a 、 -CONR a R b 、 CN, C3-C 10Cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl, 2- 1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 substituted 5-12 membered heteroaryl; 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;

[0025] Each R 2-1-1 are independently halogen, cyano, OR a 、 C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens;

[0026] Each R 2-1-2 are independently halogen, OR a 、 C3-C 10 Cycloalkyl, 3-12 heterocycloalkyl, C6-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;

[0027] Each R 2-1-3 are independently halogen, cyano, OR a 、 C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens;

[0028] Each R 2-2 are independently halogen, OR a 、 By one or more R 2-2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2-2 Substituted C5-C 10 Polycyclic cycloalkyl or one or more R 2-2-3 Substituted 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;

[0029] Each R 2-2-1 are independently halogen, OR a 、 C6-C 10 Aryl, 5-12 membered heteroaryl or C1-C6 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;

[0030] Each R 2-2-2 are independently halogen, OR a 、 C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl or C1-C6 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;

[0031] Each R 2-2-3 are independently halogen, OR a 、 Oxo, C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl or C1-C6 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;

[0032] Each R 2-3 are independently oxo (=O), -C(=O)OR a 、-C(=O)R a 、 -CONR a R b 、 Halogen, OR a 、CN、C3-C 10 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-12 membered heteroaryl, substituted by one or more R a substituted 5-12 membered heteroaryl, substituted by one or more R 2-3-1 Substituted C6-C 10 Aryl or one or more R 2-3-2 substituted C1-C6 alkyl; 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 independently 1, 2, 3 or 4; in the 3-12 membered heterocycloalkyl, the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0033] Each R 2-3-1 are independently halogen, cyano, OR a 、 or a C1-C6 alkyl group substituted by one or more halogens;

[0034] Each R 2-3-2 are independently halogen, OR a 、 C3-C 10 Cycloalkyl, 3-12 heterocycloalkyl, C6-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;

[0035] Each R a are independently hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, C3-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;

[0036] Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, C3-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;

[0037] Or, R a 、R b Together with the atoms connected thereto, they form a 3-12 membered heterocycloalkyl group; 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.

[0038] 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. The unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in some embodiments").

[0039] R 3 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0040] In some embodiments, R Y1wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0041] In some embodiments, R Y3 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0042] In some embodiments, R 1 In the embodiment, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group.

[0043] In some embodiments, R 1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0044] In some embodiments, in ring A, the heteroatoms of the 3-12 membered heterocycloalkylene group 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 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

[0045] 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 bridged heterocycloalkenylene group; for example For example

[0046] In some embodiments, R 2 In the C3-C 10 The monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0047] In some embodiments, R 2 In the C5-C 10 The polycyclic cycloalkyl groups are each independently For example

[0048] In some embodiments, R 2wherein 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 (For example and / or ),

[0049] In some embodiments, R 2 In the embodiment, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group.

[0050] In some embodiments, R 2-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0051] In some embodiments, R 2-1 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl.

[0052] In some embodiments, R 2-1 wherein 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

[0053] In some embodiments, R 2-1 In the embodiment, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group.

[0054] In some embodiments, R 2-4 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0055] In some embodiments, R 2-1-1 In the embodiment, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group.

[0056] In some embodiments, R 2-1-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0057] In some embodiments, R 2-1-2 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl.

[0058] In some embodiments, R 2-1-3 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0059] In some embodiments, R 2-2 In the C3-C 10 The monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0060] In some embodiments, R 2-2-1 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl.

[0061] In some embodiments, R 2-3 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl.

[0062] In some embodiments, R 2-3 wherein 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; for example For example

[0063] In some embodiments, R 2-3-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0064] In some embodiments, R a In the embodiment, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, isobutyl or tert-butyl.

[0065] In some embodiments, the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, isobutyl or tert-butyl.

[0066] In some embodiments, the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0067] In some embodiments, the C3-C 10 The monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0068] In some embodiments, the C5-C 10 The polycyclic cycloalkyl groups are each independently For example

[0069] In some embodiments, 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 (For example and / or

[0070] In some embodiments, the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl.

[0071] In some embodiments, 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

[0072] In some embodiments, the halogen in the C1-C6 alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0073] In some embodiments, the C1-C6 alkyl groups in the C1-C6 alkyl groups substituted by one or more halogens are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0074] In some embodiments, the C1-C6 alkyl group substituted by one or more halogens is preferably -CF3.

[0075] In some embodiments, q is 0, 1 or 2; preferably 0 or 1; more preferably 0.

[0076] In some embodiments, R 3 For H.

[0077] In some embodiments, Y 1 CR Y1 .

[0078] In some embodiments, Y 2 CR Y2 .

[0079] In some embodiments, Y 3 CR Y3 .

[0080] In some embodiments, R Y1 and R Y2 is independently H or halogen; preferably H.

[0081] In some embodiments, R Y3 are independently H or halogen.

[0082] In some embodiments, R Q1 and R Q2 is independently H or deuterium; preferably hydrogen.

[0083] In some embodiments, R X For H.

[0084] In some embodiments, each R 1 are independently C1-C6 alkyl or halogen; preferably C1-C6 alkyl.

[0085] In some embodiments, 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 bridged heterocycloalkylene group; for example, a 4-7 membered monocyclic 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, and the heteroatoms are independently selected from 1 or 2 of N, O and S, and at least one heteroatom is N.

[0086] In some embodiments, R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl,2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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-C 10 Polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 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.

[0087] In some embodiments, each R 2-1 are independently -OH, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, substituted by one or more R 2-1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 Substituted 5-12 membered heteroaryl; preferably C6-C 10 Aryl or one or more R 2-1-2 Substituted C1-C6 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.

[0088] In some embodiments, each R 2-1-1 are independently C1-C6 alkyl substituted by one or more halogens.

[0089] In some embodiments, each R 2-1-2 Independently C6-C 10 Aryl.

[0090] In some embodiments, each R 2-1-3 are independently halogen.

[0091] In some embodiments, each R 2-4 are independently halogen, OR a 、 or CN; preferably halogen.

[0092] In some embodiments, each R 2-2 Independently by one or more R 2-2-1 Substituted C3-C 10 Monocyclic cycloalkyl.

[0093] In some embodiments, each R 2-2-1 Independently C6-C 10 Aryl.

[0094] In some embodiments, each R 2-3 are independently oxo (=O), -C(=O)OR a 、-C(=O)R a 、 C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; preferably -C(=O)OR a 、-C(=O)R a 、 C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; more preferably C6-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 heteroatoms is one, two, three or four.

[0095] In some embodiments, each R 2-3-1 are independently halogen or OR a ; preferably halogen.

[0096] In some embodiments, each R a are independently C1-C6 alkyl or H.

[0097] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula II may be formate.

[0098] In some embodiments, q is 0, 1 or 2;

[0099] R 3 is H, -OH or halogen;

[0100] Y 1 CR Y1 ;

[0101] Y 2 CR Y2 ;

[0102] Y 3 CR Y3 ;

[0103] R Y1 、R Y2 and R Y3 are each independently H or halogen;

[0104] Q is CR Q1 R Q2 ;

[0105] R Q1 and R Q2 independently H;

[0106] R X is H;

[0107] Each R 1 are independently C1-C6 alkyl or halogen;

[0108] 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;

[0109] R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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;

[0110] Each R 2-1 are independently -OH, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, substituted by one or more R 2-1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 Substituted 5-12 membered heteroaryl; 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;

[0111] Each R 2-1-1 are independently C1-C6 alkyl substituted by one or more halogens;

[0112] Each R 2-1-2 Independently C6-C 10 aryl;

[0113] Each R 2-1-3 are independently halogen;

[0114] Each R 2-2 Independently by one or more R 2-2-1 Substituted C3-C 10 monocyclic cycloalkyl;

[0115] Each R 2-2-1 Independently C6-C 10 aryl;

[0116] Each R 2-3 are independently oxo (=O), -C(=O)OR a 、-C(=O)R a 、 C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; 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;

[0117] Each R 2-3-1 are independently halogen or OR a ;

[0118] Each R 2-4 are independently halogen, OR a 、 or CN; preferably halogen;

[0119] Each R a are independently C1-C6 alkyl or H.

[0120] In some embodiments, q is 0 or 1;

[0121] R 3 is H, -OH or halogen;

[0122] Y 1 CR Y1 ;

[0123] Y 2 CR Y2 ;

[0124] Y3 CR Y3 ;

[0125] R Y1 and R Y2 are independently H;

[0126] R Y3 is H or halogen;

[0127] Q is CR Q1 R Q2 ;

[0128] R Q1 and R Q2 independently H;

[0129] R X is H;

[0130] Each R 1 are independently C1-C6 alkyl;

[0131] 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;

[0132] R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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;

[0133] Each R 2-1 Independently C6-C 10 Aryl or one or more R 2-1-2 Substituted C1-C6 alkyl;

[0134] Each R 2-1-2 Independently C6-C 10 aryl;

[0135] Each R 2-2 Independently by one or more R 2-2-1 Substituted C3-C 10monocyclic cycloalkyl;

[0136] Each R 2-2-1 Independently C6-C 10 aryl;

[0137] Each R 2-3 are independently -C(=O)OR a 、-C(=O)R a 、 C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; 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;

[0138] Each R 2-3-1 are independently halogen;

[0139] Each R 2-4 are independently halogen, OR a 、 or CN; preferably halogen;

[0140] Each R a are independently C1-C6 alkyl or H.

[0141] In some embodiments, the compound represented by Formula II is a compound represented by the following Formula II-1:

[0142] in,

[0143] R 3 is H, -OH or halogen; preferably H;

[0144] Y 3 CR Y3 ;

[0145] R Y3 are independently H or halogen;

[0146] R X is H;

[0147] 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, it is 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;

[0148] R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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-C 10 Polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 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;

[0149] Each R 2-1 Independently C6-C 10 Aryl or one or more R 2-1-2 Substituted C1-C6 alkyl;

[0150] Each R 2-1-2 Independently C6-C 10 aryl;

[0151] Each R 2-4 are independently halogen;

[0152] Each R 2-2 Independently for one or more R 2-2-1 Substituted C3-C 10 monocyclic cycloalkyl;

[0153] Each R 2-2-1 Independently C6-C10 aryl;

[0154] Each R 2-3 Independently C6-C 10 Aryl or -C(=O)OR a ;

[0155] Each R a are independently C1-C6 alkyl.

[0156] In some embodiments, R 2 for

[0157] In some embodiments, for

[0158] In some embodiments, for

[0159] In some embodiments, R x For H.

[0160] In some embodiments, the compound shown in Formula II is any of the following structures:

[0161] In some embodiments, IKZF2 degrades (Hibit) DC 50 ≥50 nM; maximal degradation at 1 μM ≥50%; or, IKZF2 degradation (Hibit) DC 50 The maximum degradation rate at 1 μM was ≥50%. The IKZF2 degradation (WB) and IKZF2 degradation (Hibit) were measured under the test conditions of Effect Examples 1 and 2.

[0162] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula II is any of the following structures:

[0163] In some embodiments, IKZF2 degradation (WB) DC 50<100 nM; maximum degradation rate at 1 μM ≥75%; or, IKZF2 degradation (Hibit) DC 50 The maximum degradation rate at 1 μM was ≥50%. The IKZF2 degradation (WB) and IKZF2 degradation (Hibit) were measured under the test conditions of Effect Examples 1 and 2.

[0164] The present invention also provides a compound as shown in Formula III or a pharmaceutically acceptable salt thereof;

[0165] Among them, q, R 1 , Ring A, R 3 、Y 1 、Y 2 、Y 3 , Q and R X The definition of is as mentioned above;

[0166] R 5 H, -C(=O)-OR 5-1 or by one or more R 5-2 or substituted C3-C 10 monocyclic cycloalkyl;

[0167] R 5-1 is a C1-C6 alkyl group;

[0168] Each R 5-2 Independently C6-C 10 Aryl or one or more R 2-5-1 Substituted C6-C 10 aryl;

[0169] Each R 2-5-1 are independently C1-C6 alkyl substituted by one or more halogens.

[0170] In some embodiments, R 5 For H,

[0171] In some embodiments, the compound represented by Formula III is any of the following structures:

[0172] The present invention also provides a compound as shown in Formula IV:

[0173] q, R 1 , Ring A and R 5 The definition of is as mentioned above;

[0174] R 6 is oxo (=O) or

[0175] In some embodiments, the compound shown in Formula IV is any of the following structures:

[0176] The present invention also provides the following compounds

[0177] The present invention also provides a pharmaceutical composition comprising 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.

[0178] The present invention also provides a use of a substance Z in preparing a protein degrader targeting IKZF2 or a drug for treating and / or preventing IKZF2-related diseases, wherein the substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

[0179] The present invention also provides a use of a substance Z or the above-mentioned pharmaceutical composition in the preparation of a protein degrader targeting IKZF2 or a drug for treating and / or preventing IKZF2-related diseases, wherein the substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

[0180] 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.

[0181] The present invention also provides a method for treating and / or preventing diseases related to IKZF2, comprising administering to a patient an effective amount of a substance Z, wherein the substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

[0182] The present invention also provides a method for treating and / or preventing diseases related to IKZF2, comprising administering to a patient an effective amount of substance Z or the above-mentioned pharmaceutical composition, wherein substance Z is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

[0183] The present invention also provides a use 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.

[0184] 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.

[0185] In some embodiments, the drug is 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.

[0186] Terminology

[0187] Unless otherwise specified, the terms used in this invention have the following meanings:

[0188] As used herein, 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, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0189] In the present invention, the structural fragment This refers to the bond through which the structural fragment is connected to the rest of the molecule. For example, It refers to pyridyl.

[0190] In the present invention, the term "one or more" refers to 1, 2, 3, 4 or 5, such as 1, 2 or 3.

[0191] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0192] The term "oxo" refers to =0, where an oxygen atom replaces two hydrogen or sulfur lone pairs on the same carbon atom, i.e., a carbonyl group replaces a methylene group or a Replace sulfur.

[0193] As used herein, the term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0194] In the present invention, the term "alkoxy" refers to a group R Y -O-, R Y The same definition is given to 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.

[0195] In the present invention, the term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6), which is a monocyclic or polycyclic ring (e.g., a polycyclic ring having 2 or 3 rings). When the "cycloalkyl" is polycyclic, it is a spirocyclic cycloalkyl, a paracyclic cycloalkyl, or a bridged cycloalkyl, preferably a spirocyclic cycloalkyl, wherein the monocyclic rings share one carbon atom. Cycloalkyl groups include, but are not limited to: wait.

[0196] 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 heteroatom species (one or more of N, O and S), which is monocyclic or polycyclic (e.g., polycyclic is 2 or 3 rings). When the "heterocycloalkyl" is polycyclic, it is preferably a cyclic heterocycloalkyl, a spirocyclic heterocycloalkyl or a bridged heterocycloalkyl; more preferably a spirocyclic heterocycloalkyl and a bridged heterocycloalkyl. The monocyclic rings of the spirocyclic heterocycloalkyl share one carbon atom; the monocyclic rings of the bridged heterocycloalkyl share two or more carbon atoms and / or heteroatoms. The spirocyclic heterocycloalkyl and the bridged heterocycloalkyl are connected to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom; the heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes but is not limited to: wait.

[0197] 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-membered), 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 monocyclic or polycyclic (e.g., polycyclic is 2 or 3 rings). When the "heterocycloalkylene" is polycyclic, it is preferably a cycloheterocycloalkylene, a spirocycloheterocycloalkylene, or a bridging heterocycloalkylene; more preferably, a bridging heterocycloalkylene. The monocyclic rings of the spirocycloheterocycloalkylene share one carbon atom; the monocyclic rings of the bridging heterocycloalkylene share two or more carbon atoms and / or heteroatoms. The spirocycloheterocycloalkylene and the bridging heterocycloalkylene are connected to the rest of the molecule through a ring having a heteroatom or a ring not having a heteroatom; the heterocycloalkylene is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkylene includes, but is not limited to: wait.

[0198] In the present invention, the term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6-C 10 ) is a cyclic, unsaturated hydrocarbon group, which is monocyclic or polycyclic (e.g., polycyclic comprises two or three rings). In the case of polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl and naphthyl.

[0199] In the present invention, the term "heteroaryl" refers to a cyclic, unsaturated group with 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 heteroatom (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 one bond, and at least one ring has aromaticity. 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 aromaticity or a ring without aromaticity. Heteroaryl groups include but are not limited to wait.

[0200] In the present invention, the term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3-12, 6-10, 6, or 9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2Double bond, it is monocyclic or polycyclic (for example, polycyclic is 2 or 3 rings), and does not have aromaticity. 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.

[0201] 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 members, 6-10 members, 6 members, or 9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond, it is monocyclic or polycyclic (for example, polycyclic is 2 or 3 rings), and does not have aromaticity. When the "heterocycloalkenylene" is polycyclic, it is preferably a cycloheterocycloalkylene, a spirocycloheterocycloalkylene or a bridged heterocycloalkenylene, etc.; more preferably a bridged heterocycloalkenylene. The monocyclic rings of the bridged heterocycloalkenylene share two or more carbon atoms and / or heteroatoms, and the bridged heterocycloalkenylene is connected to the rest of the molecule through a ring with a double bond or a ring without a double bond; the bridged heterocycloalkenylene is connected to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom; the heterocycloalkenylene is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenylene includes but is not limited to wait.

[0202] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0203] The reagents and raw materials used in the present invention are commercially available.

[0204] The positive progress of the present invention is that the compounds of the present application can degrade IKZF2 efficiently and selectively. It is expected that by degrading the level of IKZF2, the function of regulatory T cells can be inhibited, allowing the immune system to more effectively attack tumors or diseases. It can be used to treat tumors or diseases and has great clinical development value. DETAILED DESCRIPTION

[0205] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0206] Synthesis Examples of Intermediates

[0207] Synthesis of M1

[0208] Under a nitrogen atmosphere, KOAc (potassium acetate, 0.9 g, 9.3 mmol) and Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 0.33 g, 0.45 mmol) were added to a solution of M1-1 (1.0 g, 3.1 mmol) and pinacol diboron (0.9 g, 3.7 mmol) in DMF (N,N-dimethylformamide, 10 mL). 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. The residue was purified by silica gel flash column chromatography [DCM (dichloromethane) / MeOH (methanol)] to give M1 (1 g, 87% yield) as a white solid. LCMS m / z = 371.1 [M+H] + .

[0209] Synthesis of M2

[0210] 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 allowed to react at room temperature for 1 hour. The mixture was diluted with 100 mL of water and 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 M2-2 (4.2 g, 37% yield) as a white solid. LCMS m / z = 204.0 [M+H] + .

[0211] Under nitrogen atmosphere, cuprous cyanide (6.88 g, 73.52 mmol) was added to a solution of M2-2 (5.0 g, 24.51 mmol) in DMF (80 mL), and the mixture was reacted at 140° C. for 16 hours. The mixture was returned to room temperature, diluted with 100 mL of water, and extracted with DCM (100 mL×3). The mixture was 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 M2-3 (2.0 g, 54% yield) as a white solid. LCMS m / z=151.1 [M+H] + .

[0212] 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, and extracted with DCM (100 mL × 3). The mixture was 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 red solid M2-4 (1.6 g, 56% yield). LCMS m / z = 214.0 [M+H] + .

[0213] 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 of the system was adjusted to 2 with 2M hydrochloric acid. The mixture was 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] + .

[0214] 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, 93% yield). LCMS m / z = 247.0 [M+H] + .

[0215] Under nitrogen atmosphere, AIBN (azobisisobutyronitrile, 166 mg, 1.01 mmol) and NBS (396 mg, 2.23 mmol) were added to a solution of M2-6 (500 mg, 2.02 mmol) in CCl4 (carbon tetrachloride, 5 mL) 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 M2-7 (540 mg, 82% yield) as a white solid. LCMS m / z = 326.9 [M+H] + .

[0216] Under nitrogen atmosphere, DIPEA (N,N-diisopropylethylamine, 595 mg, 4.60 mmol) was added to a solution of M2-7 (0.5 g, 1.53 mmol) and 3-amino-2,6-piperidinedione (295 mg, 2.30 mmol) in DMF (6 mL) 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. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to give M2 (340 mg, 50% yield) as a brown solid. LCMS m / z = 340.8 [M+H] + .

[0217] Synthesis of M3

[0218] Under nitrogen atmosphere, to a solution of M2 (200 mg, 586 μmol) in 1,4-dioxane (10 mL) were added pinacol diboronate (179 mg, 704 μmol), Pd(dppf)Cl2 (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. The residue was purified by silica gel flash column chromatography (DCM / MeOH) to give M3 (200 mg, 88% yield) as a white solid. LCMS m / z = 389.2 [M+H] + .

[0219] Synthesis of M4

[0220] Under nitrogen atmosphere, TEA (triethylamine, 2.2 g, 21.7 mmol), Pd2(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 and reacted 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. 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] + .

[0221] 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. The residue was purified by silica gel flash column chromatography (PE / EA) to give M4-3 (420 mg, 39% yield) as a yellow solid. LCMS m / z = 284.3 [M+H] + .

[0222] 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 reacted at 0°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by C18 column (acetonitrile / water / 0.01% TFA) to give M4 (270 mg, 61% yield) as a white solid. LCMS m / z = 184.2 [M+H] + .

[0223] Synthesis of M5

[0224] Under nitrogen atmosphere, (t-Bu3P)2Pd[bis(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 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 give a white solid M5-2 (6.5 g, yield 98%), LCMS m / z = 426.2 [M+H] + .

[0225] Under a hydrogen atmosphere, Pd / C (palladium on carbon, 10% purity, 1 g) was added to a solution of M5-2 (1 g, 2.35 mmol) in DMF (60 mL) and the mixture was allowed to react at room temperature for 16 hours. The mixture was filtered through a pad of celite, 60 mL of water was added, and the mixture was extracted with DCM (100 mL × 3). The mixture was 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 give M5-3 (0.9 g, 90% yield) as a white solid. LCMS m / z = 428.2 [M+H] + .

[0226] Under nitrogen atmosphere, 10 mL of 4M hydrochloric acid (1,4-dioxane) was added to a solution of M5-3 (200 mg, 0.468 mmol) in 10 mL of DCM and allowed to react at room temperature for 1 hour. The mixture was filtered, the filter cake was washed with DCM, and vacuum dried to give M5 as a white solid (150 mg, 98% yield). LCMS m / z = 328.2 [M+H] + .

[0227] Synthesis of M6

[0228] Under an oxygen atmosphere, PhSiH3 (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, and the mixture was extracted with DCM (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate) to give M6-1 (600 mg, 58% yield) as a white solid. LCMS m / z = 388.2 [M-56] + .

[0229] Under nitrogen, 10 mL of 4M hydrochloric acid (1,4-dioxane) was added to a solution of M6-1 (200 mg, 0.45 mmol) in 10 mL of DCM and allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was washed three times with diethyl ether and dried under vacuum. M6 (150 mg, 97% yield) was obtained as a white solid. LCMS m / z = 344.2 [M+H] + .

[0230] Synthesis of M7

[0231] 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. The mixture was warmed to room temperature and reacted for 4 hours. The mixture was quenched with cold saturated sodium bicarbonate solution, extracted with DCM (3×20 mL), 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 product M7-1 (200 mg, yield 54%), LCMS m / z=390.1 [M-56] + .

[0232] To a solution of M7-1 (200 mg, 0.45 mmol) in 2 mL of DCM was added 2 mL of 4 M hydrochloric acid (1,4-dioxane) at 0°C and allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure, washed three times with ether, and dried under vacuum to afford M7 (180 mg, 89% yield) as a white solid. LCMS m / z = 346.1 [M+H] + .

[0233] Synthesis of M8

[0234] 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] + .

[0235] Synthesis of M9

[0236] M1-1 was replaced with M8, and the synthetic method of M5 was used to obtain M9: white solid, LCMS m / z=346.0 [M+H] + .

[0237] Synthesis of M10

[0238] 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] + .

[0239] Synthesis of M11

[0240] M1-1 was replaced with M10, and the synthetic method of M5 was used to obtain M9: white solid, LCMS m / z=346.0 [M+H] + .

[0241] Synthesis of M12

[0242] M1-1 was replaced with M2, and the synthetic method of M5 was used to obtain M12: white solid, LCMS m / z=346.0 [M+H] + .

[0243] Synthesis of M13

[0244] M1-1 was replaced with M10, and the synthetic method of M6 was used to obtain M13: white solid, LCMS m / z=362.1 [M+H] + .

[0245] Synthesis of M14

[0246] M5-1 was replaced with N-tert-butyloxycarbonyl-nortropine, and the synthetic method of M6 was used to obtain M14: white solid, LCMS m / z=370.2 [M+H] + .

[0247] Synthesis of M15

[0248] Under nitrogen atmosphere, NaBH4 (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 allowed to react 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 give M15-2 (540 mg, 89% yield) as a white solid. LCMS m / z = 271.1 [M+Na] + .

[0249] Under nitrogen atmosphere, TFA (390 mg, 3.42 mmol) was added to a solution of M15-2 (0.3 g, 1.14 mmol) in DCM (10 mL) and the mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to give M15 as a yellow oil (300 mg, 90% yield). LCMS m / z = 164.0 [M+H] + .

[0250] Synthesis of M16

[0251] 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] + .

[0252] Synthesis of Example 1

[0253] Under nitrogen atmosphere, to a solution of 1-1 (500 mg, 2.95 mmol) in EtOH (ethanol, 10 mL) were added 1-2 (793 mg, 2.95 mmol) and K2CO3 (potassium carbonate, 61 mg, 442 μmol), 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 1-3 as a yellow solid (260 mg, 26% yield). LCMS m / z = 216.0 [M+H] + .

[0254] To a solution of 1-3 (0.1 g, 465 μmol) in MeOH (5 mL) was added NaBH4 (57.6 mg, 929 μmol) 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 give 1-4 as a white solid (90 mg, yield 89%). LCMS m / z = 217.9 [M+H] + .

[0255] 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 allowed to react 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 afford 1-5 as a white solid (90 mg, 81% yield). LCMS m / z = 372.3 [M+H] + .

[0256] 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 reaction was continued at 80 ° C for 5 hours. Return to room temperature, add 10 mL of water to dilute, and extract with DCM (20 mL × 3). Dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by preparative HPLC to give a white solid 1 (1.1 mg, yield 3%). 1 H NMR (400MHz, Methanol-d4) 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] + .

[0257] Synthesis of Example 2

[0258] Replace 1-1 with 1-phenylcyclobutylamine hydrochloride and use the synthesis method of Example 1 to Example 2: white solid, 1 H NMR(400MHz, Methanol-d4)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),2.7 9–2.73(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] + .

[0259] Synthesis of Example 3

[0260] Replace 1-1 with 3-phenyl-3-oxetanamine hydrochloride and use the synthesis method of Example 1 to Example 3: white solid, 1 HNMR(400MHz, Methanol-d4)δ7.68(d,J=8.0Hz,1H),7.42–7.30(m,5H),7.19–7.15(m,2H),5.11(dd,J=13.3,5.0Hz,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] + .

[0261] Synthesis of Example 4

[0262] Under nitrogen atmosphere, a solution of 1-3 (250 mg, 1.16 mmol) in THF (tetrahydrofuran, 10 mL) was cooled to -78 ° C. LiHMDS (lithium bistrimethylsilylamide, 1 M in THF, 1.174 mL, 1.74 mmol) was added dropwise and stirred for 1 hour. 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. The residue was purified by silica gel flash column chromatography (PE / EA) to give 26-1 (240 mg, 53% yield) as a white solid. LCMS m / z = 348.2 [M+H] + .

[0263] Under nitrogen atmosphere, Pd(dppf)Cl2·DCM ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 16 mg, 20 μmol) and K3PO4 (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. The residue was purified by silica gel flash column chromatography (DCM\MeOH) to give 13 (60 mg, 54% yield) as a white solid. 1 HNMR(500MHz,DMSO-d4)δ10.99(s,1H),7.64(d,J=8.0Hz,1H),7.57(s,1H),7.51(d,J=7.9Hz,1H),7.3 7–7.34(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) LCMS m / z=442.5[M+H] + .

[0264] Under an oxygen atmosphere, i-PrOH (5 mL) and DMF (1 mL) were added to a solution of 13 (60 mg, 136 μmol) in DCM (5 mL), and Mn(dpm) 3 (41 mg, 68 μmol) and PhSiH 3 (29 mg, 272 μmol) were reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 4 (4 mg, 6% yield) as a white solid. 1 H NMR (400MHz, Methanol-d4) δ7.71 (d, J = 8.0 Hz, 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,1 H),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] + .

[0265] Synthesis of Example 5

[0266] Under nitrogen atmosphere, compound 1-2 (1.74 g, 6.46 mmol) and K2CO3 (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). 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 5-2 (1.1 g, 78% yield) as a yellow solid. LCMS m / z = 284.2 [M+H] + .

[0267] Under nitrogen atmosphere, a solution of 5-2 (360 mg, 1.27 mmol) in THF (10 mL) was cooled to -78°C, and LiHMDS (1 M in THF, 1.27 mL, 1.27 mmol) was added dropwise. The mixture was stirred for 1 hour, and then N-phenylbis(trifluoromethanesulfonyl)imide (681 mg, 1.91 mmol) was added. 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. The residue was purified by silica gel flash column chromatography (PE / EA) to give 5-3 (320 mg, 61% yield) as a light yellow solid. LCMS m / z = 416.3 [M+H] + .

[0268] Under nitrogen atmosphere, 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) were added Pd(dppf)Cl2 (40 mg, 54 μmol) and Na2CO3 (172 mg, 1.62 mmol), 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. The residue was purified by silica gel flash column chromatography (DCM\MeOH) to give 5-4 (105 mg, 38% yield) as a light yellow solid. LCMS m / z = 510.2 [M+H] + .

[0269] Under a hydrogen atmosphere, Pd / C (10% purity, 10 mg) was added to a solution of 5-4 (10 mg, 19.63 μmol) in DMF (0.5 mL) and the mixture was allowed to react at room temperature for 16 hours. The reaction system was filtered through celite, the filter cake was washed with water and DCM, the filtrate was 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 preparative HPLC to give a white solid 5 (5 mg, yield 49%). 1H NMR (500MHz, DMSO-d6) 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=67.2,17.3Hz,3H),3.22–3.13(m,2H),2.99–2.93(m,1H),2.73–2.61(m,2H),2.13–2.0 3(m,4H),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] + .

[0270] Synthesis of Example 6

[0271] Replace 1-1 with 1-phenylcyclobutylamine hydrochloride and use the synthesis method of Example 4 to Example 6: white solid, 1 H NMR (400MHz, Methanol-d4) δ8.52 (s, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.67 (s, 1H), 7.6 0(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] + .

[0272] Synthesis of Example 7

[0273] Replace 5-1 with 1-pyridin-3-ylcyclopropylamine and use the synthesis method of Example 5 to Example 7: white solid, 1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),8.53(d,J=1.6Hz,1H),8.49(dd,J=4.8,1.6Hz,1H),7.72–7.68(m,1H), 7.60(d,J=7.9Hz,1H),7.42(s,1H),7.41–7.37(m,1H),7.34–7.30(m,1H),5.08(dd,J=13.4,5.1Hz,1H),4.39( d,J=17.3Hz,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),2.37–2.3 4(m,1H),2.04–1.94(m,4H),1.76–1.70(m,2H),1.66–1.59(m,2H),0.95–0.91(m,2H),0.83–0.79(m,2H), LCMS m / z=445.6[M+H] + .

[0274] Synthesis of Example 8

[0275] 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 (500MHz, DMSO-d6)) 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=8.3,1.2H z,1H),5.09(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] + .

[0276] Synthesis of Example 9

[0277] Replace 1-1 with 3-phenyl-3-oxetanamine hydrochloride and use the synthesis method of Example 4 to proceed to Example 9: 1 H NMR (400MHz, DMSO-d6) 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=17.2Hz,1H),3 .16(d,J=13.6Hz,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] + .

[0278] Synthesis of Example 10

[0279] Replace 5-1 with 1-1, replace M1 with M3 and use the synthesis method of Example 4 to obtain Example 10: white solid, 1 H NMR(400MHz, Methanol-d4)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] + .

[0280] Synthesis of Example 11

[0281] Replace M1 with M3 and adopt the synthesis method of 13 to Example 11: 1H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.43–7.37 (m, 1H) ,7.34–7.29(m,4H),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] + .

[0282] Synthesis of Example 12

[0283] 5-1 was replaced with 3-phenyl-3-oxetanamine hydrochloride, M1 was replaced with M3, and the synthesis method of Example 5 was used to prepare Example 12: white solid, LCMS m / z=478.0 [M+H] + .

[0284] Synthesis of Example 14

[0285] Replace 5-1 with M4 and use the synthesis method of Example 5 to Example 14: white solid, 1 H NMR(400MHz, Methanol-d4)δ7.67(d,J=7.6Hz,1H),7.41–7.26(m,7H),5.10(dd,J=13.4,5.1Hz,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] + .

[0286] Synthesis of Example 15

[0287] 5-1 was replaced with 1-phenylcyclopentylamine, and the synthesis method of Example 5 was used to prepare Example 15: white solid, LCMS m / z=472.2 [M+H] + .

[0288] Synthesis of Example 16

[0289] Replace 5-1 with (1-benzylcyclopropyl)amine and use the synthesis method of Example 5 to Example 16: white solid, 1 H NMR (400MHz, DMSO-d6) 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] + .

[0290] Synthesis of Example 17 and Example 19

[0291] 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. The mixture was allowed to warm to room temperature and allowed to react for 16 hours. A large amount of solid precipitated and was filtered. The filter cake was washed with DCM and dried under vacuum to afford 17-2 (2.2 g, 57% yield) as a yellow solid. LCMS m / z = 170.0 [M+H] + .

[0292] Under nitrogen atmosphere, K2CO3 (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 returning 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 give 17-3 (630 mg, 44% yield) as a red oil. LCMS m / z = 257.9 [M+H] + .

[0293] 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 in THF, 1.75 mL, 1.75 mmol) was added dropwise. 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 17-4 (120 mg, 23% yield) as a light yellow solid. LCMS m / z = 389.9 [M+H] + .

[0294] Under nitrogen atmosphere, Pd(dppf)Cl2 (24 mg, 32 μmol) and Na2CO3 (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 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 give 17 (68 mg, 45% yield) as a white solid. 1 H NMR(400MHz, Methanol-d4)δ7.55(dd,J=8.0,0.5Hz,1H),7.43–7.43(m,1H),7.41–7.40(m,1H),7.1 2–6.95(m,5H),6.16–6.12(m,1H),5.10(dd,J=12.0,4.0Hz,1H),4.42–4.32(m,2H),3.79–3.73(m,1 H),3.73–3.69(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] + .

[0295] Under hydrogen atmosphere, Pd(OH)2 / C (palladium hydroxide 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 give 19 (17 mg, 10% yield) as a white solid.1 H NMR(400MHz, Methanol-d4)δ7.61(d,J=8.0Hz,1H),7.51–7.47(m,2H),7.39–7.35(m,1H),7.3 4–7.30(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] + .

[0296] Synthesis of Example 18

[0297] Replace 5-1 with 1-phenylcyclopropylmethylamine and use the synthesis method of Example 5 to Example 18: white solid, 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.22(s,1H),7.61(d,J=7.6Hz,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=13.2,5.3Hz,1H),4.45–4.22(m, 2H),3.11–3.05(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] + .

[0298] Synthesis of Example 20

[0299] 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 use the synthesis method of Example 19 to Example 20: white solid, 1H NMR (400MHz, Methanol-d4) δ7.67(d,J=7.9Hz,1H),7.39(s,1H),7.33(d,J=7.9Hz,1H),7.28(d,J=1.5Hz,1 H),7.25(dd,J=8.3,1.6Hz,1H),7.15(d,J=8.2Hz,1H),5.10(dd,J=13.4,5.2Hz,1H),4.46–4.35(m,2H),2.9 4–2.82(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,2 LCMS m / z=537.8[M+H] + .

[0300] Synthesis of Example 21

[0301] Replace 5-1 with 1-phenylcyclopropylmethylamine and use the synthesis method of Example 5 to obtain Example 21: white solid, 1 H NMR(400MHz,DMSO-d6)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] + .

[0302] Synthesis of Example 22 and Example 23

[0303] Replace 5-1 with M15 and use the synthesis method of Example 5 to prepare Examples 22 and 23:

[0304] Example 22 or 23, white solid, 1H NMR(400MHz, Methanol-d4)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,3H),3.27–3.23(m,2H),3.04–2.92(m,2H),2.90–2.80(m,1H),2.7 9–2.65(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] + .

[0305] Example 22 or 23, white solid, 1 H NMR(400MHz, Methanol-d4)δ7.68(d,J=8.0Hz,1H),7.47–7.28(m,7H),5.11(dd,J=13.4,5.2Hz,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] + .

[0306] Synthesis of Example 24

[0307] Replace 5-1 with 4-phenyltetrahydropyran-4-amine and use the synthesis method of Example 5 to Example 24: white solid, 1H NMR(400MHz, Methanol-d4)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] + .

[0308] Synthesis of Example 25

[0309] To a solution of M5 (120 mg, 367 μmol) and 25-1 (51 mg, 367 μmol) in DMF (5 mL) was added STAB (

[0310] 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 25 as a white solid (19 mg, yield 12%). 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.65(d,J=7.7Hz,1H),7.49(s,1H),7.40(d,J=7.7H z,1H),5.09(dd,J=13.2,4.7Hz,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] + .

[0311] Synthesis of Example 26

[0312] M5 was replaced by M6, and the synthesis method of Example 25 was used to obtain Example 26: white solid, 1H NMR(400MHz,DMSO-d6)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),2.0 9–1.93(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] + .

[0313] Synthesis of Example 27

[0314] Replace M5 with M7 and use the synthesis method of Example 25 to Example 27: white solid, 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.73(d,J=8.0Hz,1H),7.69(s,1H),7.58(d,J=8.0H z,1H),5.11(dd,J=13.3,5.1Hz,1H),4.52–4.29(m,2H),3.55–3.51(m,2H),3.46–3.44(m,2 H),2.98–2.85(m,1H),2.81–2.72(m,3H),2.65–2.57(m,1H),2.47–2.31(m,1H),2.21–2.1 2(m,1H),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] + .

[0315] Synthesis of Example 28

[0316] A solution of 28-1 (2.0 g, 9.3 mmol) in MeOH (40 mL) was cooled to 0°C, and NaBH4 (1.14 g, 18.58 mmol) was added. The mixture was allowed to react 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. The residue was purified by silica gel flash column chromatography (PE / EA) to give 28-2 (1.9 g, 94% yield) as a colorless oil. LCMS m / z = 171.9 [M-56] + .

[0317] To a solution of 28-2 (1.1 g, 4.84 mmol) in Py (10 mL) was added TsCl (2.31 g, 12.1 mmol) and allowed to react 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. The residue was purified by silica gel flash column chromatography (PE / EA) to give 28-3 (1.2 g, 59% yield) as a white solid. LCMS m / z = 403.9 [M+Na] + .

[0318] 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), and KI (154 mg, 928 μmol) were added to a solution of M1-1 (0.3 g, 928 μmol) and 28-3 (531 mg, 1.39 mmol) in DMA (3 mL) and reacted at 100°C for 5 hours. The mixture was returned to room temperature, diluted with 10 mL of water, extracted with DCM (10 mL × 3), washed with 20 mL of saturated brine, 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 28-4 (240 mg, 48% yield) as a white solid. LCMS m / z = 397.9 [M-56] + .

[0319] To a solution of 28-4 (240 mg, 529 μmol) in DCM (2 mL) was added 2 mL of 4 M hydrochloric acid (1,4-dioxane) and the mixture was allowed to react 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 give 28-5 as a white solid (180 mg, 96% yield). LCMS m / z = 354.2 [M+H] + .

[0320] 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 reacted at room temperature for 16 hours. 10 mL of water was added for dilution 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 give 28 (3 mg, 2% yield) as a white solid. 1 H NMR (400MHz, Methanol-d4) δ8.52(s,1H),7.76(d,J=8.0Hz,1H),7.53(s,1H),7.48(d,J=8.4 Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.55(s,2H),4.51–4.40(m,2H),3.95(s,2H),3.67–3.6 2(m,2H),3.61–3.56(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] + .

[0321] Synthesis of Example 29

[0322] Replace 25-1 with spiro[2.3]hexan-5-one and use the synthesis method of Example 25 to Example 29: white solid, 1 H NMR(400MHz, Methanol-d4)7.75(d,J=7.6Hz,1H),7.50(s,1H),7.44(d,J=8.0Hz,1H),5 .13(dd,J=13.3,5.1Hz,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] + .

[0323] Synthesis of Example 30

[0324] 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-d4)δ7.74(d,J=8.0Hz,1H),7.48(s,1H),7.42(d,J=7.2Hz,1H),5.12(dd ,J=13.3,5.2Hz,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] + .

[0325] Synthesis of Example 31

[0326] To a solution of 31-1 (2 g, 8.36 mmol) in DCM (5 mL) was added dropwise TFA (5 mL) at 0°C, and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the pH was adjusted to pH>7 by adding saturated sodium bicarbonate solution. 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 lyophilized to give 31-2 as a white solid (1.03 g, yield 88%). LCMS m / z = 140.1 [M+H] + .

[0327] 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 mixture was warmed 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] + .

[0328] To a solution of M5 (58 mg, 321 μmol) and 31-3 (70 mg, 214 μmol) in DMF (3 mL) was added STAB (453 mg, 2.14 mmol) and the mixture was allowed to stand at room temperature for 16 hours. The reaction mixture was directly purified by C18 column (acetonitrile / water) to afford 31 (10 mg, 9% yield) as a white solid. 1 H 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] + .

[0329] Synthesis of Example 32

[0330] Replace 25-1 with 2-oxaspiro[3.5]nonan-7-one and use the synthesis method of Example 25 to Example 32: white solid, 1H NMR (400MHz, Methanol-d4) 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] + .

[0331] Synthesis of Examples 33, 45 and 46

[0332] Replace 25-1 with 3-oxabicyclo[3.2.1]octan-8-one and use the synthesis method of Example 25 to Example 33: white solid, 1 H NMR (400MHz, Methanol-d4) 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),4.5 9–4.39(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 give Examples 45 and 46, Example 45 or 46: white solid, 1H NMR (400MHz, Methanol-d4) 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=12.3 Hz,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] + .

[0333] Example 46 or 45: white solid, 1 H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.77(d,J=8.0Hz,1H),7.51(s,1H),7 .45(dd,J=7.9,1.1Hz,1H),5.15(dd,J=13.3,5.2Hz,1H),4.56–4.42(m,4H),3.6 0(d,J=12.2Hz,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] + .

[0334] Synthesis of Example 34

[0335] M5 was replaced by M9, and the synthesis method of Example 25 was used to obtain Example 34: white solid, 1H NMR (400MHz, Methanol-d4) δ8.47(s,1H),7.30(s,1H),7.11(d,J=10.6Hz,1H),5.09(dd,J =13.4,5.2Hz,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),2.35–2.2 4(m,2H),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] + .

[0336] Synthesis of Example 35

[0337] M5 was replaced by M11, and the synthesis method of Example 25 was used to prepare Example 35: white solid, 1H NMR (400 MHz, DMSO-d6) 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,1H),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] + .

[0338] Synthesis of Example 36

[0339] M5 was replaced by M12, and the synthesis method of Example 25 was used to obtain Example 36: white solid, 1H NMR(400MHz, Methanol-d4)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,1H),2.92–2.85(m,3H),2.82–2.71(m,1H),2.54–2.47(m,1H),2.3 9–2.34(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] + .

[0340] Synthesis of Example 37

[0341] To a solution of 67-1 (5 g, 20.9 mmol) in DCM (5 mL) was added dropwise 5 mL of 4 M hydrochloric acid (1,4-dioxane) at 0°C and allowed to react at room temperature for 2 hours. The filter cake was filtered, washed with ether, and dried under vacuum to afford a brown solid 37-2 (2 g, 69% yield). LCMS m / z = 140.1 [M+H] + .

[0342] Under an oxygen atmosphere, compound 37-2 (1 g, 7.2 mmol) was added to a 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) in DMF (10 mL). The mixture was allowed to react 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 afford 37-3 (80 mg, 5% yield) as a yellow oil. LCMS m / z = 216.3 [M+H] + .

[0343] To a solution of 37-3 (80 mg, 0.37 mmol) and M5 (121 mg, 0.37 mmol) in DMF (2 mL) was added STAB (236 mg, 1.12 mmol) and allowed to react at room temperature for 16 h. The product was directly purified by C18 column chromatography (acetonitrile / water) to afford 37 (15 mg, 10% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.64(d,J=7.8Hz,1H),7.50(s,1H),7.40(d,J=7.8Hz,1H),7.22–7 .13(m,2H),6.92(d,J=8.4Hz,2H),6.73(t,J=7.2Hz,1H),5.10(dd,J=13.4,5.0Hz,1H),4.42(d,J=17.4H z,1H),4.28(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,3 LCMS m / z=527.7[M+H] + .

[0344] Synthesis of Example 38

[0345] Replace 25-1 with 2-oxaspiro[4.5]decan-8-one and use the synthesis method of Example 25 to Example 38: white solid, 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.15(s,1H),7.61(d,J=8.0Hz,1H),7.45(s,1H),7.35(d ,J=8.8Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.41–4.21(m,2H),3.67(m,3H),3.44(s,1H),3.06 –2.99(m,2H),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 –1.75(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] + .

[0346] Synthesis of Example 39

[0347] 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 (500MHz, Methanol-d4) δ7.77(d,J=8.1Hz,1H),7.73(s,1H),7.68(d,J=8.2Hz,1H) ,5.15(dd,J=13.3,5.1Hz,1H),4.52–4.43(m,4H),4.35(s,2H),2.94–2.87(m,1H),2.8 6–2.78(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] + .

[0348] Synthesis of Example 40

[0349] 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 obtain Example 40: a white solid, 1 H NMR (400MHz, DMSO-d6) 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),2.97–2.86(m,1H),2.62–2.59(m,4H),2.42–2.35(m,3H),2.26–2.12(m,2H),2.01–1.93(m,5H),1.66–1.56(m,2H), LCMS m / z=440.3[M+H] + .

[0350] Synthesis of Example 41

[0351] 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 obtain Example 41: white solid, 1H NMR(400MHz,Methanol-d4)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,1 H),2.93–2.84(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] + .

[0352] Synthesis of Example 42

[0353] 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 obtain Example 42: white solid, 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.68–7.53(m,3H),5.10(dd,J=13.2,5.0 Hz,1H),4.90(s,1H),4.47–4.30(m,2H),4.28(s,2H),4.23(s,2H),3.48(s,2H) ,2.97–2.85(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] + .

[0354] Synthesis of Example 43

[0355] Replace M5 with M13, replace 25-1 with 3-oxabicyclo[3.2.1]octan-8-one, and use the synthesis method of Example 25 to Example 43: white solid, 1H NMR(400MHz, Methanol-d4)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),3.5 2–3.30(m,2H),3.16–3.10(m,1H),3.07–2.97(m,1H),2.95–2.71(m,3H),2.66–2.39(m,3H),2.19–1.87(m,9H),1.86–1.73(m,3H), LCMS m / z=471.9[M+H] + .

[0356] Synthesis of Example 44

[0357] Replace M5 with M12, replace 25-1 with 3-oxabicyclo[3.2.1]octan-8-one, and use the synthesis method of Example 25 to Example 44: white solid, 1 H NMR(400MHz,Methanol-d4)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] + .

[0358] Synthesis of Example 47

[0359] Replace 37-1 with N-tert-butyloxycarbonyl-nortropinone and use the synthesis method of Example 37 to Example 47: white solid, 1H NMR (400MHz, DMSO-d6) 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] + .

[0360] Synthesis of Example 48

[0361] Replace 37-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester and use the synthesis method of Example 37 to Example 48: white solid, 1 H NMR(400MHz, DMSO-d6)10.99(s,1H),8.24(s,1H),7.65(d,J=7.7Hz,1H),7.50(s,1H),7. 41(d,J=7.6Hz,1H),7.21–7.07(m,2H),6.70–6.61(m,1H),6.40(d,J=7.4Hz,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] + .

[0362] Synthesis of Example 49

[0363] Replace M5 with M14, replace 25-1 with 3-oxabicyclo[3.2.1]octan-8-one, and use the synthesis method of Example 25 to Example 49: white solid, 1H NMR(400MHz, Methanol-d4)δ8.51(s,1H),7.81(dd,J=8.1,1.6Hz,1H),7.77(s,1H),7.68(dd, J=8.1,1.2Hz,1H),5.16(dd,J=13.3,5.1Hz,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] + .

[0364] Synthesis of Example 50

[0365] Replace 37-1 with tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate and use the synthesis method of Example 37 to Example 50: white solid, 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.28(s,1H),7.64(d,J=7.8Hz,1H),7.49(s,1H),7.39(d,J=7 .8Hz,1H),7.14(t,J=7.8Hz,2H),6.63(t,J=7.4Hz,1H),6.40(d,J=7.8Hz,2H),5.12–5.10(dd,J=13 .4,6.0Hz,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] + .

[0366] Synthesis of Example 51

[0367] Replace 37-1 with 8-oxo-2-azaspiro[4-]decane-2-carboxylic acid tert-butyl ester and use the synthesis method of Example 37 to Example 51: white solid, 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.25(s,1H),7.64(d,J=7.8Hz,1H),7.49(s,1H),7.40(d,J=8.2H z,1H),7.18–7.10(m,2H),6.59–6.51(m,2H),6.47(d,J=7.4Hz,1H),5.10(d,J=8.2Hz,1H),4.42(d,J=17 .4Hz,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 LCMS m / z=541.2[M+H] + .

[0368] Synthesis of Example 52

[0369] 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. The residue was purified by silica gel flash column chromatography (PE / EA) to give 52-2 (320 mg, yield 21%) as a white solid. 1 H NMR (400MHz, Methanol-d4) δ6.54 (s, 1H), 4.32–4.17 (m, 2H), 4.00 (t, J = 10.9Hz, 2H), 1.46 (s, 9H).

[0370] Under nitrogen atmosphere, NaCO (65 mg, 612.6 μmol) and Pd(dppf)Cl (66 mg, 82 μmol) were added to a solution of 52-2 (0.15 g, 408 μmol) and M1 (152 mg, 408.4 μmol) in 1,4-dioxane (4 mL) and water (1 mL). The mixture was reacted at 60°C for 3 hours. After returning 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 52-3 as a white solid (140 mg, 55% yield). LCMS m / z = 461.9 [M+H] + .

[0371] Under a hydrogen atmosphere, Pd(OH)2 / C (15% purity, 60 mg, 64.3 μmol) was added to a solution of 52-3 (0.14 g, 303.4 μmol) in DMF (10 mL) and the mixture was allowed to react at 40°C for 16 hours. The mixture was filtered through a pad of Celite and the filter cake was washed with DMF. 10 mL of water was added and the mixture was extracted with DCM (30 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 52-4 (120.00 mg, 85% yield) as a black solid. LCMS m / z = 407.9 [M-55] + .

[0372] Under nitrogen atmosphere, TFA (89 mg, 778 mmol) was added to a solution of 52-4 (120 mg, 259 μmol) in DCM (10 mL) and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried in vacuo to give 52-5 (90 mg, 95% yield) as a black solid. LCMS m / z = 362.2 [M+H] + .

[0373] Under nitrogen atmosphere, STAB (158 mg, 743 μmol) was added to a solution of 52-5 (90 mg, 248 μmol) and 25-1 (35 mg, 248 μmol) in DMF (10 mL), 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. The residue was purified by preparative HPLC to give 52 (5.5 mg, 5% yield) as a white solid. 1H NMR(400MHz, Methanol-d4)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] + .

[0374] Synthesis of Example 53

[0375] Replace the tert-butyl group of 2-oxo-6-azanaphtho[3.4]6-carboxylate with 37-1, and use the synthetic method of Example 37 to Example 53: white solid, 1 H NMR (400MHz, Methanol-d4) δ7.73 (d, J = 8.0 Hz, 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] + .

[0376] Synthesis of Example 54

[0377] Replace 37-1 with tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2-carboxylate and use the synthesis method of Example 37 to Example 54: white solid, 1H NMR (400MHz, Methanol-d4) δ7.72(d,J=8.0Hz,1H),7.39(s,1H),7.35(d,J=7.9Hz,1H),7.21 –7.14(m,2H),6.74–6.70(m,3H),5.12(dd,J=12.0,4.0Hz,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] + .

[0378] Synthesis of Example 55

[0379] Under nitrogen atmosphere, Selectfluor (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate), 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). The mixture was allowed to react at room temperature for 0.5 h. Selectfluor (0.35 g, 1 mmol) was then added and the reaction was continued at 50°C for 1 h. The mixture was returned to room temperature and quenched with 20 mL of saturated sodium bicarbonate solution. 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 afford 55-1 (140 mg, 15% yield) as a white solid. LCMS m / z = 406.2 [M-55]. + .

[0380] 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 reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried in vacuo to give 55-2 (35 mg, 30% yield) as a black solid. LCMS m / z = 362.3 [M+H] + .

[0381] Under nitrogen atmosphere, STAB (53 mg, 249 μmol) was added to a solution of 55-2 (30 mg, 83 μmol) and 25-1 (12 mg, 83 μmol) in DMF (10 mL) and 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 55 (26.3 mg, 65% yield) as a white solid. 1 H NMR (400MHz, Methanol-d4) δ7.81–7.78(m,2H),7.71–7.68(m,1H),5.14(dd,J=13.3,5. 1Hz,1H),5.10–4.94(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] + .

[0382] Synthesis of Example 56

[0383] Under a nitrogen atmosphere, to a solution of 2-fluoropyridine (200 mg, 2.06 mmol) and 37-2 (434 mg, 2.47 mmol) in ACN (3 mL) was added Cs2CO3 (cesium carbonate 2 g, 6.18 mmol) and allowed to react at room temperature for 3 hours. The mixture was filtered through a pad of Celite, the filter cake was washed with EA, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE / EA) to give 56-1 (280 mg, 63% yield) as a white solid. LCMS m / z = 217.1 [M+H] + .

[0384] Under nitrogen atmosphere, to a solution of 56-1 (20 mg, 92 μmol) in DMF (1.5 mL) was added STAB (20 mg, 92 μmol), the reaction was allowed to proceed for 15 minutes, and intermediate M5 (34 mg, 92 μmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. 5 mL of water was added, 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 56 (23 mg, 47% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) 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=7.8 Hz,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),4.3 0(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] + .

[0385] Synthesis of Example 57

[0386] Replace 37-1 with 5-oxo-2-azaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester and use the synthesis method of Example 37 to Example 57: white solid, 1 H NMR (400MHz, Methanol-d4) δ7.72(d,J=7.9Hz,1H),7.48(s,1H),7.42(d,J=8.3Hz,1H),7.19–7.12(m,2H),6. 69–6.64(m,1H),6.45(d,J=8.5Hz,2H),5.14(dd,J=13.5,5.3Hz,1H),4.52–4.40(m,2H),4.37(d,J=7.7Hz,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),2.56–2.4 2(m,1H),2.23–2.12(m,2H),2.10–1.95(m,6H),1.92–1.86(m,2H),1.84–1.79(m,2H),1.76–1.65(m,1H), LCMS m / z=499.0[M+H] + .

[0387] Synthesis of Example 58

[0388] Under a 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. The mixture was diluted with 10 mL of water, 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 (PE / EA) to give 58-1 as a white solid (60 mg, 31% yield). LCMS m / z = 443.9 [M+H] + .

[0389] 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). The mixture was reacted at 40°C for 16 hours, filtered through celite, concentrated under reduced pressure, extracted with DCM (10 mL×3), and lyophilized with water to give 58-2 (60 mg, yield 99%) as a black solid. LCMS m / z=445.9 [M+H] + .

[0390] 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 reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure and dried in vacuo to give 58-3 (45 mg, 99% yield) as a black solid. LCMS m / z = 345.9 [M+H] + .

[0391] Under nitrogen atmosphere, STAB (92 mg, 434 μmol) was added to a solution of 58-3 (45 mg, 130 μmol) and 37-1 (20 mg, 145 μmol) in DMF (10 mL), 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 give 58 (6.7 mg, 10% yield) as a white solid. 1H NMR(400MHz, Methanol-d4)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] + .

[0392] Synthesis of Example 59

[0393] Replace 37-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, replace phenylboronic acid with 2-fluorophenylboronic acid, and use the synthetic method of Example 37 to Example 59: white solid, 1 H NMR (400MHz, DMSO-d6) 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] + .

[0394] Synthesis of Example 60

[0395] Replace 37-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, replace phenylboronic acid with 2-methoxyphenylboronic acid, and use the synthetic method of Example 37 to Example 60: white solid, 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.31(s,1H),7.65(d,J=7.8Hz,1H),7.50(s,1H),7.41(d,J=7 .7Hz,1H),6.84–6.76(m,2H),6.71–6.66(m,1H),6.35(dd,J=7.7,1.3Hz,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] + .

[0396] Synthesis of Example 61

[0397] Replace 25-1 with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester and use the synthesis method of Example 25 to Example 61: white solid, 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.63(d,J=7.8Hz,1H),7.48(s,1H),7.39(d,J=8. 2Hz,1H),5.10(dd,J=13.2,5.0Hz,1H),4.42(d,J=17.4Hz,1H),4.28(d,J=17.4Hz,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] + .

[0398] Synthesis of Example 62

[0399] 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 allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to give a yellow oil 62-2 (0.5 g, yield 95%). LCMS m / z = 112.0 [M+H] + .

[0400] Under nitrogen atmosphere, NaHCO3 (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, 18% yield). LCMS m / z = 170.0 [M+H] + .

[0401] To a solution of M5 (0.1 g, 306 μmol) and 62-3 (52 mg, 306 μmol) in DMF (2 mL) was added STAB (195 mg, 916 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 give 62 (23 mg, 15% yield) as a white solid. 1 H NMR (400MHz, Methanol-d4)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),2.5 5–2.41(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] + .

[0402] Synthesis of Example 63

[0403] Replace 25-1 with 5-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester and use the synthesis method of Example 25 to Example 63: white solid, 1H NMR (500MHz, DMSO-d6) δ10.99(s,1H),7.64(d,J=7.9Hz,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] + .

[0404] Synthesis of Example 64

[0405] Replace 25-1 with 6-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and use the synthesis method of Example 25 to Example 64: white solid, 1 H NMR(500MHz,DMSO-d6)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=17.6Hz,1H),3.66–3.37(m,9H),2.96–2.87(m,2H),2.66–2.55(m,4H) ,2.42–2.35(m,2H),2.03–1.94(m,2H),1.85–1.62(m,6H),1.37(s,9H), LCMS m / z=551.4[M+H] + .

[0406] Synthesis of Example 65

[0407] Replace 25-1 with 2-oxaspiro[3.3]heptane-5-one and use the synthesis method of Example 25 to Example 65: white solid, 1HNMR(500MHz,DMSO-d6)δ10.99(s,1H),7.65(d,J=7.8Hz,1H),7.52(s,1H),7.42(d,J=7.7 Hz,1H),5.10(dd,J=13.3,5.0Hz,1H),4.92(d,J=5.9Hz,1H),4.46(d,J=7.0Hz,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,2H),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] + .

[0408] Synthesis of Example 66

[0409] 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 obtain Example 66: white solid, 1 H NMR(500MHz,DMSO-d6)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] + .

[0410] Synthesis of Example 67

[0411] 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 obtain Example 67: white solid, 1H NMR (400MHz, Methanol-d4) 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] + .

[0412] Synthesis of Example 68

[0413] 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 allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dried in vacuo to afford 68-1 (0.15 g, 51% yield) as a white solid. LCMS m / z = 423.3 [M+H] + .

[0414] Under nitrogen atmosphere, triethylamine (61 μL, 437 μmol) was added to a solution of 68-1 (50 mg, 87.5 μmol) in DMF (1 mL). The temperature was cooled to 0°C, and a solution of acetyl chloride (10 mg, 131 μmol) in DMF (1 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. 10 mL of water was added to the reaction system, and the lyophilized residue was purified by preparative thin-layer chromatography to give 68 (7.9 mg, yield: 19%) as a white solid. 1H NMR(500MHz,DMSO-d6)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),4.19(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),2.7 2–2.54(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] + .

[0415] Synthesis of Example 69

[0416] Replace compound 63 with compound 64 and use the synthesis method of Example 68 to obtain Example 69: white solid, 1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H),7.70(d,J=7.7Hz,1H),7.47(s,1H),7.40(d,J=7.9Hz,1H),5 .11(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.2Hz,1H),4.31(d,J=17.3Hz,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 LCMS m / z=493.70[M+H] + .

[0417] Synthesis of Example 70

[0418] 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 allowed to react at room temperature for 3 hours. The mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE:EA) to give 70-2 (120 mg, 60% yield) as a colorless oil. 1 H NMR(500MHz, CDCl3)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).

[0419] Under nitrogen atmosphere, STAB (1.46 g, 6.89 mmol) was added to a solution of M5 (248 mg, 681 μmol) and 69-2 (120 mg, 688 μmol) in DMF (3 mL), and the mixture was reacted at 60°C for 16 hours. The mixture was returned to room temperature, and the pH of the system was adjusted to 8 using 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, 4% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)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) ,2.13–2.01(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] + .

[0420] Synthesis of Example 71

[0421] Replace 25-1 with 7-oxaspiro[3.5]nonan-1-one and use the synthesis method of Example 25 to Example 71: white solid, 1 H NMR (500MHz, DMSO-d6) δ10.99(s,1H),7.63(d,J=7.7Hz,1H),7.49(s,1H),7.39(d,J=7.8Hz,1H),5.10(dd,J=13 .2,4.7Hz,1H),4.41(d,J=17.2Hz,1H),4.28(d,J=16.8Hz,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] + .

[0422] Synthesis of Example 72

[0423] Replace acetyl chloride with 2-methylpropane-1-sulfonyl chloride and use the synthesis method of Example 68 to Example 72: white solid, 1H NMR (500MHz, DMSO-d6) 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),4.4 2(d,J=17.2Hz,1H),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] + .

[0424] Synthesis of Example 73

[0425] Replace acetyl chloride with isovaleryl chloride and use the synthesis method of Example 68 to Example 73: white solid, 1H NMR (500MHz, DMSO-d6) δ10.98(s,1H),7.67–7.61(m,1H),7.51(d,J=7.4Hz,1H),7.41(d,J=7.9Hz,1H),5.36(dd,J=23.4 ,6.0Hz,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),3.73–3.62(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) ,2.02–1.96(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] + .

[0426] Synthesis of Example 75

[0427] Replace 25-1 with 1-oxo-7-azaspiro[1-3]nonane-7-carboxylic acid tert-butyl ester and use the synthesis method of Example 25 to Example 75: white solid, 1 H NMR (500 MHz, DMSO-d6) δ 10. 1H NMR(500MHz,DMSO-d6)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=13.3,5.1 Hz,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) ,1.94–1.87(m,1H),1.86–1.79(m,1H),1.80–1.57(m,8H),1.57–1.50(m,1H),1.49–1.40(m,2H),1.36(s,9H), LCMS m / z=551.7[M+H] + .

[0428] Synthesis of Example 76

[0429] 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 (400MHz, DMSO-d6) δ10.98(s,1H),8.14(s,1H),7.53–7.47(m,1H),5.08(dd,J=13.3,5.1Hz,1H),4.51(d ,J=17.3Hz,1H),4.33(d,J=17.3Hz,1H),3.78–3.71(m,1H),3.61(dd,J=11.2,4.0Hz,1H),3.39–3.35(m,2H) ,3.17–3.12(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),2.02–1.92(m,1H),1.91–1.81(m,2H),1.79–1.61(m,8H),1.61–1.51(m,2H),1.42–1.32(m,2H), LCMS m / z=470.3[M+H] + .

[0430] Synthesis of Example 77

[0431] Replace 25-1 with 2-oxaspiro[3.3]heptane-5-one, replace M5 with M12, and use the synthesis method of Example 25 to Example 77: white solid, 1 H NMR (400MHz, DMSO-d6) δ10.98(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] + .

[0432] Synthesis of Example 81

[0433] Replace 25-1 with 1-oxo-7-azaspiro[1-3]nonane-7-carboxylic acid tert-butyl ester, replace M5 with M12, and use the synthetic method of Example 25 to Example 81: white solid, 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.56–7.44(m,2H),5.08(dd,J=13.4,5.1Hz,1H), 4.51(d,J=17.3Hz,1H),4.33(d,J=17.2Hz,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] + .

[0434] Synthesis of Example 82

[0435] Replace 25-1 with 6-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, replace M5 with M12, and use the synthetic method of Example 25 to Example 82: white solid, 1H NMR (400MHz, DMSO-d6) 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] + .

[0436] Synthesis of Example 83

[0437] Replace 25-1 with spiro[3.5]nonane-2-one, replace M5 with M12, and use the synthesis method of Example 25 to Example 83: white solid, 1 H NMR (400MHz, DMSO-d6) 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] + .

[0438] Synthesis of Example 84

[0439] Replace 25-1 with spiro[3.5]nonane-1-one, replace M5 with M12, and use the synthesis method of Example 25 to Example 84: white solid, 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.52–7.49(m,2H),5.08(dd,J=13.2,5.1Hz,1H),4.51 (d,J=17.3Hz,1H),4.33(d,J=17.3Hz,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] + .

[0440] Synthesis of Example 85

[0441] Replace 25-1 with spiro[3.3]heptane-2-one, replace M5 with M12, and use the synthetic method of Example 25 to Example 85: white solid, 1 H NMR (400MHz, DMSO-d6) 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] + .

[0442] Synthesis of Example 86

[0443] Replace 25-1 with 6,6-difluorospiro[3.3]heptan-2-one, replace M5 with M12, and use the synthesis method of Example 25 to Example 86: white solid, 1H NMR (400MHz, DMSO-d6) 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 LCMS m / z=475.9[M+H] + .

[0444] Synthesis of Example 87

[0445] Replace 25-1 with spiro[2.3]hexan-5-one, replace M5 with M12, and use the synthesis method of Example 25 to Example 87: white solid, 1 H NMR (400MHz, DMSO-d6) 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(m,2H),2.95–2.84(m,1H),2.64–2.53(m,1H),2.44–2.30(m,3H),2.17–2.04(m,2H),2.01–1.73(m,9H),0.53–0.35(m,4H), LCMS m / z=425.9[M+H] + .

[0446] Synthesis of Example 88

[0447] Replace 25-1 with spiro[3.4]octan-1-one, replace M5 with M12, and use the synthetic method of Example 25 to Example 88: white solid, 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),7.65–7.49(m,2H),5.10(dd,J=12.9,5.1Hz,1H),4.54(d,J=17.2Hz,1H),4.36(d,J=17.2H LCMS m / z=453.9[M+H] + .

[0448] Synthesis of Example 89

[0449] Replace 25-1 with spiro[3.4]octan-1-one and follow the synthesis method of Example 25 to Example 89: white solid, 1 H NMR (500MHz, DMSO-d6) δ10.98(s,1H),8.19(s,1H),7.64(d,J=7.8Hz,1H),7.48(s,1H),7.39(d,J =7.9Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.41(d,J=17.2Hz,1H),4.28(d,J=17.2Hz,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] + .

[0450] Effect Example 1: Protein Degradation Western Blot Detection Method

[0451] 1. Reagent Preparation

[0452] 1) Cell lysis working solution:

[0453] To 20 mL of cell lysis buffer (Beyotime Cat#P0013B), add one protease inhibitor (Roche (Cat#4693132001)) and one phosphatase inhibitor (Roche (Cat#04906837001)) and mix gently until completely dissolved.

[0454] 2) 4× sample preparation working solution:

[0455] DTT (Sigma Cat#D9779-1G) was added to 4x sample preparation buffer (Thermo Fisher Cat#NP0007) at a final concentration of 200 mM to prepare a 4x sample preparation working solution.

[0456] 3) Electrophoresis buffer:

[0457] Dilute 20x electrophoresis buffer (Thermo Fisher Cat#NP0001) to 1x with ultrapure water.

[0458] 4) Transfer buffer:

[0459] Dilute 20x transfer buffer (Thermo Fisher Cat# NP0006-1) to 1x with ultrapure water and add 20% methanol.

[0460] 5)TBST buffer:

[0461] Dilute 10×TBST (CST Cat#9997S) with ultrapure water to 1×TBST buffer

[0462] 6) Blocking solution and antibody working solution:

[0463] 5 g of BSA (Solarbio Cat#A8020) was dissolved in 100 mL of 1×TBST and stored at 4°C.

[0464] 7) Primary antibody working solution:

[0465] eRF3 / GSPT1 antibody (CST Cat#14980), Ikaros (D6N9Y) antibody (CST Cat#14859), and Helios (D8W4X) antibody (CST Cat#42427) were diluted 1:1000 to the antibody working solution.

[0466] Dilute GAPDH antibody (CST Cat#5174) at a ratio of 1:10,000 to the antibody working solution.

[0467] 8) Secondary antibody working solution:

[0468] Anti-rabbit IgG, HRP-linked (CST (Cat#7074)) antibody was diluted to the antibody working solution at a ratio of 1:5000.

[0469] 2. Protein Extraction

[0470] 1) Jurkat cells (ATCC Cat#TIB-152) were seeded into 96-well cell culture plates (Corning Cat#3599) at 5×10 cells per well. 4 cells, 100 μL culture medium (Invitrogen Cat#A1049101, Gibco Cat#10099141C, Solarbio Cat#P1400), and culture for 24 hours.

[0471] 2) Dissolve the test compound in DMSO (Sigma Cat#D8418) to a 10 mM stock solution. Make a three-fold serial dilution of the test compound in DMSO. Add 100 nL to each well and centrifuge at 1000 rpm (Eppendorf Cat#5810R) for 1 minute. Incubate the cells at 37°C in a 5% CO2 incubator for 24 hours.

[0472] 3) Centrifuge at 4000 rpm for 5 minutes using a cell culture machine (Eppendorf Cat#5810R). Discard the culture medium in the plate and 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.

[0473] 4) Add 15 μL of 4X sample preparation buffer (Thermo Fisher Cat#NP0007) to each well of a 96-well plate and mix with the protein sample, then heat at 70°C for 10 minutes.

[0474] 3 Western Blot Detection

[0475] 1) Load 10 μl of sample into each well of a precast gel (Thermo Fisher (Cat# WG1403BOX) and perform electrophoresis at a constant voltage of 120 V for approximately 60 min (power supply: Bio-Rad PowerPac HC 1645052, electrophoresis tank: Thermo Fisher XCell4 SureLock).

[0476] 2) Transfer the membrane using a PVDF membrane (Millipore Cat#IPVH00010) at a constant current of 300 mA for 1 hour (power supply: Bio-Rad PowerPac HC 1645052, transfer instrument: Bio-Rad Cat#1704071).

[0477] 3) After transfer, block with blocking solution at room temperature for 1 hour.

[0478] 4) Incubate in primary antibody working solution at 4°C overnight.

[0479] 5) Wash the membrane with 1× TBST buffer (3×10 min). Incubate with secondary antibody solution at room temperature for 1 hour.

[0480] 6) Wash the membrane with 1× TBST buffer for 3×10 min and develop the color using a color developing solution (Thermo Fisher Cat#32134).

[0481] 4DC50 Analysis

[0482] The grayscale value of each band was semi-quantitatively analyzed using Image Studio Lite Ver 5.2 software, and the DC50 of the compound was obtained using a nonlinear fitting formula using GraphPad 8.0.

[0483] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogDC50-X)*HillSlope)); X: log value of compound concentration; Y: percentage of compound inhibition.

[0484] Effect Example 2: Evaluation of IKZF2 or IKZF1 Protein Degradation in Cell Lines Using the Nano-Glo Hibit Detection System

[0485] 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).

[0486] 1. Experimental Materials

[0487] 1.1 Cell lines and culture methods

[0488] Table 2. Cell lines and culture methods

[0489] 1.2 Culture medium

[0490] Table 3. Culture media and reagents

[0491] 1.3 Multi-well plate

[0492] Greiner CELLSTAR 96-well plate, flat black plate (with lid and clear bottom), #655090.

[0493] 1.4 Reagents and instruments used in cell viability experiments

[0494] (1)Promega HiBiT Lytic Detection System Kit (Promega-N3050)

[0495] (2) 2105 EnVision plate reader, PerkinElmer.

[0496] 2. Experimental methods and steps

[0497] 2.1 Cell culture

[0498] 293FT-IKZF2-HibiT or K562-IKZF1-HibiT cell lines were cultured in a 37°C, 5% CO2 incubator according to the culture conditions shown in Table 2. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating.

[0499] 2.2 Cell plating

[0500] (1) Stain cells with trypan blue and count viable cells.

[0501] (2) Adjust the cell concentration to an appropriate level.

[0502] (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.

[0503] (4) Incubate the culture plate in an incubator at 37°C, 5% CO2, and 100% relative humidity overnight.

[0504] 2.3 Preparation of compound storage plate

[0505] (1) Prepare a 400X compound storage plate: dilute the compound with DMSO from the highest concentration to the lowest concentration.

[0506] 2.4 Preparation of 10X compound working solution and compound treatment of cells

[0507] (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 a 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 compound or DMSO, mix thoroughly by pipetting with a pipette.

[0508] (2) Dosing: Add 10 μL of 10X compound working solution 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%.

[0509] (3) Place the 96-well cell plate back into the incubator and culture for 24 hours.

[0510] 2.5 HiBiT Lytic Detection

[0511] The following steps are in accordance with Promega The assay was performed according to the instructions of the HiBiT Lytic Detection System kit (promega-N3050).

[0512] (1) Add 100 μL of detection reagent (1 mL lysis buffer + 20 μL lytic substrate + 10 μL LgBiT protein).

[0513] (2) Shake at 300 r for 3 minutes and detect the luminescent signal on a 2105 Envision plate reader.

[0514] 2.6 Data Analysis

[0515] The degradation rate (DR) of the test compound was calculated using the following formula: DR (%) = (1 – (RLU compound – RLU blank control) / (RLU vehicle control – RLU blank control)) * 100%. Degradation rates at different compound concentrations were calculated in Excel. Inhibition curves were then fitted using GraphPad Prism software using the log(inhibitor) vs. response variable slope method. Related parameters, including minimum degradation rate, maximum degradation rate (Dmax), and relative DC, were obtained. 50 .

[0516] IKZF2 degradation (WB) DC 50 (nM):

[0517] +++,<100nM; ++,≥100nM,<1000nM; +,≥1000nM

[0518] IKZF2 degradation (WB) Dmax (%):

[0519] +++, ≥75%; ++, ≥50%, <75%; +, ≤50%

[0520] IKZF2 degrades (Hibit) DC 50 (nM)

[0521] +++,<50nM;++,≥50nM,<500nM;+,≥500nM

[0522] IKZF2 degradation (Hibit) Dmax (%)

[0523] +++, ≥75%; ++, ≥50%, <75%; +, ≤50%

[0524] IKZF1 degradation (WB) DC 50 (nM)

[0525] +, ≤200nM; ++, ≥200nM, <1000nM; +++, ≥1000nM

[0526] IKZF1 degrades (Hibit) DCs 50 (nM)

[0527] +, ≤200nM; ++, ≥200nM, <1000nM; +++, ≥1000nM

[0528] GSPT1 degradation (WB) DC 50 (nM)

[0529] +, ≤200nM; ++, ≥200nM, <1000nM; +++, ≥1000nM

[0530] - indicates not detected.

[0531] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound as shown in formula II or a pharmaceutically acceptable salt thereof; in, q is 0, 1, 2, or 3; R 3 is H, -OH or halogen; Y 1 CR Y1 or N; Y 2 CR Y2 or N; Y 3 CR Y3 or N; R Y1 , R Y2 and R Y3 are 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 C1-C6 alkyl; R X is H or deuterium; Each R 1 are independently C1-C6 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 C3-C 10 Monocyclic cycloalkyl, C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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 Independently OR a , -CONR a R b 、 CN, C3-C 10 Cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl, 2- 1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 substituted 5-12 membered heteroaryl; 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 Independently OR a , -CONR a R b 、 CN, C3-C 10 Cycloalkyl, 3-12 membered heterocycloalkyl, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl, 2- 1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 substituted 5-12 membered heteroaryl; 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 are independently halogen, cyano, OR a , C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens; Each R 2-1-2 are independently halogen, OR a , C3-C 10 Cycloalkyl, 3-12 heterocycloalkyl, C6-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 are independently halogen, cyano, OR a , C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens; Each R 2-2 are independently halogen, OR a , By one or more R 2-2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2-2 Substituted C5-C 10 Polycyclic cycloalkyl or one or more R 2-2-3 Substituted 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 2-2-1 are independently halogen, OR a , C6-C 10 Aryl, 5-12 membered heteroaryl or C1-C6 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 are independently halogen, OR a , C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl or C1-C6 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 are independently halogen, OR a , Oxo, C6-C 10 Aryl, 5-12 membered heteroaryl, C1-C6 alkyl or one or more halogen-substituted C1-C6 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 are independently oxo (=O), -C(=O)OR a 、-C(=O)R a , -CONR a R b 、 Halogen, OR a 、CN、C3-C 10 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-12 membered heteroaryl, substituted by one or more R a substituted 5-12 membered heteroaryl, substituted by one or more R 2-3-1 Substituted C6-C 10 Aryl or one or more R 2-3-2 substituted C1-C6 alkyl; 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 are independently halogen, cyano, OR a , or a C1-C6 alkyl group substituted by one or more halogens; Each R 2-3-2 are independently halogen, OR a , C3-C 10 Cycloalkyl, 3-12 heterocycloalkyl, C6-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 a are independently hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, C3-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; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, C3-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; Or, R a , R b Together with the atoms connected thereto, it forms a 3-12 membered heterocycloalkyl group; 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.

2. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1)R 3 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (2)R Y1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (3)R Y3 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (4)R 1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably is methyl; (5)R 1 wherein 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)R 2 In the C3-C 10 The monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (9)R 2 In the C5-C 10 The polycyclic cycloalkyl groups are each independently For example (10)R 2 wherein 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 The Preferably and / or (11)R 2 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (12)R 2-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (13), R 2-1 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl; (14)R 2-1 wherein 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 (15)R 2-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (16)R 2-4 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (17)R 2-1-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (18)R 2-1-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (19)R 2-1-2 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl; (20)R 2-1-3 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (21)R 2-2 In the C3-C 10 The monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (22)R 2-2-1 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl; (23)R 2-3 In the C6-C 10 The aryl groups are each independently phenyl or naphthyl, preferably phenyl; (24)R 2-3 In the above, 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 (25)R 2-3-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (26)R a wherein 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 C1-C6 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) C3-C 10 The monocyclic cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (30) C5-C 10 The 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) C6-C 10 The 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 C1-C6 alkyl group substituted by one or more halogens is fluorine, chlorine, bromine or iodine, preferably fluorine; (35) The C1-C6 alkyl groups substituted by one or more halogens are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; (36) The C1-C6 alkyl group substituted by one or more halogens is preferably -CF3.

3. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets 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)Y 1 CR Y1 ; (4)Y 2 CR Y2 ; (5)Y 3 CR Y3 ; (6)R Y1 and R Y2 are independently H or halogen; preferably H; (7)R Y3 are independently H or halogen; (8)R Q1 and R Q2 are independently H or deuterium; preferably hydrogen; (9)R X is H; (10) Each R 1 are independently C1-C6 alkyl or halogen; preferably C1-C6 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)R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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-C 10 Polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 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 are independently -OH, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, substituted by one or more R 2-1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 Substituted 5-12 membered heteroaryl; preferably C6-C 10 Aryl or one or more R 2-1-2 Substituted C1-C6 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; (14) Each R 2-1-1 is independently a C1-C6 alkyl group substituted by one or more halogens; (15) Each R 2-1-2 Independently C6-C 10 Aryl; (16) Each R 2-1-3 are independently halogen; (17) Each R 2-4 are independently halogen, OR a , or CN; preferably halogen; (18) Each R 2-2 Independently for one or more R 2-2-1 Substituted C3-C 10 monocyclic cycloalkyl; (19) Each R 2-2-1 Independently C6-C 10 Aryl; (20) Each R 2-3 are independently oxo (=O), -C(=O)OR a 、-C(=O)R a , C6-C 10 Aryl, 5-12 membered heteroaromatic or one or more R 2-3-1 Substituted C6-C 10 Aryl; preferably -C(=O)OR a 、-C(=O)R a , C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; more preferably C6-C 10 Aryl or -C(=O)OR a ; 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; (21) Each R 2-3-1 are independently halogen or OR a ; preferably halogen; (22) Each R a are independently C1-C6 alkyl or H; (23) The pharmaceutically acceptable salt of the compound of Formula II is formate.

4. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It is the following plan a, plan b or plan c; Plan A: q is 0, 1, or 2; R 3 is H, -OH or halogen; Y 1 CR Y1 ; Y 2 CR Y2 ; Y 3 CR Y3 ; R Y1 , R Y2 and R Y3 are independently H or halogen; Q is CR Q1 R Q2 ; R Q1 and R Q2 independently H; R X is H; Each R 1 are independently C1-C6 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 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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 are independently -OH, halogen, C6-C 10 Aryl, 5-12 membered heteroaryl, substituted by one or more R 2-1-1 Substituted C6-C 10 Aryl, one or more R 2-1-2 Substituted C1-C6 alkyl or one or more R 2-1-3 Substituted 5-12 membered heteroaryl; 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 C1-C6 alkyl group substituted by one or more halogens; Each R 2-1-2 Independently C6-C 10 Aryl; Each R 2-1-3 are independently halogen; Each R 2-2 Independently for one or more R 2-2-1 Substituted C3-C 10 monocyclic cycloalkyl; Each R 2-2-1 Independently C6-C 10 Aryl; Each R 2-3 are independently oxo (=O), -C(=O)OR a 、-C(=O)R a , C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; 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 are independently halogen or OR a ; Each R 2-4 are independently halogen, OR a , or CN; preferably halogen; Each R a are independently C1-C6 alkyl or H; Option B: q is 0 or 1; R 3 is H, -OH or halogen; Y 1 CR Y1 ; Y 2 CR Y2 ; Y 3 CR Y3 ; R Y1 and R Y2 are independently H; R Y3 is H or halogen; Q is CR Q1 R Q2 ; R Q1 and R Q2 independently H; R X is H; Each R 1 are independently C1-C6 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; R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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 Independently C6-C 10 Aryl or one or more R 2-1-2 Substituted C1-C6 alkyl; Each R 2-1-2 Independently C6-C 10 Aryl; Each R 2-2 Independently for one or more R 2-2-1 Substituted C3-C 10 monocyclic cycloalkyl; Each R 2-2-1 Independently C6-C 10 Aryl; Each R 2-3 are independently -C(=O)OR a 、-C(=O)R a , C6-C 10 Aryl, 5-12 membered heteroaryl or one or more R 2-3-1 Substituted C6-C 10 Aryl; in the 5-12 membered heteroaryl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, The number of atoms is 1, 2, 3 or 4; Each R 2-3-1 are independently halogen; Each R 2-4 are independently halogen, OR a , or CN; preferably halogen; Each R a are 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; Y 3 CR Y3 ; R Y3 are independently H or halogen; R X 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; R 2 C5-C 10 Polycyclic cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C3-C 10 Monocyclic cycloalkyl, surrounded by one or more R 2-2 Substituted C1-C6 alkyl, one or more R 2-3 substituted 3-12 membered heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 Polycyclic cycloalkyl; 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-C 10 Polycyclic cycloalkyl, 7-10 membered spirocyclic heterocycloalkyl, 7-10 membered bridged heterocycloalkyl or one or more R 2-4 Substituted C5-C 10 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 Independently C6-C 10 Aryl or one or more R 2-1-2 Substituted C1-C6 alkyl; Each R 2-1-2 Independently C6-C 10 Aryl; Each R 2-4 are independently halogen; Each R 2-2 Independently for one or more R 2-2-1 Substituted C3-C 10 monocyclic cycloalkyl; Each R 2-2-1 Independently C6-C 10 Aryl; Each R 2-3 Independently C6-C 10 Aryl or -C(=O)OR a ; Each R a are independently C1-C6 alkyl.

5. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: It meets one or more of the following conditions: (1)R 2 for (2) for (3) for (4)R x For H.

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

7. 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 shown in Formula II is any of the following structures: Preferably, IKZF2 degradation (WB) DC 50 <100 nM; maximum degradation rate at 1 μM ≥75%; or, IKZF2 degradation (Hibit) DC 50 The maximum degradation rate at 1 μM was ≥50%.

8. A compound of formula III or a pharmaceutically acceptable salt thereof, or a compound of formula IV: in, q, R 1 , Ring A, R 3 , Y 1 , Y 2 , Y 3 , Q and R X The definition as in any one of claims 1 to 7; R 5 H, -C(=O)-OR 5-1 or one or more R 5-2 or substituted C3-C 10 monocyclic cycloalkyl; R 5-1 is a C1-C6 alkyl group; Each R 5-2 Independently C6-C 10 Aryl or one or more R 2-5-1 Substituted C6-C 10 Aryl; Each R 2-5-1 is independently a C1-C6 alkyl group substituted by one or more halogens; R 6 is oxo (=O) or Preferably, R 5 For H.

9. 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 both 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:

10. A compound as shown below:

11. A pharmaceutical composition comprising a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in formula II according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

12. 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.

13. The use according to claim 12, characterized in that The IKZF2-related diseases are one or more of tumors, diseases caused by infection with viruses, bacteria or other pathogens, or diseases related to human aging; the tumors are 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.

14. 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.

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