WEE1 INHIBITOR, PREPARATION THEREFOR, AND USE THEREOF

Abstract

The present invention relates to a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a use thereof in the preparation of a drug for treating diseases related to WEE1 activity.

Description

TECHNICAL FIELD

The present invention relates to compounds that inhibit WEE1 kinase activity, especially to the compounds represented by Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The present invention also relates to the preparation method of these compounds, pharmaceutical composition thereof, and the use thereof in the preparation of the drug for the treatment of WEE1 activity related diseases.

BACKGROUND ART

Wee1 tyrosine kinase is the checkpoint of G2 phase of cell cycle. Cell cycle is tightly regulated and controlled. When the cellular DNA is not damaged, the checkpoints of G1, S and G2 phases promote cells to enter division phase to ensure the successful completion of cell cycle (Clinical Cancer Research, 2011, 17(13):4200-4207). Cell cycle is regulated and controlled by CDKs (Cyclin-dependent kinases). CDKs family comprises 14 kinds of serine/threonine protein kinases. The activity of CDK is regulated and controlled by phosphorylation and the binding of different cyclins. The transition of cells from G2 phase to division phase is positively regulated by the phosphorylation of CDK1 (also called CDC2) and its associated cyclin B. CDK1 is in an inactive state before divison and is phosphorylated by WEE1 in tyrosine 15, and then phosphorylated by myelin transcription factor (MYT1) in threonine 14. Therefore, WEE1 is a negative regulator of cell cycle that negatively regulates the passage of cells from G2 phase to division phase by preventing cyclin B and activated CDK1 complexes from entering the nucleus. The expression and activity of WEE1 are both increased in S and G2 phases and decreased in the highly phosphorylated M phase. When cells enter G2 phase and no DNA damage occurs, polo-like protein kinase 1 (PLK1) phosphorylates WEE1, which is degraded by the ubiquitin ligase complex. PLK1 also phosphorylates and activates the protein phosphatase cell division cycle 25 analog (CDC25), which activates CDK1 by dephosphorylation. Active CDK1 binds to cyclin B and promotes cell entry into division phase (Molecular&CellularBiology, 2012, 32(20):4226).

When a cell's DNA is damaged, the checkpoints of G1, S, and G2 phases delay the cell's entry into division phase, buying time to repair the damaged DNA before the cell enters division, thus ensuring the integrity of the genome. The key regulator of the G1 phase checkpoint P53 is in a mutated form in many malignant cells (Proceedings of the National Academy of Sciences of the United States of America, 2007,104(10):3753-3758). The tumor cells with defective P53 function fail to block the cell cycle in G1 phase when DNA is damaged, and are therefore more dependent on the G2 phase checkpoint. In response to DNA damage, the G2 phase checkpoint inhibits CDK1 phosphorylation through two parallel and interconnected pathways, thereby delaying cell entry into division phase. Depending on the type of DNA damage, ataxia telangiectasia mutated (ATM) protein kinase or ataxia telangiectasia-related (ATR) protein kinase is activated. (Oncotarget, 2016, 7 (31): 49902-49916)

ATM is activated by ionizing radiation, radioactive agents, and agents that cause double-stranded DNA breaks. ATM phosphorylates and activates checkpoint kinase 2 (CHK2), CHK2 phosphorylates Ser216 of cell division cycle 25C phosphatase (CDC25C). This leads to a nuclear export and cytoplasmic segregation of CDC25C, thereby inhibiting its phosphorylation activity. Inhibition of CDC25C activity leads to inhibition of CDK1/CDK2 binding cyclin B complex phosphorylation, which puts CDK1 in an inactivated form and inhibits cell entry into division (MolecularCancer, 2014, 13(1):72).

ATR is activated by a wide range of genotoxic stimuli that cause single-stranded DNA breaks. ATR is the main kinase responsible for the phosphorylation and activation of CHK1. In contrast to CHK2, which can only be activated by ATM, CHK1 can be activated by both ATM and ATR. CHK1 phosphorylates both WEE1 and CDC25C, activates WEE1 kinase activity and inhibits CDC25C phosphatase activity. WEE1 phosphorylates CDK1-binding cyclin B, leading to cell cycle arrest in G2 phase and providing time for DNA repair (Drug News&Perspectives, 2010, 23(7):425).

WEE1 is overexpressed in many malignant tumors, such as hepatocellular carcinoma, breast cancer, malignant glioma, melanoma, adult and pediatric brain tumors. Part of these tumor cells have abnormal G1 checkpoints, and inhibition of WEE1 activity leads to G2 phase checkpoint malfunction, at this time cells with unrepaired damaged DNA will continue to divide and eventually divide to death (Molecular Cancer Therapeutics, 2013, 12(12):2675-2684). Inhibition of WEE1 activity, whether by pyrimidine derivatives (PD0166285) or small interfering RNA knockdown, will make ovarian, colon, cervical, osteosarcoma, malignant glioma, and lung cancer cells more sensitive to DNA damage produced by radiation and topoisomerase inhibition. Therefore, WEE1 inhibitors have a wide scope for development both as single drug and concomitant drugs (Cancer Biology&Therapy, 2010, 9(7):523-525).

Small molecule compounds with WEE1 kinase inhibitory activity were disclosed in the patent applications of WO2007126122, WO2008133866, WO2013012681, WO2013126656, WO2014167347, WO2015092431, WO2018011569, WO2018011570, WO2018090939, WO2018133829, WO2018171633, etc. At present, the compound with the fastest development progress is AZD1775, which has entered the phase II clinical trial and shows favorable cancer treatment results. But, AZD1775 also has rather obvious adverse reactions, and drug activity and efficacy need to be improved. Therefore, it is necessary to develop Wee1 inhibitors with higher safety and wider range of applications.

SUMMARY OF THE INVENTION

The present invention provides a compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein, R₁ is selected from a group consisting of —C_1˜6 alkyl, —C_2˜6 alkenyl, —C_2˜6 alkynyl, —C_0˜2 alkylene-CN, —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl); wherein said —C_0˜2 alkylene, —C_1˜6 alkyl, —C_2˜6 alkenyl, —C_2˜6 alkynyl, 3˜10-membered cycloalkyl, 3˜10-membered heterocycloalkyl are optionally substituted by one, two, three or four independent R¹¹;

R¹¹ is selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, halogen;

R₂ is selected from a group consisting of

R²¹ is selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —C_0˜2 alkylene-C(O)OC_1˜6 alkyl, —C_0˜2 alkylene-COOH, —C(O)C_1˜6 alkyl, halogen;

R₃ is selected from a group consisting of

X₁ is selected from a group consisting of chemical bond, O, NR^N1 or CR^C1R^C2; X₂ is selected from N or CR^C1; X₃ is selected from a group consisting of O, NR^N1 or CR^C1R^C2.

n is selected from 1, 2 or 3;

R^N1 is selected from a group consisting of H, halogen, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl);

R^C1, R^C2 are independently selected from a group consisting of H, halogen, cyano, nitro, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —C_0˜2 alkylene-NH(C_1˜6 alkyl), —C_0˜2 alkylene-N(C_1˜6 alkyl)(C_1˜6 alkyl);

R₄ is selected from -(5˜12-membered bridged heterocylcylalkyl); wherein said bridged heterocylcylalkyl is optionally substituted by one, two, three or four independent R⁴¹;

R⁴¹ is selected from a group consisting of H, oxo, —C_1˜6 alkyl, —C_2˜6 alkenyl, halogen substituted —C_1˜6 alkyl, hydroxy-substituted —C_1˜6 alkyl, halogen, cyano, nitro, —OH, —C_0˜2 alkylene-O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-C(O)R⁴², —C_0˜2 alkylene-C(O)NR⁴²R⁴³, —C_0˜2 alkylene-C(O)OR⁴², —C_0˜2 alkylene-S(O)R⁴², —C_0˜2 alkylene-S(O)NR⁴²R⁴³, —C_0˜2 alkylene-S(O)OR⁴², —C_0˜2 alkylene-S(O)₂R⁴², —C_0˜2 alkylene-S(O)₂NR⁴²R⁴³, —C_0˜2 alkylene-S(O)₂OR⁴², —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl); wherein said alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic cyclyl, aromatic heterocyclyl are optionally substituted by one, two, three or four independent R⁴⁴;

R⁴², R⁴³ are independently selected from a group consisting of H, halogen, cyano, nitro, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl);

R⁴⁴ is selected from a group consisting of H, oxo, halogen, cyano, nitro, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —C_0˜2 alkylene-NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl);

or, R⁴¹ and R^C1, or R^C2 together with the atom adjacent therewith form 3˜10-membered carbocyclyl, 3˜10-membered heterocyclyl;

R₅ is selected from a group consisting of H, oxo, halogen, cyano, nitro, —OH, —NH₂, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, hydroxy-substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —C_0˜2 alkylene-NH(C_1˜6 alkyl), —O—C_0˜2 alkylene-N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —O-(3˜10-membered cycloalkyl), —O—C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl); wherein said alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic cyclyl, aromatic heterocyclyl are optionally substituted by one, two, three or four independent R⁵¹;

R⁵¹ is selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, oxo, halogen, cyano, nitro, —OH, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —C_0˜2 alkylene-NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl);

each R₆ is independently selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, halogen, cyano, nitro, —OH, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl), —C_0˜2 alkylene-(5˜12-membered spirocyclyl), —C_0˜2 alkylene-(5˜12-membered spiro heterocyclyl), —C_0˜2 alkylene-(5˜12-membered bridged cyclyl), —C_0˜2 alkylene-(5˜12-membered bridged heterocyclyl);

wherein,

A ring is selected from a group consisting of 5˜12-membered spirocyclyl, 5˜12-membered spiro heterocyclyl, 5˜12-membered bridged cyclyl, 5˜12-membered bridged heterocyclyl; wherein said spirocyclyl, spiro heterocyclyl, bridged cyclyl, bridged heterocyclyl are optionally substituted by one, two, three or four independent R^A1;

each R^A1 is independently selected from a group consisting of H, halogen, cyano, nitro, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl), —C_0˜2 alkylene-(5˜12-membered spirocyclyl), —C_0˜2 alkylene-(5˜12-membered spiro heterocyclyl), —C_0˜2 alkylene-(5˜12-membered bridged cyclyl), —C_0˜2 alkylene-(5˜12-membered bridged heterocyclyl);

wherein,

B ring is selected from a group consisting of 3˜10-membered carbocyclyl, 3˜10-membered heterocyclyl, 5˜10-membered aromatic cyclyl, 5˜10-membered aromatic heterocyclyl, 5˜12-membered spirocyclyl, 5˜12-membered spiro heterocyclyl, 5˜12-membered bridged cyclyl, 5˜12-membered bridged heterocyclyl, 3˜10-membered fused cyclyl, 3˜10-membered fused heterocyclyl; wherein said carbocyclyl, heterocyclyl, aromatic cyclyl, aromatic heterocyclyl, spirocyclyl, spiro heterocyclyl, bridged cyclyl, bridged heterocyclyl, fused cyclyl, fused heterocyclyl are optionally substituted by one, two, three or four independent R^B1;

each R^B1 is independently selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, halogen, cyano, nitro, —OH, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl);

R₇, R₈ are independently selected from a group consisting of H, halogen, cyano, nitro, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl);

or R₇, R₈ together with the atom adjacent therewith form 3˜10-membered fused cyclyl, 3˜10-membered fused heterocyclyl, 3˜10-membered spirocyclyl, 3˜10-membered spiro heterocyclyl; wherein said fused cyclyl, fused heterocyclyl, spirocyclyl, spiro heterocyclyl are optionally substituted by one, two, three or four independent R⁷¹;

each R⁷¹ is independently selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, halogen, cyano, nitro, —OH, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl);

wherein,

C ring is selected from a group consisting of 5˜12-membered spirocyclyl, 5˜12-membered spiro heterocyclyl, 5˜12-membered bridged cyclyl, 5˜12-membered bridged heterocyclyl, 3˜10-membered fused cyclyl, 3˜10-membered fused heterocyclyl; wherein said spirocyclyl, spiro heterocyclyl, bridged cyclyl, bridged heterocyclyl, fused cyclyl, fused heterocyclyl are optionally substituted by one, two, three or four independent R^C1;

each R^C1 is independently selected from a group consisting of H, halogen, cyano, nitro, —OH, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl), —C_0˜2 alkylene-(3˜10-membered cycloalkyl), —C_0˜2 alkylene-(3˜10-membered heterocycloalkyl), —C_0˜2 alkylene-(5˜10-membered aromatic cyclyl), —C_0˜2 alkylene-(5˜10-membered aromatic heterocyclyl), —C_0˜2 alkylene-(5˜12-membered spirocyclyl), —C_0˜2 alkylene-(5˜12-membered spiro heterocyclyl), —C_0˜2 alkylene-(5˜12-membered bridged cyclyl), —C_0˜2 alkylene-(5˜12-membered bridged heterocyclyl);

R₁₀ is selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl;

R₉ is selected from —C_0˜2 alkylene-C(O)NR⁹¹R⁹², —C(O)C_1˜6 alkyl; each R⁹¹, R⁹² is independently selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl;

or R⁹¹, R⁹² together with the atom adjacent therewith form 3˜10-membered heterocyclyl; wherein said heterocyclyl is optionally substituted by one, two, three or four independent R⁹³;

each R⁹³ is independently selected from a group consisting of H, —C_1˜6 alkyl, halogen substituted —C_1˜6 alkyl, halogen, cyano, nitro, —OH, —O(C_1˜6 alkyl), —O(halogen substituted —C_1˜6 alkyl), —NH₂, —NH(C_1˜6 alkyl), —N(C_1˜6 alkyl)(C_1˜6 alkyl);

when R₃ is

B ring is 3-membered carbocyclyl and R₁ is

R₂ is not

when R₃ is

R₇, R₈ are both H and R₁ is

R₂ is not

when R₃ is

X₁ is bond, R₄ is

and R₁ is

R₂ is not

when R₃ is

X₁ is bond, R₄ is

and R₁ is

R₂ is not

when R₃ is

and R₁ is

R₂ is selected from a group consisting of

when R₃ is

and R₁ is

R₂ is not selected from

when R₂ is

R₂₁ is methyl and R₁ is

R₃ is not or

when R₂ is

R₂₁ is H and R₁ is

R₃ is not

when R₂ is

R₂₁ is H and R₁ is

R₃ is not selected from

when R₂ is

R₂₁ is H and R₁ is

R₃ is not

when R₂ is

and R₁ is

R₃ is not selected from

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₁ is selected from a group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl,

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₂ is selected from a group consisting of

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, X₁ is selected from a group consisting of chemical bond, O, NR^N1 or CR^C1R^C2; R^C1, R^C2 are independently selected from a group consisting of H, —C_1˜3 alkyl, halogen, halogen substituted —C_1˜3 alkyl, —C_1˜2 alkylene-N(C_1˜6 alkyl)(C_1˜6 alkyl);

R^N1 is selected from a group consisting of H, —C_1˜3 alkyl, halogen substituted —C_1˜3 alkyl, -(3˜10-membered heterocycloalkyl).

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₄ is selected from a group consisting of

wherein X is selected from O or NR⁴¹; X₄ is selected from O, NH or CH₂; n₁ is selected from 1 or 2; wherein said R₄ is optionally substituted by one, two, three or four independent R⁴¹;

R⁴¹ is selected from a group consisting of H, oxo, —C_1˜3 alkyl, —C_2˜6 alkenyl, halogen substituted —C_1˜3 alkyl, hydroxy-substituted —C_1˜6 alkyl, —C_0˜2 alkylene-O(C_1˜3 alkyl), —NH₂, —NH(C_1˜3 alkyl), —N(C_1˜3 alkyl)(C_1˜3 alkyl), —C(O)R⁴², —C(O)NR⁴²R⁴³, —C(O)OR⁴², -(3˜10-membered cycloalkyl), -(3˜10-membered heterocycloalkyl), —C_1˜2 alkylene-(5˜10-membered aromatic cyclyl); wherein said alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic cyclyl are optionally substituted by one, two, three or four independent R⁴⁴;

R⁴², R⁴³ are independently selected from a group consisting of H, halogen, —OH, —C_1˜3 alkyl, halogen substituted —C_1˜3 alkyl;

R⁴⁴ is selected from a group consisting of H, —C_1˜3 alkyl, halogen substituted —C_1˜3 alkyl, —O(C_1˜3 alkyl).

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₄ is selected specifically from a group consisting of

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R_s is selected from a group consisting of H, halogen, —C_1˜3 alkyl, halogen substituted —C_1˜3 alkyl, hydroxy-substituted —C_1˜3 alkyl, —O(C_1˜3 alkyl), —NH(C_1˜3 alkyl), —O—C₂ alkylene-N(C_1˜3 alkyl)(C_1˜3 alkyl), —O-(3˜-10-membered cycloalkyl), —O-(3˜10-membered heterocycloalkyl); wherein said alkyl, alkylene, cycloalkyl, heterocycloalkyl are optionally substituted by one, two, three or four independent R⁵¹;

R⁵¹ is selected from a group consisting of H, —C_1˜3 alkyl, halogen substituted —C_1˜3 alkyl.

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₅ is selected from a group consisting of methyl, ethyl, ethoxyl, F, hydroxy-substituted methyl,

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₆ is selected from a group consisting of H, —C_1˜3 alkyl, —NH(C_1˜3 alkyl), —N(C_1˜3 alkyl)(C_1˜3 alkyl).

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A ring is selected from

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, B ring is selected from a group consisting of 3˜10-membered heterocyclyl, 5˜12-membered bridged heterocyclyl, 3˜10-membered fused heterocyclyl; wherein said heterocyclyl, bridged heterocyclyl, fused heterocyclyl are optionally substituted by one, two, three or four independent R^B1;

each R^B1 is independently selected from a group consisting of H, —C_1˜3 alkyl, halogen substituted —C_1˜3 alkyl.

More preferably, B ring is selected from a group consisting of

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, C ring is selected from a group consisting of

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₇, R₈ are independently selected from a group consisting of —OH,

or R₇, R₈ together with the atom adjacent therewith form

More preferably, in the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₃ is selected from a group consisting of

More preferably, in specific, the compound represented by Formula I of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is

No. of the
compound Chemical structure
WEE1-001
WEE1-002
WEE1-003
WEE1-004
WEE1-005
WEE1-006
WEE1-007
WEE1-008
WEE1-009
WEE1-010
WEE1-011
WEE1-012
WEE1-013
WEE1-014
WEE1-015
WEE1-016
WEE1-017
WEE1-018
WEE1-019
WEE1-020
WEE1-021
WEE1-022
WEE1-023
WEE1-024
WEE1-025
WEE1-026
WEE1-027
WEE1-028
WEE1-029
WEE1-030
WEE1-031
WEE1-032
WEE1-033
WEE1-034
WEE1-035
WEE1-036
WEE1-037
WEE1-038
WEE1-039
WEE1-040
WEE1-041
WEE1-042
WEE1-043
WEE1-044
WEE1-045
WEE1-046
WEE1-047
WEE1-048
WEE1-049
WEE1-050
WEE1-051
WEE1-052
WEE1-053
WEE1-054
WEE1-055
WEE1-056
WEE1-057
WEE1-058
WEE1-059
WEE1-060
WEE1-061
WEE1-062
WEE1-063
WEE1-064
WEE1-065
WEE1-066
WEE1-067
WEE1-068
WEE1-069
WEE1-070
WEE1-071
WEE1-072
WEE1-073
WEE1-074
WEE1-075
WEE1-076
WEE1-077
WEE1-078
WEE1-079
WEE1-080
WEE1-081
WEE1-082
WEE1-083
WEE1-084
WEE1-085
WEE1-086
WEE1-087
WEE1-088
WEE1-089
WEE1-090
WEE1-091
WEE1-092
WEE1-093
WEE1-094
WEE1-095
WEE1-096
WEE1-097
WEE1-098
WEE1-099
WEE1-100
WEE1-101
WEE1-102
WEE1-103
WEE1-104
WEE1-105
WEE1-106
WEE1-107
WEE1-108
WEE1-109
WEE1-110
WEE1-111
WEE1-112
WEE1-113
WEE1-114
WEE1-115
WEE1-116
WEE1-117
WEE1-118
WEE1-119
WEE1-120
WEE1-121
WEE1-122
WEE1-123
WEE1-124
WEE1-125
WEE1-126
WEE1-127
WEE1-128
WEE1-129
WEE1-130
WEE1-131
WEE1-132
WEE1-133
WEE1-134
WEE1-135
WEE1-136
WEE1-137
WEE1-138
WEE1-139
WEE1-140
WEE1-141
WEE1-142
WEE1-143
WEE1-144
WEE1-145
WEE1-146
WEE1-147
WEE1-148
WEE1-149
WEE1-150
WEE1-151
WEE1-152
WEE1-153
WEE1-154
WEE1-155
WEE1-156
WEE1-157
WEE1-158
WEE1-159
WEE1-160
WEE1-161
WEE1-162
WEE1-163
WEE1-164
WEE1-165
WEE1-166
WEE1-167
WEE1-168

More preferably, in specific, the compound represented by Formula I of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is

More preferably, in specific, the compound represented by Formula I of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is

The present invention further provides the use of any of the abovementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of the drug for the treatment of WEE1-mediated disease(s).

The WEE1-mediated disease(s) is(are) one or more of the diseases associated with inflammation, autoimmune disease, infectious disease, cancer, precancer syndrome.

The present invention further provides a pharmaceutical composition which is prepared with the compound of any of the abovementioned compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as the pharmaceutically active ingredient, together with pharmaceutically acceptable excipients.

“Cancer” or “malignant neoplasm” means any of a number of diseases characterized by the uncontrolled abnormal cell proliferation which includes the spread of affected cells locally or through the bloodstream and lymphatic system to other parts of the body (i.e., metastasis) and any of many characteristic structural and/or molecular features. “Cancer cell” means a cell that undergoes multiple steps of tumor progression in the early, intermediate, or advanced phases. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, cancer of bone, liver cancer, renal cancer, colon cancer and prostatic cancer. In some embodiments, compounds of Formula I are used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

Autoimmune diseases are caused by the body's immune response to substances and tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type I diabetes mellitus, Grave's disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, multiple sclerosis and autoimmune retinopathy. Some embodiments of the present invention relate to the treatment of autoimmune diseases such as psoriasis or multiple sclerosis.

Inflammatory diseases include a wide range of conditions characterized by pathologic inflammation of tissues. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation due to house dust mites, and interstitial cystitis. There is significant overlap between inflammatory and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory disease and is manifested in allergic reactions and some myopathies. Many immune system diseases result in abnormal inflammation. IL-17A-mediated diseases also include autoimmune inflammatory diseases.

Compounds and derivatives provided in the present invention can be named according to IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definition of terms used in the present invention: Unless otherwise specified, the initial definition provided by the group or term herein is applicable to the group or term in the whole specification. For terms that are not specifically defined herein, they should be given meanings that can be given by those skilled in the art according to the disclosure and context.

“Substitution” means that the hydrogen atom in the molecule is replaced by other different atoms or molecules.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by prefixes. For example, the prefix C_a˜b alkyl indicates any alkyl group containing “a” to “b” carbon atoms. Therefore, for example, C_1˜4 alkyl refers to alkyl groups containing 1˜4 carbon atoms.

“Alkyl” refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C_1˜6 alkyl refers to any alkyl group containing 1-6 member atoms, such as alkyl group containing 1-4 member atoms. Alkyl groups can be linear or branched. A representative branched alkyl group has one, two or three branches. Alkyl groups can be optionally substituted by one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl group can also be a part of other groups, wherein said other group is for example —O(C_1˜6 alkyl).

“Cycloalkyl”, “cycloalkane” means a saturated or partially saturated cyclic group with carbon atoms and no cyclic heteroatoms, and with a single ring or multiple rings (including fused, combined). For polycyclic systems having aromatic and non-aromatic cyclyls without ring heteroatoms, the term “cycloalkyl” applies when the connection point is at a non-aromatic carbon atom (for example, 5,6,7,8-tetrahydronaphthalen-5-yl). The term “cycloalkyl” includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc., such as

“Alkenyl” means a straight or branched chain hydrocarbon groups having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or from 2 to 4 carbon atoms and having at least 1 vinyl unsaturated site (>C=C<). For example, (C_a-C_b)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

“Alkynyl” means a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group containing at least one triple bond. The term “alkynyl” is also intended to include those hydrocarbon groups having a triple bond and a double bond. For example, (C₂-C₆) alkynyl are intended to include ethynyl, propynyl, etc.

“Halogen” is fluorine, chlorine, bromine or iodine.

“Halogen substituted alkyl” refers to an alkyl wherein one or more hydrogen atoms are replaced by halogen; for example Halogen substituted C_1˜4 alkyl refers to an alkyl containing 1˜4 carbon atoms wherein one or more hydrogen atoms are replaced by halogen.

“Heterocyclic group”, “heterocycloalkyl”, “heterocycloalkane” refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein a heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

“Aromatic heterocyclyl” means an aromatic unsaturated ring containing at least one heteroatom; wherein heteroatom means a nitrogen atom, an oxygen atom, a sulfur atom.

“Stereoisomer” includes both enantiomers and diastereomers. The compounds of the present invention may contain asymmetric or chiral centers, and thus different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention include but not limited to diastereomers, enantiomers, atropisomerism, and mixtures thereof, such as racemic mixtures. They form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate planes of plane-polarized light. In describing optically active compounds, the prefixes D,L or R,S are used to indicate the absolute configuration of the chiral center of the molecule. These stereoisomers have the same chemical structure, but their stereo structures are different. Specific stereoisomers may be enantiomers, and mixtures of isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in a chemical reaction process that is not stereoselective or stereotactic. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers lacking optical activity. For example, the C atom marked by the “*” on the ring in the compounds numbered Wee1-92 in the table of the present invention is the chiral center.

The term “pharmaceutically acceptable” refers to a medium, carrier, diluent, excipient, and/or a salt formed thereby chemically or physically compatible with other components constituting a pharmaceutical dosage form and physiologically compatible with the receptor.

The pharmaceutical compositions of the present invention may be in any one of a number of compoundable pharmaceutical dosage forms, e.g., oral, injectable, topical, etc.; the oral dosage forms include, but are not limited to: tablets, capsules, oral liquids, granules, pills, suspension; the injectable dosage forms are selected from point injection, powde injection; the topical dosage forms are selected from patches, creams. All dosage forms can be prepared according to common pharmaceutical techniques, such as using any of the compounds of the present invention, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as the active pharmaceutical ingredient, and, if necessary, incorporating pharmaceutically acceptable carriers, to form the above pharmaceutical dosage forms suitable for administration; wherein, the unit dose of the pharmaceutically active ingredient may be 0.1 mg-1000 mg, e.g. tablets containing 0.1 mg-1000 mg, preferably 5-500 mg of the pharmaceutically active ingredient per tablet.

The term “salt” and “pharmaceutically acceptable salt” refers to an acidic and/or basic salt formed by the abovementioned compound or a stereoisomer thereof, and inorganic and/or organic acid and base, also including zwitterionic salts (internal salts), also including quaternary ammonium salt, for example alkylammonium salt. These salts can be directly obtained in the final separation and purification of the compound. Alternatively, they can be obtained by mixing the abovementioned compound, or a stereoisomer thereof, and a certain amount of acid or base appropriately (for example in same equivalence). These salts may form precipitates in the solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after the reaction in water medium. Said salt in the present invention can be compound hydrochloride salt, sulfate salt, citrate salt, benzene sulfonate salt, hydrobromide salt, hydrofluoride salt, phosphorate salt, acetate salt, propionate salt, succinate salt, oxalate salt, malate salt, succinate salt, fumarate salt, maleate salt, tartarate salt or trifluoroacetate salt.

In some embodiments, one or more compounds of the present invention can be used in combination with each other. Alternatively, the compound of the present invention can be used in combination with any other active agents. It is used to prepare drugs or pharmaceutical compositions for regulating cell functions or treating diseases. If a group of compounds are used, these compounds can be administered to the subjects simultaneously, separately and orderly.

Obviously, according to the above content of the present invention, according to the common technical knowledge and common means in this field, and without departing from the above basic technical idea of the present invention, other various forms of modification can be made to replace or change.

The advantageous effects of the present invention are:

Compared with the prior art, the compounds of the present invention have better WEE1 kinase inhibitory activity and tumor cell value-added inhibitory activity; the inhibition of cytochrome P450 enzymes and hERG potassium ion channels is reduced, and the safety is better.

In the following, the above content of the present invention will be further explained in detail through the concrete implementation in the form of examples. However, it should not be understood that the scope of the above theme of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) was given in units of 10⁻⁶ (ppm). The NMR was measured by (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus. Deuterated methyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃) and deuterated methanol (CD₃OD) were used as the charaterization solvents, and tetramethylsilane (TMS) was used as the internal standard.

The LC-MS was determined by Shimadzu LC-MS 2020 (ESI). The HPLC was determined by Shimadzu LC-20A. MPLC (medium performance liquid chromatography) was conducted by Gilson GX-281 reverse phase preparative chromatography. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as the silica gel plate for thin-layer chromatography, and the specification of thin-layer chromatography separation and purification products was 0.4 mm-0.5 mm. Column chromatography generally used Yantai Huanghai silica gel 200˜300 mesh silica gel as carrier.

The known starting materials of the present invention can be synthesized by or according to the methods known in the field, or can be purchased from Anneiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology etc.

Unless otherwise specified in Examples, the reaction was carried out under N₂ atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in Examples, the reaction temperature was room temperature. Unless otherwise specified in Examples, M refers to mole per liter.

THF: Tetrahydrofuran; DIPEA: N,N-Diisopropylethylamine;

DCM: Dichloromethane; TFA: Trifluoroacetic acid; m-CPBA: m-Chloroperoxybenzoic acid;

DMF: Dimethylformamide; PTSA: p-Toluenesulfonamide;

DMSO: Dimethyl sulfoxide; NBS:N-Bromosuccinimide; AIBN: Azobisisobutyronitrile;

Unless otherwise specified in Examples, the HPLC test conditions were as follows:

Method A:

Column: Boston Green C18 150 mm*4.6 mm 5 um; Mobile Phase A: 0.05% TFA Water B:0.05% TFA Acétonitrile; Gradient: B from 5% to 95% in 10.0 min and hold 95% for 5.0 min; Flow rate: 1.5 mL/min; Column temperature: 40° C.

Method B:

Column: Boston Green ODS 150 mm*4.6 mm 5 μm; Mobile Phase A: 0.01M NH₄HCO₃ Water B: Acétonitrile; Gradient: B from 5% to 95% in 10.0 min and hold 95% for 5.0 min; Flow rate: 1.5 mL/min; Column temperature: 40° C.

Unless otherwise specified, the SFC splitting condition is: Column: 3 μm, 150 mm*3 mm; Mobile Phase A: CO₂, B: ethanol; Flow rate: 1 mL/min; Column temperature: 40° C.

Intermediate Example 1: Synthesis of Intermediate IM-1

Step 1: Synthesis of Compound IM-1-3

The substrate IM-1-2 (8.15 g, 35 mmol) and THF (50 mL) were added to a dry single-necked flask, stirred to dissolve, then added with IM-1-1 (6.3 g, 37 mol) and DIPEA (15 mL, 75 mol), heated to 110° C. to react and monitored by LC-MS. After the reaction was completed, the solid was precipitated and filtered out after the system returned to room temperature, and oven-dried to give the crude product IM-1-3 (9.87 g, 76.6% yield), LCMS (ESI⁺) m/z: 369.2 [M+H]+.

Step 2: Synthesis of Compound IM-1-4

The substrate IM-1-3 (9.16 g, 27.5 mmol) and DCM (18 mL) were added to a dry single-necked flask, stirred to dissolve, then added slowly with TFA (18 mol), heated to 75° C. to react and monitored by LC-MS. The organic solvents were concentrated under reduced pressure after the reaction was completed, dissolved with ethanol, then added with 6M NaOH solution, stirred at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction to precipitate the solid. The solid was filtered out, washed three times with water and cold ethanol respectively, dried at room temperature to give crude product IM-1-4 (5 g, 81.7% yield), LCMS (ESI⁺) m/z: 223.1 [M+H]⁺.

Step 3: Synthesis of Compound IM-1

The substrate IM-1-4 (5.20 g, 23.4 mmol), K₂CO₃ (4.53 g, 32.8 mmol) and IM-1-5 (5.55 g, 25.7 mmol) were added to a dry double-necked flask, and then added with CuI (4.46 g, 23.4 mmol), N,N′-Dimethylethylenediamine (4.13 g, 46.8 mmol) and 1,4-Dioxane (100 mL) after three N₂ replacements, stirred evenly and then heated to 120° C. to react and monitored by LC-MS and TLC, added with ammonia after the reaction was completed, stirred, then extracted three times with ethyl acetate. The organic phase was combined and dewatered by anhydrous Na₂SO₄ and then concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound IM-1 (5.1 g, 61% yield), LCMS (ESI⁺) m/z: 358.1 [M+H]⁺.

Intermediate Example 2: Synthesis of Intermediate IM-2

Step 1: Synthesis of Compound IM-2-3

The substrate IM-2-1 (7.12 g, 50 mmol) and DMSO (30 mL) were added to a dry single-necked flask, stirred to dissolve then added with IM-2-2 (9.9 g, 50 mmol), heated to 90° C. to react and monitored by LC-MS, cooled to room temperature after the reaction was completed, the precipitated solid was filtered out and washed three times with water and a small amount of methanol respectively, dried to give product IM-2-3 (12.12 g, 76% yield), LCMS (ESI⁺) m/z: 320.3 [M+H]⁺.

Step 2: Synthesis of Compound IM-2-4

The substrate IM-2-3 (12.12 g, 38 mmol) and DCM (18 mL) were added to a dry single-necked flask, stirred to dissolve then added slowly with TFA (18 mL) and monitored by LC-MS, concentrated under reduced pressure after the reaction to remove solvents to give the residue. The residue was added with methanol (70 mL), stirred to dissolve then added with polyformaldehyde (7 g) and acetic acid (1 mL), stirred for 30 min at room temperature, added with sodium cyanoborohydride (3.8 g, 60 mmol), and heated to 50° C. to react, cooled to room temperature after the reaction to filter out the solids. The organic phase was concentrated under reduced pressure to remove solvents. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound IM-2-4 (7.6 g, 85.8% yield), LCMS (ESI⁺) m/z: 234.2[M+H]⁺.

Step 3: Synthesis of Compound IM-2

The substrate IM-2-4 (5 g, 21.5 mmol) and methanol (40 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (500 mg), stirred at room temperature after five H₂ displacements to react and monitored by LC-MS. After the reaction was completed, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the compound IM-2 (4.0 g, crude), LCMS (ESI⁺) m/z: 204.2[M+H]⁺.

Intermediate Example 3: Synthesis of Intermediate IM-3

Step 1: Synthesis of Compound IM-3

The substrate IM-1-4 (138 mg, 620.88 μmol), K₂CO₃ (101 mg, 620.88 μmol) and IM-3-1 (130 mg, 521.82 μmol) were added to a dry double-necked flask, N₂ displaced three times, then added with CuI (99 mg, 519.82 μmol), N,N′-Dimethylethylenediamine (106 mg, 1.20 mmol) and 1,4-Dioxane (10 mL), stirred evenly then heated to 120° C. to react and monitored by LC-MS, returned to room temperature after the reaction and added with ammonia, extracted three times with ethyl acetate. After the organic phase was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the ompound IM-3 (130 mg, 53.62% yield), LCMS (ESI⁺) m/z: 391.2 [M+H]⁺.

Intermediate Example 4: Synthesis of Intermediate IM-4

Step 1: Synthesis of Compound IM-4

The substrate IM-2-3 (1 g, 3.13 mmol) and methanol (10 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (200 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction was completed, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the compound IM-4 (700 mg, crude), LCMS (ESI⁺) m/z: 290.2[M+H]⁺.

Intermediate Example 5: Synthesis of Intermediate IM-5

Step 1: Synthesis of Compound IM-5

The substrate IM-3 (0.2 g, 0.51 mmol) and anhydrous THF (5 ml) were added to a single-necked flask, stirred to dissolve then added with m-CPBA (208.2 g, 1.02 mmol, purity 85%), stirred for 40 min at room temperature and monitored by LC-MS. The reactants were concentrated under reduced pressure, then separated by medium pressure liquid chromatographyto give to the compound IM-5 (160 mg), LCMS (ESI⁺) m/z: 407.1 [M+H]⁺.

Intermediate Example 6: Synthesis of Intermediate IM-6

Step 1: Synthesis of Compound IM-6

The substrate IM-1 (0.2 g, 0.56 mmol) and anhydrous THF (5 ml) were added to a single-necked flask, stirred to dissolve then added with m-CPBA (144.9 mg, 0.84 mmol, purity 85%), stirred for 40 min at room temperature and monitored by LC-MS. The reactants were concentrated under reduced pressure, then separated by medium pressure liquid chromatography to give to the compound IM-6 (150 mg, 0.40 mmol, 71.8% yield), LCMS (ESI⁺) m/z: 374.1 [M+H]⁺.

Example 1: Synthesis of Compound 1

Step 1: Synthesis of Compound 1-2

The substrate 2-bromo-6-fluoropyridine (3 g, 15 mmol) and tetrahydrofuran (25 mL) were added to dry round-bottomed flask, lowered to −40° C. and added slowly and dropwise with NaHMDS (12.79 g, 85.23 mmol) the system, stirred for 30 min at −40° C. thend added with dimethyl sulfoxide (3.21 g, 34.09 mmol), stirred continuously for 3 hours at this temperature. The reaction was quenched with water, extracted three times with ethyl acetate, the organic phase was dried with anhydrous Na₂SO₄, filtered, distilled under reduced pressure and purified by MPLC to give the compound 1-2 (1.5 g, 6.00 mmol), LCMS (ESI) m/z: 252.0 [M+H]⁺.

Step 2: Synthesis of Compound 1-3

The Compounds 1-2 (1.5 g, 6.00 mmol) and Tetrabutylammonium bromide (193.1 mg, 0.6 mmol) and dichloromethane (10 mL) were added to a dry flask at room temperature, stirred for 10 min at room temperature then added with NaOH (9.60 g, 239.9 mmol) and water (10 mL), stirred for 12 h at room temperature, the reaction was quenched with water, extracted three times with ethyl acetate, the combined organic phase was washed with saline and dried with anhydrous Na₂SO₄, filtered, distilled under reduced pressure. The residue was purified by MPLC to give the compound 1-3 (450 mg, 1.63 mmol), LCMS (ESI) m/z: 278.0 [M+H]⁺.

Step 3: Synthesis of Compound 1-4

The substrate 1-3 (93 mg, 336.77 mol), IM-1-4 (89.82 mg, 404.13 mol), CuI (64.14 mg, 336.77 mol), K₂CO₃ (65.17 mg, 505.16 mol) and N,N′-Dimethylethylenediamine (29.64 mg, 336.77 mol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (5 mL), heated to react at 120° C. for 10 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, filtered, extracted three times with ethyl acetate, the organic phase was dried with anhydrous Na₂SO₄, filtered, distilled under reduced pressure. The residue was purified by MPLC to give the compound 1-4 (50 mg, 119.76 μmol), LCMS (ESI) m/z: 418.1 [M+H]⁺.

Step 4: Synthesis of Compound 1

The m-chloroperoxybenzoic acid (18.74 mg, 107.8 μmol) was added to the tetrahydrofuran (1 mL) containing dissolved 1-4 (30 mg, 71.9 mol), stirred for 1 hour at room temperature and monitored by LC-MS, then added with N, N-diisopropylethylamine (43 mg, 0.33 mmol) and 1-5 (15.3 mg, 80.1 μmol) after the disappearance of the raw materials, stirred for 12 hours at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction. The residue was purified by High Performance Liquid Chromatography (Acid) to give the compound 1 (30 mg, 53.51 μmol). LCMS (ESI) m/z: 561.3 [M+H]⁺, HPLC method A: R_T=5.05 min, purity: 98.2%. ¹H NMR (400 MHz, Methanol-d₆) δ 8.79 (s, 1H), 8.05-8.01 (m, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.57-7.42 (m, 2H), 7.03-6.88 (m, 2H), 5.71-5.67 (m, 1H), 5.06-5.05 (m, 1H), 4.98-4.95 (m, 1H), 4.80-4.78 (m, 2H), 3.20-3.18 (m, 5H), 3.04 (s, 4H), 2.65-2.63 (m, 5H), 2.36 (s, 4H), 1.92-1.75 (m, 2H), 1.53 (d, J=2.4 Hz, 2H).

Example 2: Synthesis of Compound 2

Step 1: Synthesis of Compound 2-1

The substrate IM-1 (43 mg, 120.30 μmol) and methylbenzene (1 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (43.60 mg, 252.64 μmol) to react for 30 min at room temperature and monitored by LC-MS, added with DIPEA (80.6 mg, 623.65 mol, 108.63 μL) after the reaction and stirred for 10 min, then added with IM-4 (45.14 mg, 0.156 mmol) and monitored by LC-MS. The reactants were concentrated under reduced pressure after the reaction. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 2-1 (45 mg, 62.64% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.80 (s, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.51 (s, 2H), 6.61 (d, J=8.5 Hz, 2H), 5.71-5.61 (m, 1H), 5.31 (s, 1H), 4.99 (dd, J=10.2, 1.5 Hz, 1H), 4.83 (dd, J=17.1, 1.5 Hz, 1H), 4.68 (d, J=5.9 Hz, 2H), 4.49 (s, 1H), 4.42 (d, J=23.5 Hz, 1H), 3.55 (t, J=10.6 Hz, 1H), 3.27-3.20 (m, 2H), 2.96 (t, J=9.0 Hz, 1H), 1.93 (s, 2H), 1.46 (s, 6H), 1.39 (s, 5H), 1.32 (s, 4H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.81 (s, 1H), 8.02 (t, J=7.9 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.51 (s, 2H), 6.62 (d, J=8.5 Hz, 2H), 5.71-5.61 (m, 1H), 5.04-5.01 (m, 1H), 4.85-4.81 (m, 1H), 4.69 (d, J=5.9 Hz, 2H), 4.49-4.41 (m, 2H), 3.57 (t, J=9.0 Hz, 1H), 3.36-3.25 (m, 2H), 2.96 (t, J=8.4 Hz, 1H), 1.94 (s, 2H), 1.47 (s, 6H), 1.39 (s, 5H), 1.32 (s, 4H). LCMS (E+) m/z: 599.4 [M+H]⁺, HPLC method B: R_T=8.23 min, purity: 91.5%.

Step 2: Synthesis of Compound 2

The substrate 2-1 (40.00 mg, 66.81 mol) and DCM (3 mL) were added to a dry single-necked flask, stirred to dissolve then added slowly with TFA (3 mL) and monitored by LC-MS, concentrated under reduced pressure to remove the solvents after the reaction and give the residue. The residue was purified by medium pressure liquid chromatography (Acid process) to give the compound 2 (25 mg, 61.08% yield). ¹H NMR (400 MHz, Methanol-d₄) δ 8.77 (s, 1H), 7.97 (t, J=7.9 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.63 (dd, J=7.8, 0.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.6 Hz, 2H), 5.70 (m, 1H), 5.03 (dq, J=10.2, 1.2 Hz, 1H), 4.92 (d, J=1.2 Hz, 1H), 4.80 (d, J=6.1 Hz, 2H), 4.66 (s, 1H), 4.48 (s, 1H), 3.76 (dd, J=10.6, 2.5 Hz, 1H), 3.42-3.34 (m, 3H), 2.32 (d, J=11.1 Hz, 1H), 2.05 (d, J=11.3 Hz, 1H), 1.57 (s, 6H). LCMS (E+) m/z: 499.2 [M+H]⁺, HPLC method A: R_T=5.03 min, purity: 99.2%.

Example 3: Synthesis of Compound 3

Step 1: Synthesis of Compound 3

The substrate IM-1 (3.57 g, 10 mmol) and tetrahydrofuran (30 mL) were added in a dry single-necked flask, stirred to dissolve then added with m-CPBA (2.5 g, 15 mmol, purity 85%) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (6.45 g, 50 mmol) after the reaction and stirred for 10 min, then added with IM-2 (2.1 g, 10 mmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction to remove the solvents. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 3 (2.1 g, 41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.79 (s, 1H), 8.00 (t, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.48 (s, 2H), 6.56 (d, J=8.5 Hz, 2H), 5.71-5.61 (m, 1H), 5.32 (s, 1H), 4.99 (dd, J=10.3, 1.5 Hz, 1H), 4.82 (d, J=17.1, 1H), 4.67 (d, J=6.0 Hz, 2H), 4.27 (s, 1H), 3.42 (s, 1H), 3.13 (d, J=9.0 Hz, 1H), 2.78 (d, J=9.5, 1H), 2.52 (d, J=9.7 Hz, 2H), 2.25 (s, 3H), 1.87 (d, J=9.3 Hz, 1H), 1.76 (d, J=9.2 Hz, 1H), 1.46 (s, 6H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.80 (s, 1H), 8.02 (t, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.48 (s, 2H), 6.58 (d, J=8.6 Hz, 2H), 5.71-5.60 (d, J=10.3 Hz, 1H), 5.03 (m, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.68 (d, J=5.9 Hz, 2H), 4.29 (s, 1H), 3.49 (s, 1H), 3.35 (d, J=9.5 Hz, 1H), 3.17 (d, J=9.4 Hz, 1H), 2.82 (d, J=9.7 Hz, 1H), 2.56 (d, J=9.7 Hz, 1H), 2.27 (s, 3H), 1.91 (d, J=9.6 Hz, 1H), 1.81 (d, J=9.6 Hz, 1H), 1.47 (s, 6H). LCMS (E+) m/z: 513.2 [M+H]⁺, HPLC method B: R_T=6.02 min, purity: 98.4%.

Example 4: Synthesis of Compound 4

Step 1: Synthesis of Compound 4-3

The substrate 4-1 (114 mg, 910.78 mol) and methanol (2 mL) were added in a dry single-necked flask, stirred to dissolve with stirring and added with NaBH4 (38 mg, 1.00 mmol) to react for 1 hour at room temperature and monitored by LC-MS, quenched by slow addition of dilute hydrochloric acid in an ice bath after the reaction and concentrated under reduced pressure to remove the solvents. The residue was added with DMSO (4 mL), stirred to dissolve with stirring, added with potassium tert-butoxide (337 mg, 2.36 mmol) and then added with the compound 4-2 (141 mg, 999.29 mol), heated up to 80° C. to react and monitored by LC-MS, extracted three times with ethyl acetate after the reaction and concentrated under reduced pressure, then purified by medium pressure liquid chromatography (Alkali process) to give the compound 4-3 (99 mg, 50.71% yield), LCMS (ESI⁺) m/z: 249.2[M+H]⁺.

Step 2: Synthesis of Compound 4-4

The substrate 4-3 (99 mg, 398.75 mol) and ethanol (4 mL) were added to a dry single-necked flask, stirred to dissolve then added with Fe (67 mg, 1.20 mmol) and CH₃COOH (47.89 mg, 797.50 mol, 45.65 L), heated up to 80° C. to react and monitored by LC-MS, filtered by diatomaceous earth after the reaction and washed with ethyl acetate, concentrated under reduced pressure to give the crude product 4-4 (80 mg, crude), LCMS (ESI⁺) m/z: 219.2[M+H]⁺.

Step 3: Synthesis of Compound 4

The substrate IM-1 (71 mg, 0.2 mmol) and methylbenzene (2 mL) were added in a dry single-necked flask, stirred to dissolve then added with m-CPBA (52 mg, 0.3 mmol, purity 85%) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (83.58 mg, 646.69 μmol, 112.64 μL) after the reaction and stirred for 10 min, then added with the compound 4-4 (52.39 mg, 0.24 mmol) and monitored by LC-MS, concentrated under reduced pressure to remove the solvents after the reaction to give the residue. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 4 (8 mg, 6.32% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.84 (s, 1H), 8.04 (t, J=7.9 Hz, 1H), 7.73 (d, J=7.2, 1H), 7.62-7.60 (m, 3H), 6.90 (d, J=7.7 Hz, 2H), 5.71-5.62 (m, 1H), 5.33 (s, 1H), 4.99 (dd, J=10.3, 1.4 Hz, 1H), 4.82 (dd, J=10.3, 1.4 Hz, 1H), 4.68 (d, J=5.9 Hz, 2H), 4.44-4.42 (m, 1H), 2.77-2.60 (m, 6H), 2.04-2.03 (m, 1H), 1.84-1.81 (m, 1H), 1.66-1.63 (m, 1H), 1.57-1.54 (m, 1H), 1.46 (s, 6H), 1.36-1.33 (m, 1H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.85 (s, 1H), 8.04 (t, J=7.9 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.64-7.59 (m, 3H), 6.92 (d, J=8.5 Hz, 2H), 5.72-5.62 (m, 1H), 5.03 (d, J=10.3 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.9 Hz, 2H), 4.49 (s, 1H), 2.81-2.63 (m, 6H), 2.06 (s, 1H), 1.86 (s, 1H), 1.70-1.68 (m, 1H), 1.62 (d, J=7.4 Hz, 1H), 1.47 (s, 6H), 1.42-1.37 (m, 1H). LCMS (E+) m/z: 528.2 [M+H]⁺, HPLC method B: R_T=6.34 min, purity: 82.9%.

Example 5: Synthesis of Compound 5

Step 1: Synthesis of Compound 5

The substrate IM-3 (30 mg, 77 μmol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (20 mg, 116 μmol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (50 mg, 385 μmol) after the reaction and stirred for 10 min, then added with the compound IM-2 (20 mg, 98.39 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction to give the residue. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 5 (15 mg, 55.87% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1H), 8.77 (s, 1H), 7.76 (t, J=8.0 Hz, 1H), 7.50 (s, 2H), 7.30 (d, J=7.9 Hz, 1H), 6.59-6.55 (m, 3H), 5.68-5.58 (m, 1H), 5.00 (d, J=10.1 Hz, 1H), 4.89 (d, J=17.0 Hz, 1H), 4.74 (s, 2H), 4.26 (s, 1H), 3.40 (s, 1H), 3.37 (s, 6H), 3.30 (s, 1H), 3.13 (d, J=9.0 Hz, 1H), 2.78-2.76 (m, 1H), 2.47 (s, 1H), 2.24 (s, 3H), 1.85 (d, J=9.3 Hz, 1H), 1.75 (d, J=9.1 Hz, 1H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.79 (s, 1H), 7.80 (t, J=7.9 Hz, 1H), 7.50-7.48 (m, 2H), 7.30 (d, J=7.8 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.58 (d, J=8.7 Hz, 2H), 5.69-5.59 (m, 1H), 5.05-5.03 (m, 1H), 4.92-4.87 (m, 1H), 4.74 (s, 2H), 4.27 (s, 1H), 3.44 (s, 1H), 3.36 (s, 6H), 3.35-3.32 (m, 1H), 3.16 (d, J=9.4 Hz, 1H), 2.79 (d, J=9.7 Hz, 1H), 2.48 (d, J=9.9 Hz, 1H), 2.24 (s, 3H), 1.89 (d, J=9.5 Hz, 1H), 1.78 (d, J=9.4 Hz, 1H). LCMS (E+) m/z: 546.3 [M+H]⁺, HPLC method B: R_T=5.56 min, purity: 92%.

Example 6: Synthesis of Compound 6

Step 1: Synthesis of Compound 6-1

The substrate 4-1 (1 g, 6.2 mmol) and ethanol/water (10:1, 20 mL) were added to a dry single-necked flask, stirred to dissolve then added with p-Nitrobenzaldehyde (1 g, 6.6 mmol) and NaOH (620 mg, 15.5 mmol) to react at room temperature and monitored by LC-MS. After the reaction was completed, the solid was precipitated and filtered out, washed three times with a small amount of ethanol, and dried naturally to give the compound 6-1 (1 g, 63% yield), LCMS (E+) m/z: 259.2 [M+H]⁺.

Step 2: Synthesis of Compound 6-2

The substrate 6-1 (103 mg, 0.4 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (15 mg), H₂ displaced five times then stirred at room temperature to react and monitored by LC-MS. After the reaction was completed, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the compound 6-2 (80 mg, crude), LCMS (ESI⁺) m/z: 231.2[M+H]⁺.

Step 3: Synthesis of Compound 6

The substrate IM-3 (30 mg, 77 mol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (20 mg, 116 mol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (50 mg, 385 μmol) after the reaction and stirred for 10 min, then added with 6-2 (20 mg, 86.84 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction to give the residue. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 6 (5 mg, 17.74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.85 (s, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.30 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.61 (d, J=7.9 Hz, 1H), 5.69-5.60 (m, 1H), 5.02-4.99 (m, 1H), 4.90 (dd, J=17.1, 1.7 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.37 (s, 6H), 2.99-2.86 (m, 4H), 2.76-2.69 (m, 3H), 2.33-2.29 (m, 2H), 1.92-1.88 (m, 3H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.86 (s, 1H), 7.83 (t, J=7.9 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.0 Hz, 1H), 5.70-5.61 (m, 1H), 5.07-5.04 (m, 1H), 4.90 (d, J=17.2 Hz, 1H), 4.75 (d, J=5.9 Hz, 2H), 3.36 (s, 6H), 3.09-2.85 (m, 4H), 2.79-2.72 (m, 3H), 2.38-2.32 (m, 2H), 1.91-1.89 (m, 3H). LCMS (E+) m/z: 573.6 [M+H]⁺, HPLC method B: R_T=5.05 min, purity: 87.7%.

Example 7: Synthesis of Compound 7

Step 1: Synthesis of Compound 7

The substrate IM-3 (30 mg, 77 mol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (20 mg, 116 mol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (50 mg, 385 μmol) after the reaction and stirred for 10 min, then added with 4-4 (20 mg, 91.62 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction to remove the solvents. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 7 (5 mg, 19.08% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), δ 8.82 (s, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.61 (s, 2H), 7.28 (d, J=7.8 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.60 (d, J=8.1 Hz, 1H), 5.69-5.59 (m, 1H), 5.02-4.99 (m, 1H), 4.89 (d, J=17.2 Hz, 1H), 4.74 (s, 2H), 4.41 (d, J=7.8 Hz, 1H), 3.18 (s, 3H), 3.16 (s, 3H), 2.79-2.70 (m, 6H), 2.03-2.02 (m, 1H), 1.91-1.80 (m, 1H), 1.67-1.63 (m, 1H), 1.57-1.54 (m, 1H), 1.38-1.33 (m, 1H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.83 (s, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.60 (s, 2H), 7.29 (d, J=7.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.66 (d, J=8.0 Hz, 1H), 5.68-5.62 (m, 1H), 5.05 (d, J=10.4 Hz, 1H), 4.89 (d, J=16.9 Hz, 1H), 4.75 (s, 2H), 4.48 (s, 1H), 3.36 (s, 6H), 2.78-2.72 (m, 6H), 2.05 (s, 1H), 1.84 (s, 1H), 1.70-1.59 (m, 2H), 1.40-1.33 (m, 1H). LCMS (E+) m/z: 561.5 [M+H]⁺, HPLC method B: R_T=5.10 min, purity: 90.2%.

Example 8: Synthesis of Compound 8

Step 1: Synthesis of Compound 8-2

The substrate 4-2 (1 g, 7.09 mmol), compound 8-1 (1.70 g, 8.50 mmol) and K₂CO₃ (2.45 g, 17.72 mmol) were added to a dry single-necked flask, dissolved with DMF (10 mL) and heated up to 90° C. to react for 1 hour and monitored by LC-MS, extracted three times with water and ethyl acetate after the reaction. The organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then concentrated under reduced pressure with organic solvents to give the crude product which can be used without purification for the following reaction directly to give the compound 8-2 (2.1 g, crude), a kind of yellow oil. LCMS (E+) m/z: 322.4 [M+H]⁺.

Step 2: Synthesis of Compound 8-3

The substrate 8-2 (2.1 g, 6.53 mmol) was added to a dry single-necked flask, dissolved with HCl/1,4-Dioxane (10 mL) to react at room temperature for 1 hour and monitored by LC-MS, concentrated under reduced pressure after the reaction, extracted three times with saturated sodium carbonate solution and ethyl acetate. The organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then concentrated under reduced pressure with organic solvents to give crude product which can be used without purification for the following reaction directly to give the compound 8-3 (1.3 g, crude), a kind of yellow oil. LCMS (E+) m/z: 222.4 [M+H]⁺.

Step 3: Synthesis of Compound 8-4

The substrate 8-3 (700 mg, 3.16 mmol) and compound 4-1 (396.00 mg, 3.16 mmol) were added to a dry single-necked flask, dissolved with MeOH/AcOH (10 mL) to react at room temperature for 1 hour and monitored by LC-MS, concentrated under reduced pressure after the reaction and extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄. The organic solvents were concentrated under reduced pressure. The residual impurities were removed with MPLC to give the compound 8-4 (300 mg, 907.93 mol, 28.70% yield), a kind of yellow oil. LCMS (E+) m/z: 331.4 [M+H]⁺.

Step 4: Synthesis of Compound 8-5

The substrate 8-4 (300 mg, 907.93 μmol) and formaldehyde (136.31 mg, 4.54 mmol) were added to a dry single-necked flask, dissolved with MeOH/AcOH (8 mL), heated up to 50° C. to react for 3 hours, then added with NaCNBH3 (142.64 mg, 2.27 mmol) in the system and heated up to 70° C. to react overnight and monitored by LC-MS, concentrated under reduced pressure after the reaction and extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then concentrated under reduced pressure with organic solvents. The residual impurities were removed with MPLC to give the compound 8-5 (283 mg, 739.44 μmol, 81.44% yield), a kind of yellow solid. LCMS (E+) m/z: 345.5 [M+H]⁺.

Step 5: Synthesis of Compound 8-6

The substrate 8-5 (1.5 g, 4.74 mmol) was added to a dry single-necked flask, dissolved with MeOH/AcOH (10 mL), then added with Pd/C (172.73 mg, 1.42 mmol), H₂ displaced three times then reacted for 3 hours at room temperature and monitored by LC-MS, filtered with diatomaceous earth after the reaction. The filterate was concentrated under reduced pressure. The crude product can be used without purification for the following reaction directly to give the compound 8-6 (1.5 g, crude), a kind of black oil. LCMS (E+) m/z: 315.5 [M+H]⁺.

Step 6: Synthesis of Compound 8

The substrate 8-6 (50 mg, 159.00 μmol) and compound IM-5 (64.63 mg, 159.00 μmol) were added to a dry single-necked flask, dissolved with THF (3 mL) then added with PTSA (54.76 mg, 318.00 μmol), heated up to 110° C. to react with stirring for 5 hours and monitored by LC-MS. After the reaction was completed, the organic solvents were concentrated under reduced pressure and extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then concentrated under reduced pressure. The residual impurities were removed with MPLC to give the compound 8 (23 mg, 35.02 μmol, 22.02% yield), a kind of yellow solid. ¹H NMR (600 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.80 (s, 1H), 7.79 (s, 1H), 7.56 (s, 2H), 7.30 (d, J=7.9 Hz, 1H), 6.91 (d, J=8.6 Hz, 2H), 6.59 (d, J=8.2 Hz, 1H), 5.68-5.59 (m, 1H), 5.00 (d, J=10.1 Hz, 1H), 4.89 (d, J=17.0 Hz, 1H), 4.74 (s, 2H), 3.74-3.66 (m, 2H), 3.37 (s, 6H), 2.94-2.91 (m, 1H), 2.79-2.57 (m, 9H), 2.06 (s, 3H), 1.97-1.93 (m, 1H), 1.75-1.53 (m, 6H), 1.42 (d, J=11.1 Hz, 1H), 1.24 (d, J=11.7 Hz, 1H). LCMS(ESI⁺) m/z: 657.4 [M+H]⁺, HPLC method B:R_T=5.54 min, purity: 98.9%.

Example 9: Synthesis of Compound 9

Step 1: Synthesis of Compound 9-2

The substrate 4-1 (161 mg, 1 mmol) was added to a dry single-necked flask, dissolved with ethanol/water (10:1, 10 mL) then added with 9-1 (186 mg, 1.1 mmol) and NaOH (100 mg, 2.5 mmol) to react at room temperature and monitored by LC-MS. After the reaction was completed, the solid was precipitated and filtered out, washed three times with a small amount of ethanol, and dried to give the compound 9-2 (150 mg, 50% yield), LCMS (E+) m/z: 303.1 [M+H]⁺.

Step 2: Synthesis of Compound 9-3

The substrate 9-2 (81 mg, 0.27 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (15 mg), H₂ displaced five times then stirred to react at room temperature and monitored by LC-MS. After the reaction was completed, Pd/C was removed by diatomaceous earth, the organic solvents were concentrated under reduced pressure to give the compound 9-3 (42 mg, crude), LCMS (ESI⁺) m/z: 275.2 [M+H]⁺.

Step 3: Synthesis of Compound 9

The substrate IM-3 (40 mg, 110.71 μmol) and THF (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (20 mg, 116 mol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (50 mg, 385 μmol) after the reaction and stirred for 10 min, then added with the compound 9-3 (36.45 mg, 132.85 mol) and monitored by LC-MS, concentrated under reduced pressure after the reaction to give the residue which was purified by medium pressure liquid chromatography (Alkali process) to give the compound 9 (35 mg, 51.26% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.82 (s, 1H), 7.77-7.75 (m, 1H), 7.59 (s, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.67-5.60 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.88 (d, J=17.1 Hz, 1H), 4.74 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.37 (s, 6H), 3.06-3.03 (m, 2H), 2.85-2.84 (m, 1H), 2.71-2.64 (m, 4H), 2.28 (s, 1H), 1.95-1.87 (m, 4H), 1.32 (t, J=6.9 Hz, 3H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.82 (s, 1H), 7.81-7.77 (m, 1H), 7.58 (s, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.90 (d, J=8.9 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 5.67-5.60 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.88 (d, J=17.1 Hz, 1H), 4.73 (s, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.36 (s, 6H), 3.03 (d, J=14.9 Hz, 2H), 2.86 (s, 1H), 2.71-2.65 (m, 4H), 2.29 (s, 1H), 1.96-1.87 (m, 4H), 1.32 (t, J=6.9 Hz, 3H). LCMS (E+) m/z: 617.2 [M+H]⁺, HPLC method B: R_T=6.66 min, purity: 95.4%.

Example 10: Synthesis of Compound 10

Step 1: Synthesis of Compound 10-1

The substrate 4-1 (1 g, 6.2 mmol) and ethanol/water (10:1, 20 mL) were added to a dry single-necked flask, stirred to dissolve then added with p-Nitrobenzaldehyde (1 g, 6.6 mmol) and NaOH (620 mg, 15.5 mmol) to react at room temperature and monitored by LC-MS. After the reaction was completed, the solid was precipitated and filtered out, washed three times with a small amount of ethanol, and dried naturally to give the compound 10-1 (1 g, 63% yield), LCMS (E+) m/z: 259.2 [M+H]⁺.

Step 2: Synthesis of Compound 10-2

The substrate 10-1 (103 mg, 0.4 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (15 mg), H₂ displaced five times then stirred at room temperature to react and monitored by LC-MS. After the reaction was completed, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the compound 10-2 (65 mg, crude), LCMS (ESI⁺) m/z: 231.2[M+H]⁺.

Step 3: Synthesis of Compound 10

The substrate IM-3 (40 mg, 110.71 μmol) and THF (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (29 mg, 116 mol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (85.85 mg, 664.24 mol) after the reaction and stirred for 10 min, then added with 10-2 (30.6 mg, 132.85 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 10 (15 mg, 22.22% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 8.87 (s, 1H), 7.83 (t, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 5.69-5.60 (m, 1H), 5.01 (d, J=10.1 Hz, 1H), 4.89 (d, J=17.0 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.41 (s, 6H) 3.03-2.98 (m, 2H), 2.89-2.86 (m, 1H), 2.78-2.71 (m, 4H), 2.32-2.31 (m, 1H), 1.97-1.89 (m, 4H). ¹H NMR (400 MHz, DMSO-d₆, D₂O) δ 8.87 (s, 1H), 7.84 (t, J=7.9 Hz, 1H), 7.74 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H), 5.70-5.60 (m, 1H), 5.03 (d, J=10.2 Hz, 1H), 4.89 (d, J=17.0 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.36 (d, J=2.1 Hz, 6H), 3.03-2.98 (m, 2H), 2.93-2.86 (m, 1H), 2.78-2.69 (m, 4H), 2.33-2.32 (m, 1H), 1.99-1.84 (m, 4H). LCMS (E+) m/z: 573.1 [M+H]⁺, HPLC method B: R_T=6.24 min, purity: 93.9%.

Example 11: Synthesis of Compound 11

Step 1: Synthesis of Compound 11-2

The substrate 4-2 (2 g, 14.17 mmol), compound 11-1 (3.17 g, 17.01 mmol) and K₂CO₃ (4.89 g, 35.44 mmol) were added to a dry single-necked flask, dissolved with DMF (10 mL) and heated up to 90° C. to react for 1 hour and monitored by LC-MS, extracted three times with water and ethyl acetate after the reaction, and the organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then the organic solvents were concentrated under reduced pressure to give crude product which can be used without purification for the following reaction directly to give the compound 11-2 (4 g, crude), a kind of yellow solid. LCMS (E+) m/z: 308.3 [M+H]⁺.

Step 2: Synthesis of Compound 11-3

The substrate 11-2 (4 g, 13.01 mmol) was added to a dry single-necked flask, dissolved with HCl/1,4-Dioxane (10 mL) to react at room temperature for 1 hour and monitored by LC-MS. The organic phase was concentrated under reduced pressure after the reaction, extracted three times with saturated sodium carbonate solution and ethyl acetate, then combined, washed with saturated saline and dried with anhydrous Na₂SO₄. The organic solvents were concentrated under reduced pressure to give crude product which can be used without purification for the following reaction directly to give the compound 11-3 (2.5 g, crude), a kind of yellow solid, LCMS (E+) m/z: 208.2 [M+H]⁺.

Step 3: Synthesis of Compound 11-4

The substrate 11-3 (1 g, 4.83 mmol) and free base of compound 4-1 (724.81 mg, 5.79 mmol) were added to a dry single-necked flask, dissolved with MeOH/AcOH (10 mL) to react at room temperature for 1 hour and monitored by LC-MS. The organic phase was concentrated under reduced pressure after the reaction, extracted three times with saturated sodium carbonate solution and ethyl acetate, then combined, washed with saturated saline and dried with anhydrous Na₂SO₄. The organic solvents were concentrated under reduced pressure to remove the residual impurities by MPLC to give the compound 11-4 (1.5 g, 4.27 mmol, 88.42% yield), a kind of yellow solid. LCMS (E+) m/z: 317.4 [M+H]⁺.

Step 4: Synthesis of Compound 11-5

The substrate 11-4 (1.5 g, 4.74 mmol) and Pd/C (172.73 mg, 1.42 mmol) were added to a dry single-necked flask, dissolved with MeOH/AcOH (10 mL), H₂ displaced five times to react at room temperature for 3 hours and monitored by LC-MS, filtered with diatomaceous earth after the reaction. The filterate was concentrated under reduced pressure. The crude product can be used without purification for the following reaction directly to give the compound 11-5 (1.5 g, crude), a kind of black oil. LCMS (E+) m/z: 287.4 [M+H]⁺.

Step 5: Synthesis of Compound 11

The substrate 11-5 (35 mg, 122.20 mol) and compound IM-5 (49.67 mg, 122.20 mol) were added to a dry single-necked flask and dissolved with THF (3 mL), added with PTSA (52.61 mg, 305.50 μmol) and heated up to 110° C. to react with stirring for 5 hours and monitored by LC-MS. The organic phase was concentrated under reduced pressure after the reaction, extracted three times with water and ethyl acetate, then combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then concentrated under reduced pressure to remove the residual impurities by MPLC to give the compound 11 (21 mg, 32.56 μmol, 26.65% yield), a kind of green solid. ¹H NMR (600 MHz, DMSO-d₆) δ 10.13 (s, 1H), 8.80 (s, 1H), 7.80 (s, 1H), 7.59 (s, 2H), 7.30 (d, J=7.7 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 5.64 (ddt, J=18.3, 13.6, 6.4 Hz, 1H), 5.00 (d, J=10.1 Hz, 1H), 4.90 (d, J=17.0 Hz, 1H), 4.75 (s, 2H), 3.37 (s, 6H), 3.13-3.09 (m, 6H), 2.98-2.91 (m, 2H), 2.80-2.63 (m, 4H), 2.63-2.55 (m, 2H), 2.03-2.00 (m, 2H), 1.77-1.60 (m, 2H), 1.43-1.39 (m, 1H), 1.29-1.25 (m, 1H). LCMS (ESI⁺) m/z: 629.5 [M+H]⁺, HPLC method B: R_T=5.94 min, purity: 97.5%.

Example 12: Synthesis of Compound 12

Step 1: Synthesis of Compound 12-2

The substrate IM-2-1 (416 mg, 2.1 mmol) and DMSO (8 mL) were added to a dry single-necked flask, stirred to dissolve then added with K₂CO₃ (387 mg, 2 mmol) and compound 12-1 (310 mg, 2 mmol), heated up to 90° C. to react and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred until solid precipitated. The solids were filtered out and washed three times with water and a small amount of methanol respectively, then dried to give the product 12-2 (200 mg, 30% yield), LCMS (ESI⁺) m/z: 334.2 [M+H]⁺.

Step 2: Synthesis of Compound 12-3

The substrate 12-2 (200 mg, 0.6 mmol) and DCM (5 mL) were added to a dry single-necked flask, stirred to dissolve, added slowly with TFA (5 mL) and monitored by LC-MS, concentrated under reduced pressure after the reaction. The residue was added with methanol (5 mL), stirred to dissolve, added with polyformaldehyde (180 mg) and acetic acid (500 μL), stirred for 30 min at room temperature, then added with sodium cyanoborohydride (75 mg, 1.2 mmol), heated up 50° C. to react and monitored by LC-MS, cooled to room temperature after the reaction and filtered to remove the solids. The organic phase was concentrated under reduced pressure and purified by medium pressure liquid chromatography (Alkali process) to give the compound 12-3 (120 mg, 81% yield), LCMS (ESI⁺) m/z: 248.2[M+H]⁺.

Step 3: Synthesis of Compound 12-4

The substrate 12-3 (120 mg, 0.48 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (12 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the compound 12-4 (90 mg, 86.4% yield). LCMS (ESI⁺) m/z: 218.2 [M+H]⁺.

Step 4: Synthesis of Compound 12

The substrate IM-1 (52 mg, 0.15 mmol) and THF (3 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (121 mg, 0.6 mmol, purity 85%) to react at room temperature for 1 hour and monitored by LC-MS, added with DIPEA (98 mg, 758.28 μmol) after the reaction and stirred for 10 min, added with 12-4 (33 mg, 151.86 μmol) and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 12 (13 mg, 15.38% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.82 (s, 1H), 8.00-7.98 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.7 Hz, 2H), 7.28 (dd, J=8.8, 2.6 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.69-5.63 (m, 1H), 5.32 (s, 1H), 4.99 (dd, J=10.3, 1.5 Hz, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.68 (d, J=6.0 Hz, 2H), 3.97 (s, 1H), 3.39 (s, 1H), 3.25-3.21 (m, 2H), 2.80-2.74 (m, 2H), 2.32 (s, 3H), 2.22 (s, 3H), 1.83 (d, J=9.3 Hz, 1H), 1.72 (d, J=9.2 Hz, 1H), 1.46 (s, 6H). ¹H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.82 (s, 1H), 8.03-8.01 (m, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.65-7.57 (m, 2H), 7.29 (dd, J=8.7, 2.7 Hz, 1H), 6.76 (d, J=8.7 Hz, 1H), 5.70-5.63 (m, 1H), 5.03-5.01 (m, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.8 Hz, 2H), 3.98 (s, 1H), 3.42 (s, 1H), 3.27-3.23 (m, 2H), 2.81-2.74 (m, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 1.86 (d, J=9.5 Hz, 1H), 1.75 (d, J=9.4 Hz, 1H), 1.47 (s, 6H). LCMS (E+) m/z: 527.3 [M+H]⁺, HPLC method B: R_T=6.53 min, purity: 94.6%.

Example 13: Synthesis of Compound 13

Step 1: Synthesis of Compound 13-2

The substrate 13-1 (1.03 g, 10 mmol) and DMSO (15 mL) were added to a dry single-necked flask, stirred to dissolve then added with K₂CO₃ (2 g, 14 mmol) and p-fluoronitrobenzene (1.43 g, 10 mmol), heated up to 100° C. to react and monitored by LC-MS, cooled to room temperature after the reaction to filter out the solids. The filterate was concentrated under reduced pressure and purified by medium pressure liquid chromatography (Acid process) to give the compound 13-2 (2 g, 89% yield), LCMS (ESI⁺) m/z: 225.1 [M+H]⁺.

Step 2: Synthesis of Compound 13-3

The substrate 13-2 (44 mg, 0.2 mmol) and THF (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with HATU (84 mg, 0.22 mmol) and DIPEA (28 mg, 0.22 mmol), stirred for 30 min at room temperature and added with methylamine hydrochloride (67 mg, 1 mmol), heated up to 65° C. to react and monitored by LC-MS, cooled to room temperature after the reaction and washed three times with ethyl acetate. The organic phase was concentrated under reduced pressure to give the crude product 13-3 (24 mg, crude), LCMS (ESI⁺) m/z: 238.3 [M+H]⁺.

Step 3: Synthesis of Compound 13-4

The substrate 13-3 (24 mg, 0.1 mmol) and methanol (4 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (5 mg), stirred at room temperature to react after five H₂ displacements and monitored by LC-MS. After the reaction, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the crude product 13-4 (18 mg, crude), LCMS (ESI⁺) m/z: 208.2 [M+H]⁺.

Step 4: Synthesis of Compound 13

The substrate IM-1 (31 mg, 86 mol) and THF (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (26 mg, 129 μmol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (55 mg, 425 μmol) after the reaction and stirred for 10 min, added with 13-4 (18 mg, 85 μmol), heated up to 80° C. to react and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 13 (7 mg, 16% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.79 (s, 1H), 7.97-4.95 (m, 1H), 7.75 (d, J=4.4 Hz, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.49 (s, 2H), 6.59 (d, J=8.0 Hz, 2H), 5.69-5.62 (m, 1H), 5.33 (s, 1H), 5.04-4.95 (m, 1H), 4.98 (d, J=10.0 Hz, 1H), 4.82 (d, J=17.0 Hz, 1H), 4.67 (d, J=5.9 Hz, 2H), 3.78 (s, 2H), 3.41-3.40 (m, 2H), 2.60 (d, J=4.7 Hz, 3H), 1.46 (s, 6H), 1.08 (t, J=7.0 Hz, 3H). ¹H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.80 (s, 1H), 8.00-7.97 (m, 1H), 7.82 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.49 (s, 1H), 6.59 (d, J=8.2 Hz, 2H), 5.69-5.63 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.0 Hz, 1H), 4.68 (s, 2H), 3.81 (s, 2H), 3.42 (q, J=7.0 Hz, 2H), 2.62 (d, J=4.6 Hz, 3H), 1.47 (s, 6H), 1.08 (t, J=7.0 Hz, 3H). LCMS (E+) m/z: 517.3 [M+H]⁺, HPLC method B: R_T=6.25 min, purity: 90.5%.

Example 14: Synthesis of Compound 14

Step 1: Synthesis of Compound 14-1

The substrate 13-2 (44 mg, 0.2 mmol) and THF (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with HATU (84 mg, 0.22 mmol) and DIPEA (28 mg, 0.22 mmol), stirred for 30 min at room temperature and added with N-methylpiperazine (40 mg, 0.4 mmol), heated up to 65° C. to react and monitored by LC-MS, cooled to room temperature after the reaction and washed three times with ethyl acetate. The organic phase was concentrated under reduced pressure to give the crude product 14-1 (50 mg, crude), LCMS (ESI⁺) m/z: 307.2 [M+H]⁺.

Step 2: Synthesis of Compound 14-2

The substrate 14-1 (50 mg, 0.16 mmol) and methanol (4 mL) were added to a dry single-necked flask, stirred to dissolve then added with Pd/C (5 mg), stirred at room temperature to react after five H₂ displacements and monitored by LC-MS. After the reaction, Pd/C was removed by diatomaceous earth and the organic phase was concentrated under reduced pressure to give the product 14-2 (40 mg, crude), LCMS (ESI⁺) m/z: 277.2 [M+H]⁺.

Step 3: Synthesis of Compound 14

The substrate IM-1 (38 mg, 106 μmol) and THF (2 mL) were added to a dry single-necked flask, stirred to dissolve then added with m-CPBA (40 mg, 200 mol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (65 mg, 500 μmol) after the reaction and stirred for 10 min, added with 14-2 (40 mg, crude), heated up to 80° C. to react and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 14 (12.2 mg, 17.58% yield). ¹H NMR (600 MHz, Methanol-d₄) δ 8.76 (s, 1H), 7.96-7.93 (m, 1H), 7.76 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 5.73-5.67 (m, 1H), 5.03 (d, J=10.2 Hz, 1H), 4.91 (d, J=10.2 Hz, 1H), 4.80 (d, J=5.8 Hz, 2H), 4.59 (s, 2H), 4.23 (s, 2H), 3.76 (s, 2H), 3.44 (q, J=7.0 Hz, 2H), 2.90-2.85 (m, 4H), 2.62 (s, 3H), 1.57 (s, 6H), 1.18 (t, J=7.0 Hz, 3H). LCMS (E+) m/z: 586.4 [M+H]⁺, HPLC method B: R_T=6.23 min, purity: 91.9%.

Example 15: Synthesis of Compound 15

Step 1: Synthesis of Compound 15-2

The substrate 15-1 (2.44 g, 12.50 mmol), NBS (3.33 g, 18.70 mmol) and AIBN (0.2 g, 1.21 mmol) were added to a single-necked flask, dissolved with CCl₄ (20 ml) and N₂ disreplaced three times, stirred overnight under N₂ protection and monitored by TLC as the flask was placed in an oil bath at 85° C., concentrated under reduced pressure to remove the solvents. The crude product can be used without purification for the following reaction directly to give the crude product 15-2 (3 g, 11.03 mmol, 88.1% yield).

Step 2: Synthesis of Compound 15-3

The crude product 15-2 (3 g, 11.03 mmol) was added with 4-amino-1-methylpiperidine (1.8 g, 15.77 mmol) to dissolve, then heated up to 40° C. to react with stirring for 2 h. The reaction was monitored by LC-MS until completion. The reaction was separated by column chromatography to give the compound 15-3 (1.3 g, 4.72 mmol, 42.86% yield), LCMS (ESI⁺) m/z: 276.1 [M+H]⁺.

Step 3: Synthesis of Compound 15-4

The substrate 15-3 (0.6 g, 1.70 mmol) was added to a flask and dissolved with anhydrous methanol (10 ml), then added with Pd/C (10% wt.) (60 mg), stirred overnight at room temperature after 3 times of H₂ displacements and monitored by LC-MS, then filtered with diatomaceous earth after the reaction and the filtrate was concentrated under reduced pressure and purified by column chromatography to give the compound 15-4 (474 mg, 1.92 mmol, 88.7% yield), LCMS (ESI⁺) m/z: 246.2 [M+H]⁺.

Step 4: Synthesis of Compound 15

The substrate IM-5 (39.3 mg, 0.097 mmol), The substrate 15-4 (47.43 mg, 0.19 mmol), anhydrous acetonitrile (4 ml) and TFA (55.18 mg, 0.48 mmol) were added to a microwave reaction tube for microwave reaction for 4 h at 90° C. and monitored by LC-MS, quenched with saturated NaHCO₃ solution after the reaction, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated saline and dried with anhydrous Na₂SO₄, then concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the compound 15 (10 mg, 0.017 mmol, 17.6% yield). ¹H NMR (600 MHz, Chloroform-d₆) δ 8.89 (s, 1H), 8.03 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.71-7.68 (m, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.69-5.63 (m, 1H), 5.05-4.96 (m, 2H), 4.92 (d, J=6.3 Hz, 2H), 4.37 (s, 3H), 3.34 (s, 6H), 3.11 (s, 2H), 2.44 (s, 3H), 2.33 (s, 2H), 2.05 (s, 2H), 1.89 (d, J=12.5 Hz, 2H). LCMS (ESI⁺) m/z: 588.1 [M+H]⁺, HPLC method B: R_T=5.34 min, purity: 96.5%.

Example 16: Synthesis of Compound 16

Step 1: Synthesis of Compound 16-2

Pyridine (7.91 g, 100 mmol) and acetonitrile (40 mL) were added to a dry single-necked flask, stirred well, added with 2-chloroacetamide (9.35 g, 100 mmol), and then heated to 90° C. to react overnight, cooled to room temperature after the reaction, filtered out the solid, washed three times with petroleum ether, and recrystallized with ethanol to give the product 16-2 (10.8 g, 62% yield)

Step 2: Synthesis of Compound 16-4

The substrate 16-2 (3.6 g, 21.15 mmol) and n-butanol (50 mL) were added to a dry single-necked flask, stirred well, added with 16-3 (1.82 g, 7.05 mmo), acetic acid (1.5 mL) and piperidine (2.5 mL), and heated up to 120° C. to react and monitored by LC-MS. After the reaction, the solid was filtered out, the filtrate was extracted with CHCl₃ (containing 5% MeOH) three times, the organic phase was concentrated under reduced pressure, and the resulting solid was recrystallized with methanol to give the product 16-4 (1.92 g, 91% yield), LCMS (ESI⁺) m/z: 298.2 [M+H]⁺.

Step 3: Synthesis of Compound 16-5

The substrate 16-4 (500 mg, 1.68 mmol) and methanol (15 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (50 mg), H₂ displaced five times, stirred to react at room temperature and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give the product 16-5 (310 mg, 69% yield), LCMS (ESI⁺) m/z: 268.1 [M+H]⁺.

Step 4: Synthesis of Compound 16

The substrate IM-1 (70 mg, 200 μmol) and tetrahydrofuran (4 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (60 mg, 300 μmol, 85% purity) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (129.24 mg, 1.00 mmol) after the reaction, stirred for 10 min, then added with 16-5 (53.47 mg, 200.00 μmol) to react at 80° C. in microwave and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 16 (6.3 mg, 5.22% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 11.81 (s, 1H), 10.43 (s, 1H), 8.93 (s, 1H), 8.08-8.05 (m, 1H), 7.81-7.78 (m, 3H), 7.64 (d, J=7.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 6.22 (s, 1H), 5.71-5.65 (m, 1H), 5.35 (s, 1H), 5.01 (d, J=10.2 Hz, 1H), 4.84 (d, J=17.2 Hz, 1H), 4.69 (d, J=5.9 Hz, 2H), 3.47 (s, 2H), 3.09 (s, 1H), 3.00 (s, 2H), 1.84 (s, 2H), 1.56 (s, 2H), 1.47 (s, 6H). 1H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.93 (s, 1H), 8.09-8.06 (m, 1H), 7.81-7.76 (m, 3H), 7.65 (d, J=7.6 Hz, 1H) 7.59 (d, J=8.4 Hz, 2H), 6.27 (s, 1H), 5.71-5.64 (m, 1H), 5.04 (d, J=10.2 Hz, 1H), 4.84 (d, J=17.1 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 3.93 (s, 2H), 3.16 (s, 1H), 3.02 (s, 2H), 1.88 (s, 2H), 1.57 (s, 2H), 1.48 (s, 6H). LCMS (E+) m/z: 577.3 [M+H]⁺, HPLC method B: R_T=5.96 min, purity: 95.5%.

Example 17: Synthesis of Compound 17

Step 1: Synthesis of Compound 17-3

The compound 17-2 (130 mg, 0.88 mmol), DIPEA (0.58 g, 4.4 mmol) were sequentially dissolved in DMSO (1 ml) in a dry round-bottomed flask, then added with 17-1 (1.1 mmol, 148 mmol) and stirred for 2 hours at room temperatue and monitored by LC-MS, diluted with water after the reaction, extracted three times with ethyl acetate, washed with saturated brine, and the organic phase was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure for the following reaction directly without purification to give the crude product 17-3 (150 mg, 0.64 mmol, 65.6% yield), LCMS (ESI⁺) m/z: 235.1 [M+H]⁺.

Step 2: Synthesis of Compound 17-4

The compound 17-3 (150 mg, 0.64 mmol), a catalytic amount of Pd/C (45 mg), and MeOH (3 mL) were added to a 50 mL round-bottomed flask, H₂ displaced 3 times, and stirred vigorously at room temperature for 12 hours under H₂ atmosphere, monitored by LC-MS, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the compound 17-4 (100 mg, 0.49 mmol, 76.1% yield), LCMS (ESI⁺) m/z: 205.1 [M+H]⁺.

Step 3: Synthesis of Compound 17

A solution of THF (1 mL) containing dissolved IM-1 (51 mg, 0.18 mmol) was added with m-CPBA (39 mg, 0.18 mmol) and stirred for 10 min at room temperature, monitored by LC-MS then by TLC, added with DIPEA (122 mg, 0.75 mmol) after the disappearance of the raw materials, and stirred for 20 min at room temperature. Subsequently, 17-4 (51 mg, 0.15 mmol) was added and stirred for 1 hour at room temperature, monitored by LC-MS, added with water after the reaction, extracted with ethyl acetate for three times, and the organic phase was dried with anhydrous Na₂SO₄ and then concentrated under reduced pressure, and the crude product was purified by acidic preparative high-performance liquid chromatography (AP-HPLC) to give the compound 17 (26 mg, 0.05 mmol, 35.5% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.13 (s, 1H), 8.81 (s, 1H), 8.04 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 6.82 (d, J=8.5 Hz, 2H), 5.69-5.64 (m, 1H), 5.32 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.68 (s, 2H), 4.42 (s, 2H), 2.82-2.72 (m, 2H), 1.84 (s, 4H), 1.49 (s, 1H), 1.46 (s, 6H), 1.38 (s, 2H). LCMS (E+) m/z: 514.5[M+H]⁺, HPLC method A: R_T=7.13 min, purity: >99.9%.

Example 18: Synthesis of Compound 18

Step 1: Synthesis of Compound 18-2

The compound 18-1 (4 g, 20 mmol) was added to a dry single-necked flask, dissolved in DCM (50 ml), added with TFA (25 mL) at room temperature and stirred for 30 min, and monitored by LC-MS, the solvents were removed by vacuum after the reaction, then diluted with water, extracted three times with ethyl acetate, and the organic phase was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product 18-2 (1.8 g, crude) for the following reaction directly without purification. LCMS (ESI⁺) m/z: 100.1 [M+H]⁺.

Step 2: Synthesis of Compound 18-4

The compound 18-2 (1 g, 7 mmol) was added to a dry single-necked flask, dissolved in DMSO (10 mL), added subsequently with 18-3 (1 g, 10.5 mmol) and K₂CO₃ (4.8 g, 35 mmol). The reaction mixture was stirred overnight at room temperature and monitored by LC-MS, diluted with 100 mL water after the reaction, extracted three times with ethyl acetate, and the organic phase was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product 18-4 (1.35 g, crude) for the following reaction directly without purification. LCMS (ESI⁺) m/z: 221.1 [M+H]⁺.

Step 3: Synthesis of Compound 18-6

The compound 18-4 (1.35 g, 6.2 mmol), 18-5 (1.47 g, 7.4 mmol) were dissolved in methanol (15 ml) in a dry round-bottomed flask, added with acetic acid (1 ml) to react for 30 min, then added with Sodium cyanoborohydride (584 mg, 9.3 mmol) and heated up to 60° C., stirred for 4 h, monitored by LC-MS. The solvents were removed under reduced pressure after the reaction, then added with water, extracted three times with ethyl acetate, and the organic phase was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product 18-6 (1.75 g, crude), LCMS (ESI⁺) m/z: 403.2 [M+H]⁺.

Step 4: Synthesis of Compound 18-7

The compound 18-6 (1.75 g, 4.4 mmol), a catalytic amount of Pd/C (200 mg), and MeOH (20 mL) were added to a 50 mL round-bottomed flask, and stirred for 12 hours at room temperature under H₂ atmosphere, monitored by LC-MS. The reaction solution was concentrated under reduced pressure after the reaction. The residue was purified by column chromatography to give the compound 18-7 (1.46 g, 3.9 mmol, 90.2% yield). LCMS (ESI⁺) m/z: 373.3 [M+H]⁺.

Step 5: Synthesis of Compound 18-8

The compound 18-7 (1.75 g, 4.4 mmol) was dissolved in THF in a round-bottomed flask, added slowly with a tetrahydrofuran solution (10 ml, 20 mmol) of 2 M LiAlH₄ under N₂ protection at 0° C., heated up to 65° C. and stirred for 6 h at this temperature, monitored by LC-MS, cooled to 0° C. After the reaction, subsequently added with water (0.76 ml) and 10% aqueous solution of NaOH, quenched with water (2.3 ml), stirred for 30 min at room temperature, dried with anhydrous Na₂SO₄, and filtered with diatomaceous earth. The filtrate was concentrated under vacuum then purified by column chromatography to give the compound 18-8 (736 mg, 2.5 mmol, 65.6% yield). LCMS (ESI⁺) m/z: 287.2 [M+H]⁺.

Step 6: Synthesis of Compound 18

Following the synthesis method of step 3 in Example 17, 17-4 (51 mg, 0.15 mmol) in step 3 was replaced with 18-8 (42.1 mg, 0.15 mmol) in the same synthesis method to give the compound 18 (20 mg, 33.6 μmol, 22.9% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.19 (s, 1H), 8.84 (s, 1H), 8.04 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.7 Hz, 3H), 7.00 (d, J=8.5 Hz, 3H), 5.70-5.63 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.2 Hz, 1H), 4.68 (s, 3H), 4.45 (s, 1H), 3.82 (s, 6H), 3.37 (s, 2H), 2.92 (s, 3H), 2.69 (t, J=12.4 Hz, 2H), 2.23 (d, J=64.4 Hz, 2H), 2.07 (d, J=11.8 Hz, 1H), 1.78-1.63 (m, 2H), 1.47 (s, 6H). LCMS (ESI⁺) m/z: 596.4 [M+H]⁺. HPLC method A: R_T=6.35 min, purity: 96.9%.

Example 19: Synthesis of Compound 19

Step 1: Synthesis of Compound 19-2

The compound 19-1 (200 mg, 0.1 mmol) and DMSO (5 mL) were added to a dry single-necked flask, then added with K₂CO₃ (470 mg, 3.4 mmol) and p-fluoronitrobenzene (141 mg, 1 mmol) under stirring, heated up to 110° C. to react and monitored by LC-MS, cooled to room temperature after the reaction, added with iodomethane (CH₃I) (141 mg, 1 mmol), then heated up to 90° C. to react and monitored by LC-MS, cooled to room temperature after the reaction to filter out the solid. The filterate was concentrated under reduced pressure and purified by medium pressure liquid chromatography (Alkali process) to give the product 19-2 (50 mg, 19% yield), LCMS (ESI⁺) m/z: 262.3 [M+H]⁺.

Step 2: Synthesis of Compound 19-3

The substrate 19-2 (50 mg, 0.19 mmol) and methanol (2 mL) were added to a dry single-necked flask, stirred to dissolve, added with Pd/C (10 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, the organic phase was concentrated under reduced pressure to give the product 19-3 (40 mg, crude), LCMS (ESI⁺) m/z: 232.2 [M+H]⁺.

Step 3: Synthesis of Compound 19

The substrate IM-1 (52 mg, 0.15 mmol) and tetrahydrofuran (3 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (121 mg, 0.6 mmol, 85% purity) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (95.17 mg, 736.42 μmol) after the reaction, stirred for 10 min, then added with 19-3 (40 mg, crude) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 19 (35 mg, 40.96% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.80 (s, 1H), 7.99-7.96 (m, 1H), 7.75 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.47 (s, 2H), 6.62 (d, J=8.3 Hz, 2H), 6.19 (d, J=23.4 Hz, 1H), 5.69-5.63 (m, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.67 (s, 2H), 3.89 (s, 2H), 3.51 (s, 2H), 3.29 (s, 3H), 2.97 (s, 3H), 2.22 (s, 2H), 2.00 (d, J=7.8 Hz, 2H), 1.76 (d, J=14.1 Hz, 1H), 1.46 (s, 6H). ¹H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.81 (s, 1H), 8.01-7.98 (m, 1H), 7.74 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.49 (s, 2H), 6.64 (d, J=8.4 Hz, 2H), 5.69-5.63 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.0 Hz, 1H), 4.68 (s, 2H), 3.90-3.88 (m, 2H), 3.43-3.42 (m, 4H), 3.14-3.12 (m, 1H), 2.97 (s, 3H), 2.23-2.20 (m, 2H), 2.03 (s, 2H), 1.82 (s, 1H), 1.47 (s, 6H). LCMS (E+) m/z: 541.3 [M+H]⁺, HPLC method B: R_T=5.65 min, purity: 93.2%.

Example 20: Synthesis of Compound 20

Step 1: Synthesis of Compound 20-2

The compound 20-1 (136 mg, 1 mmol) and DMSO (8 mL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (332 mg, 2.4 mmol) and p-fluoronitrobenzene (141 mg, 1 mmol), heated up to 90° C. to react and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred till the solid precipitated, washed three times with water, then washed with a small amount of methanol, and dried to give the product 20-2 (180 mg, 81.8% yield), LCMS (ESI⁺) m/z: 221.2 [M+H]⁺.

Step 2: Synthesis of Compound 20-3

The substrate 20-2 (180 mg, 0.82 mmol) and methanol (7 mL) were added to a dry single-necked flask, stirred to dissolve, added with Pd/C (18 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, the organic phase was concentrated under reduced pressure to give the crude product 20-3 (120 mg, crude), LCMS (ESI⁺) m/z: 191.1 [M+H]⁺.

Step 3: Synthesis of Compound 20

The substrate IM-1 (52 mg, 0.15 mmol) and tetrahydrofuran (3 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (121 mg, 0.6 mmol, 85% purity) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (98 mg, 758.28 μmol) after the reaction and stirred for 10 min, then added with 20-3 (46 mg, 151.86 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 20 (25 mg, 0.05 mmol, 33.84% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.80 (s, 1H), 8.02-8.01 (m, 1H), 7.75 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53-7.38 (m, 2H), 6.62 (d, J=7.2 Hz, 2H), 5.70-5.63 (m, 1H), 5.33 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.69 (s, 2H), 4.60 (s, 1H), 4.53 (s, 1H), 3.75 (d, J=6.8 Hz, 1H), 3.67 (d, J=7.4 Hz, 1H), 3.50 (d, J=9.0 Hz, 1H), 2.95 (d, J=9.0 Hz, 1H), 1.93 (d, J=9.2 Hz, 1H), 1.84 (d, J=8.8 Hz, 1H), 1.47 (s, 6H). ¹H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.82 (s, 1H), 8.05-8.02 (m, 1H), 7.74 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.52 (s, 2H), 6.63 (d, J=7.6 Hz, 2H), 5.70-5.64 (m, 1H), 5.03 (d, J=10.2 Hz, 1H), 4.84 (d, J=17.0 Hz, 1H), 4.70 (s, 2H), 4.62 (s, 1H), 4.51 (s, 1H), 3.78 (d, J=7.4 Hz, 1H), 3.68 (d, J=7.6 Hz, 1H), 3.52 (d, J=9.4 Hz, 1H), 2.96 (d, J=9.2 Hz, 1H), 1.95 (d, J=9.0 Hz, 1H), 1.86 (d, J=9.0 Hz, 1H), 1.48 (s, 6H). LCMS (E+) m/z: 500.1 [M+H]⁺, HPLC method B: R_T=6.69 min, purity: 99.6%.

Example 21: Synthesis of Compound 21

Step 1: Synthesis of Compound 21-3

The compound 21-1 (3.0 g, 19.34 mmol) and DMSO (20 mL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (2.67 g, 19.34 mmol) and 21-2 (3.82 g, 19.34 mmol), heated up to 100° C. to react for 3 h and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred till the solid precipitated and filtered out, washed three times with water, then washed with a small amount of methanol, and dried to give the product 21-3 (6 g, 18.00 mmol, 93.06% yield), LCMS (ESI⁺) m/z: 334.4 [M+H]⁺.

Step 2: Synthesis of Compound 21-4

The compound 21-3 (6.67 g, 20.01 mmol), TFA (2.28 g, 20.01 mmol) and DCM (50 mL) were added to a dry single-necked flask, stirred to dissolve to react for 18 hours at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction, extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline, dried with anhydrous Na₂SO₄. The filterate was concentrated under reduced pressure after filtration to give the crude product 21-4 (4 g, crude), LCMS (ESI⁺) m/z: 234.3 [M+H]⁺.

Step 3: Synthesis of Compound 21-6

The compound 21-4 (3 g, 12.86 mmol), compound 21-5 (1.46 g, 12.86 mmol), NaBH₃CN (1.2 g, 19.11 mmol) and methanol (30 mL) were added to a dry single-necked flask, stirred to dissolve, heated up to 60° C. to react for 18 hours and monitored by LC-MS, concentrated under reduced pressure after the reaction, extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline, dried with anhydrous Na₂SO₄. The filterate was concentrated under reduced pressure after filtration and purified by medium pressure liquid chromatography to give the crude product 21-6 (3 g, 9.08 mmol, 70.60% yield), LCMS (ESI⁺) m/z: 331.4 [M+H]⁺.

Step 4: Synthesis of Compound 21-7

The substrate 21-6 (200 mg, 0.61 mmol) and methanol (10 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (40 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the crude product 21-7 (50 mg, 27.5% yield), LCMS (ESI⁺) m/z: 301 [M+H]⁺.

Step 5: Synthesis of Compound 21

The substrate IM-1 (17.8 mg, 50.08 μmol) and tetrahydrofuran (2 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (12.9 mg, 74.74 μmol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (98 mg, 758.28 μmol) after the reaction and stirred for 10 min, then added with 21-7 (15.05 mg, 50.08 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give 21 (5 mg, 8.16 μmol, 16.29% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.82 (s, 1H), 7.99-7.97 (m, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.29-7.27 (m, 1H), 6.72 (d, J=9.0 Hz, 1H), 5.69-5.63 (m, 1H), 5.33 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.82 (d, J=17.4 Hz, 1H), 4.68 (d, J=5.9 Hz, 2H), 3.95 (s, 1H), 3.66 (s, 1H), 3.20 (q, J=8.4 Hz, 2H), 3.02 (d, J=8.4 Hz, 1H), 2.68 (d, J=7.8 Hz, 2H), 2.56 (d, J=9.0 Hz, 1H), 2.22 (s, 3H), 2.16 (s, 1H), 2.12 (s, 3H), 1.91 (s, 1H), 1.88 (s, 1H), 1.74-1.69 (m, 4H), 1.46 (s, 6H), 1.38-1.25 (m, 2H). LCMS (ESI⁺) m/z: 610.6 [M+H]⁺. HPLC method A: R_T=4.45 min, purity: 99.5%.

Example 22: Synthesis of Compound 22

Step 1: Synthesis of Compound 22-2

The compound 22-1 (158 mg, 499.31 μmol), TFA (3 mL) and DCM (3 mL) were added to a dry single-necked flask, stirred to dissolve to react for 18 hours at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction, extracted three times with water and ethyl acetate. The orgnanic phase was combined, washed with saturated saline, dried with anhydrous Na₂SO₄. The filterate was concentrated under reduced pressure after filteration to give the crude product 22-2 (100 mg, crude), LCMS (ESI⁺) m/z: 217.3 [M+H]⁺.

Step 2: Synthesis of Compound 22-3

The compound 22-2 (100 mg, 462.28 μmol) and DMSO (4 mL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (97 mg, 701.88 μmol) and compound 4-2 (72 mg, 510.28 μmol), heated up to 100° C. to react for 3 hours and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred till the solid precipitated then filtered out, washed three times with water, then washed with a small amount of methanol, and dried to give the product 22-3 (150 mg, 444.56 μmol, 96.17% yield), LCMS (ESI⁺) m/z: 338.4 [M+H]⁺.

Step 3: Synthesis of Compound 22-4

The substrate 22-3 (50 mg, 148.19 μmol) and methanol (4 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (8 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the crude product 22-4 (20 mg, 65.06 μmol, 43.90% yield), LCMS (ESI⁺) m/z: 308.4 [M+H]⁺.

Step 4: Synthesis of Compound 22

The substrate 22-4 (24.70 mg, 80.34 μmol) and tetrahydrofuran (2 mL) were added into a dry single-necked flask, stirred to dissolve, then added with DIPEA (51.91 mg, 401.68 μmol, 69.96 μL) and compound IM-6 (30 mg, 80.34 μmol) to react for 1 hour at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography to give the compound 22 (5 mg, 7.30 μmol, 9.09% yield).

¹H NMR (600 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.79-7.78 (m, 1H), 7.61-7.55 (m, 3H), 7.18-7.17 (m, 5H), 6.77 (d, J=8.4 Hz, 2H), 5.70-5.63 (m, 1H), 5.33 (s, 1H), 5.00 (d, J=10.3 Hz, 1H), 4.83 (d, J=17.2 Hz, 1H), 4.68 (s, 2H), 3.59 (d, J=11.3 Hz, 2H), 3.38 (s, 2H) 3.08 (d, J=11.3 Hz, 2H), 2.87 (d, J=10.6 Hz, 2H), 2.26 (d, J=10.7 Hz, 2H), 2.09 (s, 2H), 1.70 (d, J=12.2 Hz, 1H), 1.60 (d, J=12.1 Hz, 1H), 1.47 (s, 6H). ¹H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.81 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.61-7.58 (m, 3H), 7.18 (s, 5H), 6.78 (d, J=8.6 Hz, 2H), 5.69-5.63 (m, 1H), 5.02 (d, J=10.3 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.68 (s, 2H), 3.64 (s, 2H), 3.39 (s, 2H), 3.08 (d, J=10.9 Hz, 2H), 2.87 (d, J=10.8 Hz, 2H), 2.28 (s, 2H), 2.10 (s, 2H), 1.70 (d, J=11.9 Hz, 1H), 1.60 (d, J=12.2 Hz, 1H), 1.47 (s, 6H). LCMS (E+) m/z: 617.4 [M+H]⁺, HPLC method B: R_T=6.01 min, purity: 90.1%.

Example 23: Synthesis of Compound 23

Step 1: Synthesis of Compound 23-1

The substrate 22-1 (200 mg, 632.04 μmol) and methanol (5 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (20 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the crude product 23-1 (140 mg, crude), LCMS (ESI⁺) m/z: 227.3 [M+H]⁺.

Step 2: Synthesis of Compound 23-2

The compound 23-1 (128.31 mg, 566.97 μmol) and DMSO (3 mL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (96.74 mg, 0.7 mmol) and p-fluoronitrobenzene (4-2, 80 mg, 566.97 μmol), heated up to 90° C. to react for 6 hours and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred till the solid precipitated then filtered out, washed three times with water, then washed with a small amount of methanol, and dried to give the product 23-2 (120 mg, crude), LCMS (ESI⁺) m/z: 348.4 [M+H]⁺.

Step 3: Synthesis of Compound 23-3

The compound 23-2 (69 mg, 198.61 μmol), TFA (3 mL) and DCM (3 mL) were added to a dry single-necked flask, stirred to dissolve to react for 18 hours at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction, extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline, dried with anhydrous Na₂SO₄. After filtration, the filterate was concentrated under reduced pressure to give the crude product 23-3 (49 mg, crude), LCMS (ESI⁺) m/z: 248.3 [M+H]⁺.

Step 4: Synthesis of Compound 23-4

The substrate 23-3 (49.46 mg, 0.2 mmol) was added into a dry single-necked flask, stirred to dissolve with methanol (4 mL), then added with formaldehyde (34.06 mg, 1.00 mmol) and acetic acid (11 mL), stirred for 10 min then added with NaCNBH₃ (25.14 mg, 400.00 μmol), heated up to 50° C. to react for 2 hours and monitored by LC-MS, concentrated under reduced pressure after the reaction, extracted three times with water and ethyl acetate. The organic phase was combined, washed with saturated saline, dried with anhydrous Na₂SO₄. After filtration, the filterate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the compound 23-4 (30 mg, 114.80 μmol, 57.40% yield), LCMS (ESI⁺) m/z: 262.3 [M+H]⁺.

Step 5: Synthesis of Compound 23-5

The substrate 23-4 (30 mg, 114.80 μmol) and methanol (3 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (8 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the product 23-5 (20 mg, crude), LCMS (ESI⁺) m/z: 232.3 [M+H]⁺.

Step 6: Synthesis of Compound 23

The substrate 23-5 (18.58 mg, 80.34 μmol) and tetrahydrofuran (2 mL) were added into a dry single-necked flask, stirred to dissolve, then added with DIPEA (51.91 mg, 401.68 μmol, 69.96 μL) and compound IM-6 (30 mg, 80.34 μmol) to react for 1 h at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography to give the compound 23 (8 mg, 13.58 μmol, 16.91% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.80 (s, 1H), 8.04 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.61-7.56 (m, 3H), 6.73 (d, J=8.6 Hz, 2H), 5.65-5.63 (m, 1H), 5.33 (s, 1H), 4.99 (dd, J=10.3, 1.6 Hz, 1H), 4.83 (dd, J=17.1, 1.7 Hz, 1H), 4.68 (d, J=6.1 Hz, 2H), 3.57 (d, J=11.2 Hz, 2H), 3.46 (s, 3H), 3.00 (dd, J=11.3, 4.8 Hz, 2H), 2.88 (s, 2H), 2.17-2.09 (m, 4H), 1.66-1.54 (m, 2H), 1.46 (s, 6H). ¹H NMR (600 MHz, DMSO-d₆, D₂O) δ 8.80 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.62-7.55 (m, 3H), 6.75 (s, 2H), 5.67-5.63 (m, 1H), 5.02-5.01 (m, 1H), 4.84-4.82 (m, 1H), 4.68 (d, J=6.1 Hz, 2H), 3.71 (s, 3H), 3.58 (d, J=11.4 Hz, 2H), 2.99-2.89 (m, 4H), 2.12-2.04 (m, 4H), 1.66-1.57 (m, 2H), 1.47 (s, 6H). LCMS (E+) m/z: 541.3 [M+H]⁺, HPLC method B: R_T=5.29 min, purity: 94.1%.

Example 24: Synthesis of Compound 24

Step 1: Synthesis of Compound 24-2

The substrate 24-1 (2 g, 10.25 mmol) and carbon tetrachloride (40 mL) were added to a dry single-necked flask, stirred well, added with NBS (2.74 g, 15.37 mmol) and AIBN (269.24 mg, 1.64 mmol), and N₂ displaced five times, heated up to 70° C. with stirring and refluxing for 12 hours and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography to give thr compound 24-2 (1.3 g, 4.74 mmol, 46.3% yield), LCMS (ESI⁺) m/z: 274.1 [M+H]⁺.

Step 2: Synthesis of Compound 24-4

The substrate 24-2 (200 mg, 0.73 mmol) and 24-3 (166.42 mg, 1.46 mmol) were added to a dry single-necked flask, heated up to 50° C. with stirring and refluxing for 1 hour and monitored by LC-MS, concentrated under reduced pressure after the reaction, and added with a small amount of ethyl acetate. The solid was filtered out, the residue was purified by medium pressure liquid chromatography to give the compound 24-4 (180 mg, 0.65 mmol, 89.67% yield), LCMS (ESI⁺) m/z: 276.1 [M+H]⁺.

Step 3: Synthesis of Compound 24-5

The substrate 24-4 (180 mg, 0.65 mmol) and methanol (3 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (8 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the product 24-5 (100 mg, crude), LCMS (ESI⁺) m/z: 246.3 [M+H]⁺.

Step 4: Synthesis of Compound 24-6

The substrate IM-3 (0.2 g, 0.51 mmol) and anhydrous THF (5 mL) were added into a single-necked flask, stirred to dissolve, then added with m-CPBA (208.2 g, 1.02 mmol, 85% purity), stirred for 40 min at room temperature and monitored by LC-MS. After the reaction, the reactant was concentrated under reduced pressure and separated by medium pressure liquid chromatography (Alkali process) to give the compound 24-6 (130 mg, 0.31 mmol, 60.0% yield), LCMS (ESI⁺) m/z: 423.5 [M+H]⁺.

Step 5: Synthesis of Compound 24

The substrate 24-6 (31 mg, 73.38 μmol), 24-5 (36.00 mg, 146.75 μmol), TsOH (50.48 mg, 293.50 μmol) and anhydrous ACN (0.3 mL) were added to a dry microwaveable tube, stirred to dissolve, heated up to 110° C. after the tube closed to react for 4 hours by microwave and monitored by LC-MS, cooled to room temperature after the reaction, quenched by adding saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, the organic phase was combined, washed with saturated brine, dried with anhydrous Na₂SO₄, concentrated under reduced pressure, and then separated by medium pressure liquid chromatography to give the product 24 (1.5 mg, 2.55 μmol, 3.48% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.91 (s, 1H), 8.46 (s, 1H), 7.95 (s, 1H), 7.77 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H), 5.66 (ddt, J=16.4, 10.2, 6.0 Hz, 1H), 5.02 (dd, J=10.3, 1.6 Hz, 1H), 4.90 (dd, J=17.1, 1.6 Hz, 1H), 4.80 (s, 2H), 4.42 (s, 2H), 4.08-3.97 (m, 1H), 3.38 (s, 6H), 2.89 (d, J=11.1 Hz, 2H), 2.22 (s, 3H), 2.07 (t, J=11.8 Hz, 2H), 1.82 (dd, J=12.1, 3.8 Hz, 2H), 1.71 (d, J=13.3 Hz, 2H). LCMS (ESI⁺) m/z: 588.1 [M+H]⁺, HPLC method B: R_T=5.22 min, purity: 92.3%.

Example 25: Synthesis of Compound 25

Step 1: Synthesis of Compound 25-2

The compound 25-1 (0.5 g, 2.36 mmol) and DMSO (lOmL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (651.05 mg, 4.71 mmol) and p-fluoronitrobenzene (4-2, 332.33 mg, 2.36 mmol), heated up to 100° C. to react for 6 hours and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred till the solid precipitated then filtered out, washed three times with water, then washed with a small amount of methanol, and dried to give the product 25-2 (0.7 g, 2.10 mmol, 89.15% yield), LCMS (ESI⁺) m/z: 333.4 [M+H]⁺.

Step 2: Synthesis of Compound 25-3

The substrate 25-2 (0.5 g, 1.50 mmol) and methanol (10 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (910 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the product 25-3 (0.4 g, 1.32 mmol, 87.91% yield), LCMS (ESI⁺) m/z: 304.2 [M+H]⁺.

Step 3: Synthesis of Compound 25-4

The substrate 25-3 (150 mg, 0.5 mmol) and THF (4 mL) were added into a single-necked flask, stirred to dissolve, then added with LiAlH₄ (112.57 mg, 2.97 mmol), heated up to 65° C. to react for 2 hours and monitored by LC-MS, cooled to room temperature after the reaction, added with water and stirred till the solid precipitated then filtered out, washed three times with water, then washed with a small amount of methanol, and dried to give the product 25-4 (80 mg, 0.36 mmol, 74.46% yield), LCMS (ESI⁺) m/z: 218.3 [M+H]⁺.

Step 4: Synthesis of Compound 25

The substrate IM-1 (21.70 mg, 99.88 μmol) and tetrahydrofuran (2 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (25.86 mg, 149.82 μmol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (64.54 mg, 499.40 mol, 86.98 μL) after the reaction and stirred for 10 min, then added with 25-4 (21.70 mg, 99.88 mol) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 25 (9 mg, 16.06 μmol, 16.08% yield). 1H NMR (600 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.80 (s, 1H), 8.03-8.01 (m, 1H), 7.75 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.51 (s, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.70-5.99 (m, 1H), 5.31 (s, 1H), 5.00-4.98 (m, 1H), 4.84-4.81 (m, 1H), 4.68 (d, J=6.0 Hz, 2H), 4.20 (s, 2H), 2.47-2.44 (m, 2H), 2.30-2.28 (m, 2H), 2.06 (s, 3H), 1.88 (d, J=6.6 Hz, 2H), 1.83 (d, J=6.0 Hz, 2H), 1.46 (s, 6H). LCMS (ESI⁺) m/z: 527.3 [M+H]⁺. HPLC method B: R_T: 7.83 min, purity: 94.0%.

Example 26: Synthesis of Compound 26

Step 1: Synthesis of Compound 26-3

The substrate 26-1 (1.27 g, 12.72 mmol), 26-2 (2 g, 8.48 mmol), t-BuONa (1 g, 10.17 mmol) and toluene (15 mL) were added to a dry microwaveable tube, stirred to dissolve, deoxidized with N₂ for 10 min, added with Pd₂(dba)₃ (778 mg, 0.85 mmol), BINAP (264.6 mg, 0.43 mmol), and then deoxidized with N₂ for 10 min, heated to 110° C. in an oil bath after the tube closed to react for 12 hours and monitored by LC-MS, cooled to room temperature after the reaction, filtered with diatomaceous earth, the filterate was concentrated under reduced pressure, and then separated by medium pressure liquid chromatography to give the product 26-3 (1.57 g, 6.15 mmol, 72.58% yield), LCMS (ESI⁺) m/z: 255.2 [M+H]⁺.

Step 2: Synthesis of Compound 26-5

The substrate 26-3 (650 mg, 2.55 mmol) was added to a dry single-necked flask, dissolved with acetone (6 mL) and water (7 mL), then added with 26-4 (637.87 mg, 3.82 mmol), Pd(OAc) 2 (57.25 mg, 0.25 mmol), and sodium carbonate (542 mg, 2.55 mmol), N₂ displaced three times, then heated to 50° C. for 12 hours under N₂ protection and monitored by LC-MS, cooled to room temperature after the reaction, extracted three times with water and ethyl acetate, the organic phase was combined, washed with saturated brine, dried with anhydrous Na₂SO₄. The residue was purified by medium pressure liquid chromatography to give the product 26-5 (240 mg, 807.13 μmol, 31.68% yield), LCMS (ESI⁺) m/z: 298.4 [M+H]⁺.

Step 3: Synthesis of Compound 26-6

The substrate 26-5 (240 mg, 807.13 μmol) and methanol (10 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (30 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the product 26-6 (160 mg, 598.43 μmol, 74.14% yield), LCMS (ESI⁺) m/z: 268.4 [M+H]⁺.

Step 4: Synthesis of Compound 26

The substrate IM-1 (47.5 mg, 132.89 μmol) and tetrahydrofuran (0.5 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (54 mg, 265.79 μmol) to react for 1 h at room temperature and monitored by LC-MS, added with DIPEA (85.88 mg, 664.47 μmol, 115.74 μL) after the reaction and stirred for 10 min, then added with 26-6 (21.70 mg, 99.88 μmol) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 26 (1.5 mg, 2.35 μmol, 1.77% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.90 (s, 1H), 8.11 (t, J=8.2 Hz, 1H), 7.80 (dd, J=8.3, 6.2 Hz, 2H), 7.63 (d, J=7.7 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 5.68 (ddt, J=16.5, 10.3, 5.9 Hz, 1H), 5.35 (s, 1H), 5.01 (d, J=10.2 Hz, 1H), 4.88-4.79 (m, 1H), 4.70 (d, J=6.0 Hz, 2H), 3.18 (t, J=5.0 Hz, 4H), 2.47 (t, J=5.0 Hz, 4H), 2.23 (s, 3H), 1.47 (s, 6H). LCMS (ESI) m/z: 577.3 [M+H]⁺, HPLC method B: R_T=9.20 min, purity: 97.8%.

Example 27: Synthesis of Compound 27

Step 1: Synthesis of Compound 27-2

The compound 27-1 (400 mg, 2.02 mmol) and DMSO (5 mL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (836.50 mg, 6.05 mmol) and p-fluoronitrobenzene (313.14 mg, 2.22 mmol), heated up to 65° C. to react for 10 hours and monitored by LC-MS, extracted three times with water and ethyl acetate after the reaction, the organic phase was combined, washed with saturated brine, dried with anhydrous Na₂SO₄, concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the product 27-2 (633 mg, 1.98 mmol, 98.24% yield), LCMS (ESI⁺) m/z: 320.4 [M+H]⁺.

Step 2: Synthesis of Compound 27-3

The substrate 27-2 (633 mg, 1.98 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (60 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the product 27-3 (459 mg, crude), LCMS (ESI⁺) m/z: 290.4 [M+H]⁺.

Step 3: Synthesis of Compound 27-4

The substrate 27-3 (150 mg, 518.36 μmol) and THF (5 mL) were added into a single-necked flask, stirred to dissolve, then added with LiAlH₄ (19.67 mg, 518.36 mol), heated up to 65° C. to react for 4 hours and monitored by LC-MS, quenched by adding 10% aqueous sodium hydroxide solution after the reaction under an ice bath, filtered, and the filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the product 27-4 (36.59 mg, 180.00 μmol, 34.73% yield), LCMS (ESI⁺) m/z: 204.3 [M+H]⁺.

Step 4: Synthesis of Compound 27

The substrate IM-1 (53.61 mg, 0.15 mmol) and tetrahydrofuran (0.5 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (38.83 mg, 225.00 μmol) to react for 1 hour at room temperature and monitored by LC-MS, added with DIPEA (96.93 mg, 750.00 mol, 130.63 μL) after the reaction and stirred for 10 min, then added with 27-4 (36.59 mg, 180.00 mol) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 27 (18.9 mg, 33.81 μmol, 22.54% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.60 (d, J=7.7 Hz, 3H), 6.72 (d, J=8.5 Hz, 2H), 5.70-5.61 (m, 1H), 5.32 (s, 1H), 4.99 (dd, J=10.3, 1.6 Hz, 1H), 4.83 (dd, J=17.1, 1.7 Hz, 1H), 4.68 (d, J=6.1 Hz, 2H), 3.64 (s, 2H), 3.46 (d, J=10.9 Hz, 2H), 2.51 (s, 3H), 2.05-1.98 (m, 2H), 1.57 (s, 1H), 1.46 (s, 6H). LCMS (E+) m/z: 513.2 [M+H]⁺, HPLC Method B R_T=11.32 min, purity: 92.6%.

Example 28: Synthesis of Compound 28

Step 1: Synthesis of Compound 28-2

The substrate 28-1 (332 mg, 1.56 mmol) and DMSO (5 mL) were added to a dry single-necked flask, stirred to dissolve, then added with K₂CO₃ (648.42 mg, 4.69 mmol) and p-fluoronitrobenzene (242.73 mg, 1.72 mmol), heated up to 80° C. to react for 12 hours and monitored by LC-MS, extracted three times with water and ethyl acetate after the reaction, the organic phase was combined, washed with saturated brine, dried with anhydrous Na₂SO₄, concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the product 28-2 (512 mg, 1.54 mmol, 98.20% yield), LCMS (ESI⁺) m/z: 334.4 [M+H]⁺.

Step 2: Synthesis of Compound 28-3

The substrate 28-2 (640 mg, 1.92 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred well, added with Pd/C (60 mg), H₂ displaced five times, stirred at room temperature to react and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the product 28-3 (570 mg, crude), LCMS (ESI⁺) m/z: 304.2 [M+H]⁺.

Step 3: Synthesis of Compound 28-4

The substrate 28-3 (200 mg, 659.20 μmol) and THF (5 mL) were added into a single-necked flask, stirred to dissolve, then added with LiAlH₄ (125.08 mg, 3.30 mmol), heated up to 65° C. to react for 4 hours and monitored by LC-MS, quenched by adding 10% aqueous sodium hydroxide solution after the reaction under an ice bath, filtered, and the filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to give the product 28-4 (89 mg, 409.55 μmol, 62.13% yield), LCMS (ESI⁺) m/z: 218.2 [M+H]⁺.

Step 4: Synthesis of Compound 28

The substrate IM-1 (53.61 mg, 0.15 mmol) and tetrahydrofuran (1 mL) were added into a dry single-necked flask, stirred to dissolve, then added with m-CPBA (38.83 mg, 225.00 μmol) to react at room temperature for 1 hour and monitored by LC-MS, added with DIPEA (96.93 mg, 750.00 mol, 130.63 μL) after the reaction and stirred for 10 min, then added with 28-4 (32.60 mg, 150.00 mol) and monitored by LC-MS, concentrated under reduced pressure after the reaction, and the residue was purified by medium pressure liquid chromatography (Alkali process) to give the compound 28 (26.8 mg, 48.90 μmol, 32.60% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.81 (s, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.65-7.43 (m, 3H), 6.79 (d, J=8.6 Hz, 2H), 5.66 (ddt, J=16.4, 10.2, 6.0 Hz, 1H), 5.32 (s, 1H), 4.99 (dd, J=10.3, 1.4 Hz, 1H), 4.82 (dd, J=17.1, 1.5 Hz, 1H), 4.68 (d, J=5.9 Hz, 2H), 3.35 (d, J=10.5 Hz, 2H), 3.24 (s, 2H), 2.81 (d, J=10.3 Hz, 2H), 2.25 (s, 3H), 2.00-1.94 (m, 2H), 1.66 (d, J=7.6 Hz, 2H), 1.46 (s, 6H). LCMS (E+) m/z: 527.4 [M+H]⁺, HPLC Method B R_T=10.46 min, purity: 96.1%.

Example 29: Synthesis of Compound 29

Step 1: Synthesis of Compound 29-2

The substrate 29-1 (233 mg, 891.63 μmol) and methanol (lOmL) were added to a dry single-necked flask, stirred to dissolve, added with Pd/C (10 mg), H₂ displaced five times, stirred at room temperature to react for 2 hours and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the compound 29-2 (200 mg, 866 μmol), LCMS (ESI) m/z: 232.2[M+H]⁺.

Step 2: Synthesis of Compound 29

The substrate IM-1 (38.63 mg, 108.07 μmol) was added to a dry single-necked vial, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (30 mg, 162.10 μmol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (20.95 mg, 162.10 μmol) and 29-2 (25 mg, 0.18 mmol) were added to the reaction solution to react overnight at room temperature and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 29 (18 mg, 33.29 μmol). LCMS(ESI) m/z: 541.4 [M+H]⁺, HPLC Method B R_T=5.14 min, purity >90.0%. ¹H NMR (600 MHz, Methanol-d₄) δ 8.76 (s, 1H), 7.95-7.93 (m, 1H), 7.76-7.74 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.44 (s, 2H), 6.70-6.62 (m, 2H), 5.72-5.68 (m, 1H), 5.03 (d, J=10.2 Hz, 1H), 4.95-4.88 (m, 2H), 4.80 (d, J=6.0 Hz, 2H), 4.00 (d, J=8.6 Hz, 1H), 3.94-3.89 (m, 1H), 3.53-3.45 (m, 4H), 3.35 (s, 3H), 3.22-3.18 (m, 1H), 2.41-2.33 (m, 2H), 2.16-2.12 (m, 2H), 1.98-1.95 (m, 1H), 1.57 (s, 6H).

Example 30: Synthesis of Compound 30

Step 1: Synthesis of Compound 30-2

The substrate 30-1 (200 mg, 912.24 μmol) was added to a dry single-necked flask and dissolved in tetrahydrofuran (3 mL), then added with triethylamine (461 mg, 4.56 mmol) and trifluoroethyl trifluoromethanesulfonateto (317 mg, 1.37 mmol), heated from room temperature to 80° C., stirred overnight and monitored by LC-MS, concentrated by distillation under reduced pressure after the reaction to give the compound 30-2 (235 mg, 780 μmol), LCMS (ESI) m/z: 302.1[M+H]⁺.

Step 2: Synthesis of Compound 30-3

The substrate 30-2 (235 mg, 780 μmol) and methanol (3 mL) were added to a dry single-necked flask, stirred to dissolve, added with Pd/C (25 mg), H₂ displaced five times to react for 2 hours at room temperature and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the compound 30-3 (183 mg, 675 μmol), LCMS (ESI) m/z: 272.2[M+H]⁺.

Step 3: Synthesis of Compound 30

The substrate IM-1 (27 mg, 75.54 μmol) was added to a dry single-necked vial, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (23 mg, 113.31 mol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (48.81 mg, 377.1 mol) and 30-3 (30.7 mg, 113.31 μmol) were added to the reaction solution to react overnight at room temperature and monitored by LC-MS, then the reaction solution was cooled to room temperature after reaction, concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 30 (10.7 mg, 18.43 μmol). LCMS(ESI) m/z: 581.3 [M+H]⁺, HPLC Method B Rt=8.07 min, purity >89.7%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.80 (s, 1H), 7.99-7.96 (m, 1H), 7.75 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.47 (s, 2H), 6.62 (d, J=8.4 Hz, 2H), 6.19 (d, J=23.4 Hz, 1H), 5.69-5.63 (m, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.67 (s, 2H), 3.89 (s, 2H), 3.51 (s, 2H), 3.29 (s, 3H), 2.97 (s, 3H), 2.22 (s, 2H), 2.00 (d, J=7.8 Hz, 2H), 1.76 (d, J=14.4 Hz, 1H), 1.46 (s, 6H). D₂O: ¹H NMR (600 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.01-7.98 (m, 1H), 7.74 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.49 (s, 2H), 6.64 (d, J=8.4 Hz, 2H), 5.69-5.63 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.68 (s, 2H), 3.90-3.88 (m, 2H), 3.43-3.42 (m, 4H), 3.14-3.12 (m, 1H), 2.97 (s, 3H), 2.23-2.20 (m, 2H), 2.03 (s, 2H), 1.82 (s, 1H), 1.47 (s, 6H).

Example 31: Synthesis of Compound 31

Step 1: Synthesis of Compound 31-2

The substrate 31-1 (2.0 g, 7.80 mmol) and methanol (10 mL) were added to a dry single-necked flask, stirred to dissolve, added with Pd/C (200 mg), H₂ displaced five times to react for 2 hours at room temperature and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the compound 31-2 (1.6 g, 7.07 mmol), LCMS (ESI) m/z: 232.2[M+H]⁺.

Step 2: Synthesis of Compound 31

The substrate IM-1 (100 mg, 279.78 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (120 mg, 559.55 μmol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (180.79 mg, 1.40 mmol) and 31-2 (126.61 mg, 559.55 μmol) were added to the reaction solution to react overnight at room temperature and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 31 (40 mg, 74.68 μmol). LCMS (ESI) m/z: 536.2 [M+H]⁺, HPLC method B: R_T=8.58 min, purity: >96.1%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.33 (s, 1H), 8.89 (s, 1H), 8.04-8.02 (m, 1H), 7.80-7.71 (m, 3H), 7.61 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.81 (d, J=7.4 Hz, 1H), 6.73-6.71 (m, 1H), 6.70-6.67 (m, 2H), 5.68-5.64 (m, 1H), 5.32 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.69 (d, J=6.0 Hz, 2H), 4.27-4.26 (m, 2H), 3.68-3.66 (m, 2H), 1.46 (s, 7H).

Example 32: Synthesis of Compound 32

Step 1: Synthesis of Compound 32-1

The compound 4-1 (800 mg, 6.39 mmol) was dissolved in ethanol (10 mL) in a dry single-necked flask, then added sequentially with potassium hydroxide (717 mg, 12.78 mmol), and p-nitrobenzaldehyde (1.16 g, 7.67 mmol). The reaction mixture was stirred overnight at room temperature and monitored by LC-MS, then concentrated under reduced pressure. The residue was purified by MPLC to give the compound 32-1 (863 mg, 3.34 mmol). LCMS (ESI) m/z: 259.1[M+H]⁺.

Step 2: Synthesis of Compound 32-2

Trimethylsulfoxonium iodide (2.94 g, 13.37 mmol), sodium hydroxide (1.07 g, 26.73 mmol) was dissolved in tetrahydrofuran (20 mL) in a single-necked flask, N₂ displaced to react for 1 hour at room temperature, then added with 32-1 (863 mg, 3.34 mmol), N₂ displaced again, stirred at 65° C. for 1 hour, the reaction was monitored by LC-MS, concentrated under reduced pressure after the reaction to remove solvents, then extracted three times with ethyl acetate and water, the organic phase was dried with anhydrous Na₂SO₄, filtered, the residue was purified by column chromatography to give the compound 32-2 (493 mg, 1.81 mmo). LCMS (ESI) m/z: 273.1[M+H]⁺.

Step 3: Synthesis of Compound 32-3

The substrate 32-2 (493 mg, 1.81 mmol) and methanol (5 mL) were added to a dry single-necked flask, stirred to dissolve, added with Pd/C (50 mg), H₂ displaced five times, stirred at room temperature to react for 2 hours and monitored by LC-MS. After the reaction, Pd/C was removed with diatomaceous earth, washed with methanol, the organic phase was concentrated under reduced pressure to give the compound 32-3 (395 mg, 1.63 mmol), LCMS (ESI) m/z: 243.2[M+H]⁺.

Step 4: Synthesis of Compound 32

The substrate IM-1 (36 mg, 100.72 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (26 mg, 151 μmol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (65 mg, 504 mol) and 32-3 (48.8 mg, 201 μmol) were added to the reaction solution to react overnight at room temperature and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 32 (7.2 mg, 13.05 μmol). LCMS (ESI) m/z: 552.3[M+H]⁺, HPLC method A: R_T=9.90 min, purity: >99.1%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.88 (s, 1H), 8.04-8.02 (m 1H), 7.75 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 3H), 7.26 (d, J=8.4 Hz, 2H), 5.67-5.65 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.69 (d, J=6.0 Hz, 2H), 2.96-2.93 (m, 2H), 2.77-2.70 (m, 1H), 2.49 (d, J=12.6 Hz, 1H), 2.45-2.43 (m, 1H), 2.21-2.20 (m, 1H), 2.01-1.97 (m, 1H), 1.92-1.89 (m, 2H), 1.87-1.79 (m, J=2.6 Hz, 1H), 1.67-1.62 (m, 1H), 1.59 (d, J=9.6 Hz, 1H), 1.46 (s, 6H).

Example 33: Synthesis of Compound 33

Step 1: Synthesis of Compound 33-2

The compound 23-5 (100 mg, 404.38 μmol) was dissolved in tetrahydrofuran (5 ml) in a dry single-necked flask, then added sequentially with triethylamine (409.19 mg, 4.04 mmol) and 33-1 (140.79 mg, 606.57 μmol). The reaction mixture was stirred for 3 hours at 80° C., then concentrated under reduced pressure after reaction. The residue was purified by MPLC to give the compound 33-2 (70 mg, 212.56 μmol). LCMS (ESI) m/z: 330.1 [M+H]⁺.

Step 2: Synthesis of Compound 33-3

The compound 33-2 (80 mg, 0.24 mmol) was dissolved in methanol (3 mL) in a round-bottomed flask, added with Pd/C (10 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. The reaction solution was filtered with diatomaceous earth and washed with methanol for 2 times. The filterate was concentrated under reduced pressure to give the compound 33-3 (20 mg, 0.17 mmol). LCMS (ESI) m/z: 300.2 [M+H]⁺.

Step 3: Synthesis of Compound 33

The substrate IM-6 (48.55 mg, 130.00 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (84.01 mg, 650.00 μmol) and 33-3 (44 mg, 146.99 μmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure to remove the solvents after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 33 (20 mg, 31.77 μmol). LCMS (ESI) m/z: 609.2 [M+H]⁺, HPLC method A: R_T=5.8 min, purity: 96.7%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.80 (s, 1H), 8.01-8.00 (m, 1H), 7.77 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.54-7.40 (m, 2H), 6.75 (d, J=8.4 Hz, 2H), 5.67-5.63 (m, 1H), 5.37 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=16.8 Hz, 1H), 4.69 (s, 2H), 3.47 (s, 2H), 3.08 (s, 4H), 2.95 (s, 2H), 2.70 (s, 2H), 2.07 (s, 2H), 1.66-1.59 (m, 2H), 1.47 (s, 6H). D₂O: ¹H NMR (600 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.02-8.01 (m, 1H), 7.75 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.54 (s, 2H), 6.75 (d, J=7.8 Hz, 2H), 5.68-5.64 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.84 (d, J=16.8 Hz, 1H), 4.70 (s, 2H), 3.52 (d, J=10.8 Hz, 2H), 3.09-3.04 (m, 4H), 2.94 (d, J=10.2 Hz, 2H), 2.69 (d, J=10.2 Hz, 2H), 2.08 (s, 2H), 1.67-1.58 (m, 2H), 1.48 (s, 6H).

Example 34: Synthesis of Compound 34

Step 1: Synthesis of Compound 34-1

The substrate 23-5 (100 mg, 404.38 μmol) was dissolved in N,N-dimethylformamide (3 mL) in a dry single-necked flask, then added with 2-bromoethyl methyl ether (84 mg, 606 μmol), K₂CO₃ (111.77 mg, 808.76 μmol) and KI (13.43 mg, 80.88 μmol). The reaction was carried out at 85° C. for 3 hours and monitored by LC-MS, then the reaction solution was cooled to room temperature after reaction, extracted three times with water and ethyl acetate, the organic phase was dried with anhydrous Na₂SO₄, filtered, the residue was purified by column chromatography to give the compound 34-1 (65 mg, 212.86 μmol). LCMS (ESI) m/z: 306.2 [M+H]⁺.

Step 2: Synthesis of Compound 34-2

The substrate 34-1 (80 mg, 261.98 μmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (10 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reaction solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 34-2 (29 mg, 0.10 mmol). LCMS (ESI) m/z: 276.2 [M+H]⁺.

Step 3: Synthesis of Compound 34

The substrate IM-6 (37 mg, 99.08 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then added with N,N-diisopropylethylamine (64.03 mg, 495.41 μmol) and 34-2 (28.65 mg, 104.04 μmol) to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure to remove solvents after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 34 (10 mg, 17.10 μmol). LCMS (ESI) m/z: 585.3 [M+H]⁺, HPLC method A: R_T=5.4 min, purity: 96.4%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.61-7.56 (m, 3H), 6.75 (s, 2H), 5.69-5.63 (m, 1H), 5.32 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4, 1H), 4.68 (d, J=4.2 Hz, 2H), 3.54 (d, J=10.2 Hz, 2H), 3.40 (s, 4H), 3.18 (s, 3H), 3.06-2.98 (m, 4H), 2.44-2.29 (m, 2H), 2.13 (s, 2H), 1.68-1.57 (m, 2H), 1.46 (s, 6H). D₂O: ¹H NMR (600 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.03 (s, 1H), 7.76-7.75 (m, 1H), 7.61 (d, J=7.8 Hz, 1H) 7.56-7.50 (m, 2H), 6.77 (s, 2H), 5.69-5.63 (m, 1H), 5.01 (d, J=10.2 Hz, 1H), 4.83 (d, J=16.8 Hz, 1H), 4.68 (d, J=4.8 Hz, 2H), 3.63 (s, 2H), 3.55 (d, J=10.8 Hz, 2H), 3.41 (s, 2H), 3.18 (s, 3H), 3.05-2.96 (m, 4H), 2.45-2.36 (m, 2H), 2.14 (s, 2H), 1.66-1.63 (m, 2H), 1.47 (s, 6H).

Example 35: Synthesis of Compound 35

Step 1: Synthesis of Compound 35-2

The compound 35-1 (2.59 g, 11 mmol) was added under N₂ protection to a 100 mL dry round-bottomed flask, then added with tetrahydrofuran (25 mL) to dissolve, lowered to −78° C. and slowly added dropwise with n-LiBu (5.5 mL, 2 M in THF, 11 mmol) into the reaction system, stirred for 30 min at −78° C. then added with N-methyl-4-piperidone (1.24 g, 11.00 mmol), slowly heated to room temperature and stirred for 1 hour, quenched with saturated NH₄Cl solution and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure, and the residue was purified by column chromatography to give the compound 35-2 (2.63 g, 9.73 mmol). LCMS (ESI) m/z: 270.1[M+H]⁺.

Step 2: Synthesis of Compound 35-3

The substrate 35-2 (675.4 mg, 2.5 mmol), ammonia (1.75 g, 50.00 mmol), Cu₂O (17.9 mg, 0.125 mmol), NaI (242.66 mg, 1.62 mmol), K₂CO₃ (69.10 mg, 0.5 mmol) and N,N′-dimethylethylenediamine (22 mg, 0.25 mmol) were added to a dry microwave tube under N₂ protection, then added with ethylene glycol (5 mL), heated up 110° C. to react for 12 hours under N₂ atmosphere and monitored by LC-MS. The reaction system was cooled to room temperature after the reaction, filtered, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, then concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 35-3 (346 mg, 1.68 mmol). LCMS (ESI) m/z: 207.2 [M+H]⁺.

Step 3: Synthesis of Compound 35

The substrate IM-1 (71.5 mg, 0.2 mmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (51.8 mg, 0.3 mmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (129.2 mg, 1.00 mmol) and 35-3 (61.9 mg, 0.3 mmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 35 (16 mg, 31.03 μmol). ¹H NMR (600 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.88 (s, 1H), 8.06-8.04 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.65 (d, J=26.4 Hz, 3H), 7.43 (d, J=8.4 Hz, 2H), 5.67-5.64 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.73 (s, 1H), 4.68 (d, J=6.0 Hz, 2H), 2.58 (d, J=10.8 Hz, 2H), 2.40-2.38 (m, 2H), 2.23 (s, 3H), 2.01-1.91 (m, 2H), 1.61-1.55 (m, 2H), 1.46 (s, 6H). LCMS(ESI) m/z: 516.3 [M+H]⁺, HPLC R_T=4.68 min, purity >92.7%.

Example 36: Synthesis of Compound 36

Step 1: Synthesis of Compound 36-2

The compound 36-1 (5 g, 44.22 mmol) was added under N₂ protection to a dry single-necked flask, dissolved in dichloromethane (50 mL), then added sequentially with triethylamine (8.95 g, 88.44 mmol, 12.33 mL), 4-dimethylaminopyridine (540.22 mg, 4.42 mmol) and di-tert-butyl dicarbonate (10.62 g, 48.64 mmol). The reaction mixture was stirred for 2 hours at room temperature and monitored by LC-MS, then diluted with water after the reaction and extracted three times with dichloromethane. The organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to give the compound 36-2 (4.62 g, 21.67 mmol). LCMS (ESI) m/z: 214.1[M+H]⁺.

Step 2: Synthesis of Compound 36-3

The substrate 36-2 (4.62 g, 21.67 mmol) was added to a 50 mL round-bottomed flask, dissolved in ethanol (3 mL), added with a catalytic amount of Pd/C (400 mg), stirred for 6 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with ethanol, the filterate was concentrated under reduced pressure to give the compound 36-3 (3.85 g, 21.01 mmol). LCMS (ESI) m/z: 184.1 [M+H]⁺.

Step 3: Synthesis of Compound 36-4

The substrate 36-3 (493 mg, 1.81 mmol) was added to a dry single-necked flask and dissolved in methanol (40 mL), added with formaldehyde (1.26 g, 42.03 mmol) and acetic acid (2 mL), stirred for 30 min at room temperature, added with sodium cyanoborohydride (3.30 g, 52.54 mmol), heated up to 50° C. to react for 12 hours, then diluted with water after the reaction, added with saturated NaHCO₃ to make it alkaline, extracted three times with dichloromethane. The organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to give the compound 36-4 (4.01 g, 18.98 mmol). LCMS (ESI) m/z: 212.1 [M+H]⁺.

Step 4: Synthesis of Compound 36-5

The substrate 36-4 (4.01 g, 18.98 mmol) was added to a dry single-necked flask and dissolved in dichloromethane (40 ml), added with trifluoroacetic acid (21.64 g, 189.81 mmol, 14.53 mL) to react for 30 min at room temperature and monitored by LC-MS, the solvent was removed by distillation under reduced pressure to give the compound 36-5 (1.86 g, 16.73 mmol). LCMS (ESI) m/z: 112.1 [M+H]⁺.

Step 5: Synthesis of Compound 36-6

The substrate 36-5 (1.86 g, 16.73 mmol) was added in a dry single-necked flask and dissolved in dimethyl sulfoxide (15 ml), added sequentially with p-fluoronitrobenzene (2.36 g, 16.73 mmol) and K₂CO₃ (5.78 g, 41.84 mmol). The reaction mixture was stirred overnight at 100° C. and monitored by LC-MS, then diluted with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, then concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 36-6 (3.56 g, 15.33 mmol). LCMS (ESI) m/z: 233.1 [M+H]⁺.

Step 6: Synthesis of Compound 36-7

The substrate 36-6 (3.56 g, 15.33 mmol) was added to a dry single-necked flask, dissolved in ethanol (35 mL), added with a catalytic amount of Pd/C (350 mg), stirred for 3 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with ethanol, the filterate was concentrated under reduced pressure to give the compound 36-7 (2.95 g, 14.59 mmol). LCMS (ESI) m/z: 203.1 [M+H]⁺.

Step 7: Synthesis of Compound 36

The substrate IM-I (45.51 mg, 225.00 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (38.83 mg, 225.00 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (96.93 mg, 750.00 μmol) and 36-7 (53.61 mg, 0.15 mmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 36 (9 mg, 17.59 μmol). LCMS(ESI) m/z: 512.2 [M+H]⁺, HPLC Method B R_T=7.26 min, purity >98.0%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.91 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.45 (s, 1H), 5.71-5.66 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.84 (d, J=17.4 Hz, 1H), 4.70 (d, J=6.0 Hz, 2H), 2.70 (s, 6H), 1.47 (s, 6H).

Example 37: Synthesis of Compound 37

Step 1: Synthesis of Compound 37-1

The substrate 23-5 (150 mg, 606.57 μmol) was added to a dry single-necked flask, dissolved in N,N-Dimethylformamide (3 mL), then added with 1,2-Fluoroethane bromide (84 mg, 661.65 μmol), K₂CO₃ (165 mg, 1.19 mmol) and KI (20 mg, 120.5 μmol) to react for 3 hours at 90° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, added with water, filtered and washed with methanol. The organic phase was concentrated under reduced pressure to give the compound 37-1 (80 mg, 272.7 μmol). LCMS (ESI) m/z: 394.2 [M+H]⁺.

Step 2: Synthesis of Compound 37-2

The substrate 37-1 (80 mg, 272.7 μmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (10 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 37-2 (50 mg, 0.19 mmol). LCMS (ESI) m/z: 264.2 [M+H]⁺.

Step 3: Synthesis of Compound 37

The substrate IM-6 (42 mg, 112.47 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then added with N,N-diisopropylethylamine (72.68 mg, 562.36 μmol) and 37-2 (30 mg, 113.92 μmol) to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure to remove solvents after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 37 (25 mg, 42.65 μmol). LCMS (ESI) m/z: 585.3 [M+H]⁺, HPLC method A: R_T=5.4 min, purity: 96.4%. ¹H NMR (600 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.82 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.36 (s, 2H), 7.26 (d, J=7.2 Hz, 1H), 6.76 (s, 2H), 5.67-5.60 (m, 1H), 4.97 (d, J=10.2 Hz, 1H), 4.87 (d, J=17.4 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H), 4.55-4.74 (m, 2H), 3.94 (brs, 1H), 3.57-3.55 (m, 2H), 3.10-2.93 (m, 4H), 2.70-2.51 (m, 4H), 2.12 (s, 2H), 1.67 (s, 2H), 1.51 (s, 6H), 1.25 (brs, 1H).

Example 38: Synthesis of Compound 38

Step 1: Synthesis of Compound 38-1

The substrate IM-4 (500 mg, 1.57 mmol) was added to a dry single-necked flask, dissolved in dichoromethane (3 ml), then added with trifluoroacetic acid (1 ml) to react for 1 hour at room temperature and monitored by LC-MS, the solvent was removed after the reaction by distillation under reduced pressure to give the compound 38-1 (330 mg, 1.51 mmol). LCMS (ESI) m/z: 220.1 [M+H]⁺.

Step 2: Synthesis of Compound 38-2

The substrate 38-1 (100 mg, 456.12 μmol) was added to a dry single-necked flask, dissolved in N,N-dimethylformamide (2 mL), then added with 2-Bromoethanol (57.00 mg, 456.12 mmol), K₂CO₃ (94.55 mg, 684.18 μmol) and KI (15.14 mg, 91.22 μmol) to react for 2 hours at 90° C. and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, added with water, filtered and washed with methanol. The organic phase was concentrated under reduced pressure to give the compound 38-2 (93 mg, 353 mmol). LCMS (ESI) m/z: 264.1 [M+H]⁺.

Step 3: Synthesis of Compound 38-3

The substrate 38-2 (93 mg, 353.22 μmol) was added under N₂ protection to a dry single-necked flask, dissolved in tetrahydrofuran (2.5 mL), then added with triethylamine (142.97 mg, 1.41 mmol), lowered to 0° C. and added with acetyl chloride (41.59 mg, 529.83 μmol), then slowly heated to room temperature and stirred for 1 hour, monitored by LC-MS, then concentrated under reduced pressure after the reaction to give the compound 38-3 (96 mg, 314.8 μmol). LCMS (ESI) m/z: 292.1 [M+H]⁺.

Step 4: Synthesis of Compound 38-4

The substrate 38-3 (277 mg, 907.22 μmol) was added to a mL round-bottomed flask, dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (30 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 38-4 (177 mg, 642 μmol). LCMS (ESI) m/z: 262.2 [M+H]⁺.

Step 5: Synthesis of Compound 38-5

The substrate IM-1 (40 mg, 111.91 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (38.62 mg, 223.82 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (72.32 mg, 559.55 μmol) and 38-4 (30.81 mg, 111.91 μmol) were added to the reaction solution to react for 4 h at room temperature and monitored by LC-MS, then concentrated under reduced pressure to give the crude product 38-5 (300 mg, crude). LCMS (ESI) m/z: 571.3 [M+H]⁺.

Step 6: Synthesis of Compound 38

The substrate 38-5 (300 mg, crude) was added to a dry single-necked flask, and added with methanol (3 mL) to dissolve, then added with NaOH (41.05 mg, 1.03 mmol) and water (0.2 mL) to react for 30 min at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction, diluted with water and extracted three times with ethyl acetate. The crude product was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 38 (10.36 mg, 19.09 μmol). LCMS (ESI) m/z: 543.2 [M+H]⁺. HPLC method A: R_T=4.82 min, purity: 100.0%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.79 (s, 1H), 8.02-7.99 (m, 1H), 7.74 (s, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.49 (s, 2H), 6.55 (d, J=7.8 Hz, 2H), 5.67-5.63 (m, 1H), 5.32 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.82 (d, J=17.4 Hz, 1H), 4.69-4.67 (m, 2H), 4.37-4.35 (m, 1H), 4.26 (s, 1H), 3.54 (s, 1H), 3.38-3.36 (m, 3H), 3.14 (d, J=9.0 Hz, 1H), 2.87 (d, J=9.0 Hz, 1H), 2.48-2.46 (m, 2H), 1.83-1.77 (m, 2H), 1.46 (s, 6H).

Example 39: Synthesis of Compound 39

Step 1: Synthesis of Compound 39

The substrate IM-3 (30.49 mg, 150.00 μmol) was added to a dry single-necked flask, added with tetrahydrofuran (1 mL) to dissolve, added with m-Chloroperoxybenzoic acid (25.88 mg, 150.00 mol) to react for 30 min at room temperature, then added with N,N-diisopropylethylamine (19.39 mg, 150.00 μmol) and 27-4 (30.49 mg, 150.00 μmol) to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 39 (26 mg, 38.83 μmol). LCMS(ESI) m/z: 546.2[M+H]⁺, HPLC Method B R_T=5.93 min, purity >81.5%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.78 (s, 1H), 7.78 (s, 1H), 7.61 (s, 2H), 7.32 (d, J=7.8 Hz, 1H), 6.71 (d, J=7.8 Hz, 2H), 6.59 (d, J=8.4 Hz, 1H), 5.68-5.60 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.90 (d, J=17.4 Hz, 1H), 4.75 (s, 2H), 3.60 (s, 2H), 3.44 (d, J=11.4 Hz, 2H), 3.38 (s, 6H), 3.35 (d, J=8.4 Hz, 2H), 2.44 (s, 1H), 2.00 (s, 3H), 1.55-1.53 (m, 1H).

Example 40: Synthesis of Compound 40

Step 1: Synthesis of Compound 40-2

The substrate 40-1 (0.4 g, 2 mmol) was added to a dry single-necked flask, dissolved in dimethyl sulfoxide (15 mL), then added sequentially with p-Fluoronitrobenzene (0.28 g, 2 mmol) and K₂CO₃ (1.11 g, 4 mmol). The reaction mixture was stirred overnight at 100° C. and monitored by LC-MS, then diluted with water after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, then concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 40-2 (0.63 g, 2.56 mmol). LCMS (ESI) m/z: 248.1[M+H]⁺.

Step 2: Synthesis of Compound 40-3

The substrate 40-2 (71.4 mg, 300 μmol) was added under N₂ protection to a dry single-necked flask, dissolved in tetrahydrofuran (2.5 mL), then added with triethylamine (121.4 mg, 1.2 mmol), lowered to 0° C. and added with acetic anhydride (61.2 mg, 600 μmol), then slowly heated to room temperature and stirred for 12 hours, monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 40-3 (25.3 mg, 87.4 μmol). LCMS (ESI) m/z: 290.2 [M+H]⁺.

Step 3: Synthesis of Compound 40-4

The substrate 40-3 (173 mg, 598 μmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (18 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 40-4 (122 mg, 470 μmol). LCMS (ESI) m/z: 260.2 [M+H]⁺.

Step 4: Synthesis of Compound 40

The substrate IM-1 (35.7 mg, 100 μmol) was added to a dry single-necked flask, added with tetrahydrofuran (1 mL) to dissolve, added with m-Chloroperoxybenzoic acid (25.85 mg, 150 μmol) to react for 30 min at room temperature, then added with N,N-diisopropylethylamine (64.54 mg, 500 μmol) and 40-4 (51.81 mg, 0.2 mmol), heated up to 60° C. to react for 4 hours and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 40 (18 mg, 31.65 μmol). LCMS(ESI) m/z: 569.3[M+H]⁺, HPLC Method B Rt=6.28 min, purity >63.4%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.82 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.67-7.47 (m, 3H), 6.93 (d, J=8.4 Hz, 2H), 5.68-5.64 (m, 1H), 5.32 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.82 (d, J=17.4 Hz, 1H), 4.68 (s, 2H), 4.37-4.35 (m, 1H), 4.13-4.06 (m, 1H), 3.69 (s, 2H), 3.62 (d, J=7.8 Hz, 1H), 2.66-2.55 (m, 3H), 2.39 (s, 1H), 1.79 (d, J=13.2 Hz, 1H), 1.59 (d, J=13.2 Hz, 1H), 1.46 (s, 6H), 1.45-1.42 (m, 1H), 1.36-1.24 (m, 2H).

Example 41: Synthesis of Compound 41

Step 1: Synthesis of Compound 41-1

The substrate 38-1 (140 mg, 638.57 μmol) was added to a dry single-necked flask, dissolved in N,N-Dimethylformamide (3 mL), then added with 2-Iodopropane (131 mg, 770.63 μmol) and K₂CO₃ (124 mg, 897.25 μmol) to react for 3 hours at 90° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, added with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 41-1 (80 mg, 306.14 μmol). LCMS (ESI) m/z: 262.2 [M+H]⁺.

Step 2: Synthesis of Compound 41-2

The substrate 41-1 (80 mg, 306.14 μmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (20 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 41-2 (60 mg, crude). LCMS (ESI) m/z: 232.2 [M+H]⁺.

Step 3: Synthesis of Compound 41

The substrate IM-6 (45 mg, 120.50 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then added with N,N-diisopropylethylamine (77.87 mg, 602.52 μmol) and 41-2 (30 mg, 129.68 μmol) to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure to remove solvents after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 41 (20 mg, 36.99 μmol). LCMS (ESI) m/z: 541.3 [M+H]⁺, HPLC method A: R_T=5.1 min, purity: 95.3%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.79 (s, 1H), 8.02-7.99 (m, 1H), 7.78-7.75 (m, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.55-7.41 (m, 2H), 6.57 (d, J=7.8 Hz, 2H), 5.69-5.63 (m, 1H), 5.33 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.84 (d, J=16.8 Hz, 1H), 4.68 (s, 2H), 4.26 (s, 1H), 3.71 (s, 1H), 3.32-3.30 (m, 1H), 3.16 (d, J=9.0 Hz, 1H), 3.01 (d, J=7.8 Hz, 1H), 2.41-2.36 (m, 2H), 1.81 (s, 2H), 1.46 (s, 6H), 0.98-0.93 (m, 3H). D₂O: ¹H NMR (600 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.03-7.99 (m, 1H), 7.73 (s, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.49-7.37 (m, 2H), 6.59 (d, J=7.2 Hz, 2H), 5.69-5.63 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.83 (d, J=16.8 Hz, 1H), 4.68 (s, 2H), 4.26 (s, 1H), 3.78 (s, 1H), 3.32 (d, J=7.8 Hz, 1H), 3.19 (d, J=9.0 Hz, 1H), 3.03 (d, J=9.0 Hz, 1H), 2.42-2.35 (m, 2H), 1.84 (d, J=6.6 Hz, 2H), 1.47 (s, 6H), 1.0-0.94 (m, 6H).

Example 42: Synthesis of Compound 42

Step 1: Synthesis of Compound 42-1

The compound 27-2 (330 mg, 1.03 mmol) was added to a dry single-necked flask, dissolved in dichloromethane (5 ml), then added with trifluoroacetic acid (2 ml) to react for 30 min at room temperature and monitored by LC-MS. After the reaction, the solvents were removed by distillation under reduced pressure to give the compound 42-1 (280 mg, crude). LCMS (ESI) m/z: 220.1 [M+H]⁺.

Step 2: Synthesis of Compound 42-2

The substrate 42-1 (300 mg, 1.37 mmol) was added to a dry single-necked flask, dissolved in N,N-Dimethylformamide (3 mL), then added with 2-Iodopropane (348.92 mg, 2.05 mmol) and K₂CO₃ (567.35 mg, 4.11 mmol) to react for 12 hours at 70° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, added with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 42-2 (280 mg, 1.07 mmol). LCMS (ESI) m/z: 262.2 [M+H]⁺.

Step 3: Synthesis of Compound 42-3

The substrate 42-2 (0.8 g, 3.06 mmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (10 mL), added with a catalytic amount of Pd/C (20 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 42-3 (500 mg, 2.16 mmol). LCMS (ESI) m/z: 232.2 [M+H]⁺.

Step 4: Synthesis of Compound 42

The substrate IM-1 (42.89 mg, 120.00 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (31.07 mg, 180.00 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (77.54 mg, 600.00 μmol) and 42-3 (33.31 mg, 144.00 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 42 (30 mg, 51.77 μmol). LCMS(ESI) m/z: 541.4[M+H]⁺, HPLC Method B R_T=7.02 min, purity >93.3%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.76 (s, 1H), 7.60-7.47 (m, 3H), 6.69 (d, J=8.4 Hz, 2H), 5.68-5.64 (m, 1H), 5.31 (s, 1H), 5.00-4.98 (m, 1H), 4.86-4.79 (m, 1H), 4.68 (d, J=5.4 Hz, 2H), 3.71 (d, J=6.0 Hz, 2H), 3.42 (d, J=11.2 Hz, 2H), 3.24 (d, J=10.8 Hz, 2H), 2.50-2.43 (m, 1H), 2.37-2.35 (m, 1H), 1.50 (d, J=8.4 Hz, 1H), 1.46 (s, 6H), 0.88 (d, J=6.0 Hz, 6H).

Example 43: Synthesis of Compound 43

Step 1: Synthesis of Compound 43-1

The substrate 27-1 (0.33 g, 1.66 mmol) was added to a dry single-necked flask and dissolved in methanol (4 mL), added with formaldehyde (226.77 mg, 6.66 mmol) and acetic acid (0.5 mL), stirred for 10 min at room temperature, then added with Sodium cyanoborohydride (1.41 g, 6.66 mmol) to react for 12 hours at room temperature, diluted with water after the reaction, extracted three times with dichloromethane, and the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 43-1 (300 mg, 1.41 mmol). LCMS (ESI) m/z: 213.2[M+H]⁺.

Step 2: Synthesis of Compound 43-2

The compound 43-1 (300 mg, 1.41 mmol) was added to a dry single-necked flask and dissolved in dichloromethane (3 ml), added with trifluoroacetic acid (1 ml) to react for 30 min at room temperature and monitored by LC-MS. The solvents were removed by distillation under reduced pressure after the disappearance of the raw materials to give the compound 43-2 (0.12 g, 1.07 mmol).

Step 3: Synthesis of Compound 43-3

The compound 43-2 (0.22 g, 1.96 mmol) was added in a dry single-necked flask and dissolved in dimethyl sulfoxide (5 ml), added sequentially with p-fluoronitrobenzene (304.41 mg, 2.16 mmol) and K₂CO₃ (1.36 g, 9.81 mmol). The reaction mixture was stirred for 3 hours at 100° C. and monitored by LC-MS, then diluted with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 43-3 (260 mg, 1.11 mmol). LCMS (ESI) m/z: 234.1[M+H]⁺.

Step 4: Synthesis of Compound 43-4

The compound 43-3 (0.3 g, 1.29 mmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 3 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 43-4 (200 mg, 983.85 μmol). LCMS (ESI) m/z: 204.2 [M+H]⁺.

Step 5: Synthesis of Compound 43

The substrate IM-1 (42.89 mg, 120.00 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (31.07 mg, 180.00 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (77.54 mg, 600.00 μmol) and 43-4 (29.27 mg, 144.00 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 43 (32 mg, 55.12 μmol). LCMS(ESI) m/z: 513.2[M+H]⁺, HPLC Method B R_T=6.47 min, purity >88.3%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.80 (s, 1H), 7.99-7.97 (m, 1H), 7.74 (s, 1H), 7.60-7.58 (m, 1H), 7.48 (s, 2H), 6.45 (d, J=8.4 Hz, 2H), 5.64-5.63 (m, 1H), 5.31 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.68 (d, J=5.6 Hz, 2H), 4.23 (d, J=5.6 Hz, 2H), 2.97 (d, J=10.8 Hz, 2H), 2.71 (d, J=11.4 Hz, 2H), 2.42-2.39 (m, 1H), 2.08 (s, 3H), 1.96 (d, J=7.2 Hz, 1H), 1.46 (s, 6H).

Example 44: Synthesis of Compound 44

Step 1: Synthesis of Compound 44-1

The substrate 38-1 (300 mg, 1.37 mmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (2 mL), then added with 1,2-Fluoroethane bromide (173.72 mg, 1.37 mmol), K₂CO₃ (378 mg, 2.74 mmol) and KI (45.43 mg, 273.67 μmol) to react overnight at 90° C. and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, added with water, filtered, washed by methanol. The organic phase was concentrated under reduced pressure to give the compound 44-1 (320 mg, 1.21 mmol). LCMS (ESI) m/z: 266.1 [M+H]⁺.

Step 2: Synthesis of Compound 44-2

The compound 44-1 (320 mg, 1.21 mmol) was added to a round-bottomed flask, dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (30 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 44-2 (200 mg, 849.98 μmol). LCMS (ESI) m/z: 236.2 [M+H]⁺.

Step 3: Synthesis of Compound 44

The substrate IM-1 (74 mg, 207.03 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (90 mg, 414.07 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (133.79 mg, 1.04 mmol, 180.30 μL) and 44-2 (97.43 mg, 414.07 μmol) were added to the reaction solution to react for 4 h at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 44 (11.5 mg, 21.12 μmol). LCMS (ESI) m/z: 545.3 [M+H]⁺, HPLC method A: R_T=4.95 min, purity: >84.1%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.79 (s, 1H), 8.02-8.00 (m, 1H), 7.74 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.50 (s, 2H), 6.57 (d, J=8.4 Hz, 2H), 5.68-5.65 (m, 1H), 5.31 (s, 1H), 4.99 (d, J=10.2, 1H), 4.82 (d, J=17.4 Hz, 1H), 4.67 (s, 2H), 4.49-4.42 (m, 1H), 4.38-4.36 (m, 1H), 4.29 (s, 1H), 3.57 (s, 1H), 3.35 (d, J=9.0 Hz, 1H), 3.12 (d, J=9.0 Hz, 1H), 2.90 (d, J=9.6 Hz, 1H), 2.83-2.64 (m, 2H), 2.53 (d, J=9.6 Hz, 1H), 1.84 (d, J=9.6 Hz, 1H), 1.79 (d, J=9.0 Hz, 1H).

Example 45: Synthesis of Compound 45

Step 1: Synthesis of Compound 45-2

The substrate 36-1 (1.13 g, 9.99 mmol), 45-1 (2.20 g, 10.99 mmol), CuI (1.90 g, 9.99 mmol), K₂CO₃ (1.38 g, 9.99 mmol) and N,N′-Dimethylethylenediamine (880.93 mg, 9.99 mmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (15 mL), heated up to 120° C. to react for 3 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, filtered, extracted three times with ethyl acetate, the organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 45-2 (0.8 g, 3.44 mmol). LCMS (ESI) m/z: 233.1 [M+H]⁺.

Step 2: Synthesis of Compound 45-3

The compound 45-2 (800 mg, 3.44 mmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (10 mL), added with a catalytic amount of Pd/C (40 mg), stirred for 3 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 45-3 (500 mg, 2.47 mmol). LCMS (ESI) m/z: 203.1 [M+H]⁺.

Step 3: Synthesis of Compound 45

The substrate IM-1 (39 mg, 109.11 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (28.25 mg, 163.67 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (70.51 mg, 545.56 μmol, 95.02 μL) and 45-3 (33.10 mg, 163.67 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 45 (32 mg, 62.55 μmol). LCMS(ESI) m/z: 512.2[M+H]⁺, HPLC Method B R_T=7.60 min, purity >100.0%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.04-8.01 (m, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.79-7.68 (m, 2H), 7.52 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 5.71-5.64 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.85-4.77 (m, 1H), 4.65 (d, J=6.0 Hz, 2H), 2.97 (s, 6H), 1.46 (s, 6H).

Example 46: Synthesis of Compound 46

Step 1: Synthesis of Compound 46-2

CH₃ONa (297 mg, 5.52 mmol), CH₃NO₂ (306.35 mg, 5.02 mmol) and methanol (8 mL) were added to a dry single-necked flask. The reaction mixture was stirred for 30 min at room temperature, then added with 46-1 (1 g, 5.02 mmol), stirred overnight at room temperature, concentrated under reduced pressure after the reaction and the pH was adjusted dropwise with acetic acid to 7.0, then extracted three times with dichloromethane. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compounds 46-2 (640 mg, 2.46 mmol).

Step 2: Synthesis of Compound 46-3

The compound 46-2 (100 mg, 384.19 μmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (10 mL), added with a catalytic amount of Pd/C (40 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 46-3 (80 mg, 347.4 μmol). LCMS (ESI) m/z: 236.2 [M+H]⁺.

Step 3: Synthesis of Compound 46-4

The substrate 46-3 (1 g, 4.34 mmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (10 mL), then added with K₂CO₃ (1.2 g, 8.68 mmol) and Chloroacetyl chloride (540.40 mg, 4.78 mmol) to react for 5 hours at room temperature, diluted with water after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 46-4 (480 mg, 1.56 mmol). LCMS (ESI) m/z: 266.1 [M+H]⁺.

Step 4: Synthesis of Compound 46-5

The substrate 46-4 (60 mg, 195.58 μmol) was added to a dry single-necked flask and dissolved in isopropanol (6 mL), then added with t-BuOK (112 mg, 998.13 μmol), stirred for 3 hours at room temperature, concentrated under reduced pressure after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the crude product 46-5 (50 mg, crude). LCMS (ESI) m/z: 215.1 [M+H]⁺.

Step 5: Synthesis of Compound 46-6

The substrate 46-5 (26 mg, 96.18 μmol) was added to a dry single-necked flask, and dissolved in tetrahydrofuran (4.4 mL), then added with 2M Borane tetrahydrofuran solution (0.19 mL, 384.72 μmol), stirred for 2 hours at 70° C., concentrated under reduced pressure after the reaction, added with methanol and N,N,N′,N′-Tetramethylethylenediamine, stirred overnight at 78° C., then concentrated under reduced pressure after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the crude product 46-6 (25 mg, crude). LCMS (ESI) m/z: 257.2 [M+H]⁺.

Step 6: Synthesis of Compound 46-7

The compound 46-6 (25 mg, 97.53 μmol) was added in a dry single-necked flask and dissolved in dimethyl sulfoxide (2 ml), added sequentially with p-fluoronitrobenzene (13.76 mg, 97.53 μmol) and K₂CO₃ (19 mg, 137.48 μmol). The reaction mixture was stirred for 5 hours at 100° C. and monitored by LC-MS, then diluted with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 46-7 (30 mg, 79.48 μmol). LCMS (ESI) m/z: 234.1[M+H]⁺.

Step 7: Synthesis of Compound 46-8

The compound 46-7 (18 mg, 47.69 μmol) was added to a dry single-necked flask and dissolved in dichloromethane (1 ml), added with trifluoroacetic acid (1 ml) to react for 30 min at room temperature and monitored by LC-MS. The solvents were removed by distillation under reduced pressure after the disappearance of the raw materials to give the compound 46-8 (13 mg, crude).

Step 8: Synthesis of Compound 46-9

The substrate 46-8 (13 mg, 46.88 μmol) was added to a dry single-necked flask and dissolved in methanol (2 mL), added with formaldehyde (16 mg, 469.76 μmol) and acetic acid (50 μL), stirred for 10 min at room temperature, then added with Sodium cyanoborohydride (10 mg, 159.13 μmol) to react for 2 hours at 50° C., concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 46-9 (10 mg, 34.32 μmol). LCMS (ESI) m/z: 262.2[M+H]⁺.

Step 9: Synthesis of Compound 46-10

The compound 46-9 (50 mg, 171.62 μmol) was added to a 50 mL round-bottomed flask, dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 46-10 (30 mg, 114.7 μmol). LCMS (ESI) m/z: 236.2 [M+H]⁺.

Step 10: Synthesis of Compound 46

The substrate IM-6 (42 mg, 112.47 μmol) and tetrahydrofuran (4 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (72.68 mg, 562.36 μmol) and 46-10 (30 mg, 114.78 μmol) were added to react for 2 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 46 (32 mg, 56.07 μmol). LCMS (ESI) m/z: 571.2 [M+H]⁺, HPLC method B: R_T=6.53 min, purity: 99.5%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.15 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.75 (d, J=6.6 Hz, 1H), 7.62-7.59 (m, 3H), 6.91 (d, J=8.4 Hz, 2H), 5.70-5.63 (m, 1H), 5.34 (s, 1H), 5.02-4.99 (m, 1H), 4.83 (d, J=16.8 Hz, 1H), 4.68 (d, J=5.4 Hz, 2H), 3.81-3.74 (m, 2H), 3.20 (d, J=12.0 Hz, 1H), 3.16-3.14 (m, 1H), 2.99-2.96 (m, 1H), 2.89 (d, J=12.0 Hz, 1H), 2.66-2.64 (m, 1H), 2.32 (s, 1H), 2.32-2.21 (m, 5H), 1.74-1.66 (m, 2H), 1.57-1.52 (m, 1H), 1.46 (s, 6H), 1.44-1.38 (m, 1H). D₂O: ¹H NMR (600 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.05 (s, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.63-7.59 (m, 3H), 6.92 (d, J=9.0 Hz, 2H), 5.70-5.63 (m, 1H), 5.02 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.69 (d, J=5.4 Hz, 2H), 3.82-3.77 (m, 2H), 3.18-3.13 (m, 2H), 3.00-2.96 (m, 1H), 2.91 (d, J=12.0 Hz, 1H), 2.67-2.64 (m, 1H), 2.51-2.44 (m, 2H), 2.35-2.26 (m, 4H), 1.71-1.67 (m, 2H), 1.57-1.54 (m, 1H), 1.50-1.47 (m, 7H).

Example 47: Synthesis of Compound 47

Step 1: Synthesis of Compound 47-1

The compound 4-1 (323 mg, 2 mmol) was dissolved in ethanol (10 ml) in a dry single-necked flask, added sequentially with KOH (337 mg, 6 mmol) and p-Bromo benzaldehyde (370 mg, 2 mmol). The reaction mixture was stirred overnight at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 47-1 (456 mg, 1.6 mmol). LCMS (ESI) m/z: 292.1[M+H]⁺.

Step 2: Synthesis of Compound 47-2

Trimethylsulfoxonium iodide (1.6 g, 8 mmol), NaH (0.64 g, 16 mmol) were dissolved in tetrahydrofuran (20 mL) in a single-necked flask, N₂ displaced to react for 1 hour at room temperature, then added with 47-1 (582 mg, 2 mmol), N₂ displaced again, stirred for 1 hour at 65° C. and monitored by LC-MS, concentrated under reduced pressure after the reaction to remove solvents, then extracted three times with ethyl acetate and water respectively, the organic phase was dried with anhydrous Na₂SO₄, filtered, the residue was purified by column chromatography to give the compound 47-2 (284 mg, 0.93 mmol). LCMS (ESI) m/z: 306.1[M+H]⁺.

Step 3: Synthesis of Compound 47-3

The substrate IM-3 (78 mg, 0.2 mol) was added to a dry single-necked flask, then added with tetrahydrofuran (1 mL) to dissolve, added with m-Chloroperoxybenzoic acid (52 mg, 0.3 mmol) to react for 30 m, at room temperature, then N,N-diisopropylethylamine (129 mg, 1 mmol) and ammonia (0.1 mL, 0.4 mmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 47-3 (58 mg, 0.16 mmol). LCMS (ESI) m/z: 585.2[M+H]⁺.

Step 4: Synthesis of Compound 47

The substrate 47-3 (58 mg, 0.16 mmol), 47-2 (70 mg, 0.23 mmol), CuI (61 mg, 320.29 8 μmol), K₂CO₃ (44.2 mg, 319.83 μmol) and N,N-Dimethylethylenediamine (56 mg, 635.28 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (4 mL), heated up to 110° C. to react for 6 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, the solvents were removed under reduced pressure. The residue was purified by MPLC to give the compound 47 (61 mg, 104.33 μmol). LCMS (ESI) m/z: 585.2 [M+H]⁺, HPLC method B: R_T=6.54 min, purity: 100%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.23 (s, 1H), 8.86 (s, 1H), 7.80-7.77 (m, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.30-7.25 (m, 3H), 6.61 (d, J=8.0 Hz, 1H), 5.65-5.62 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.90 (d, J=17.4 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 3.37 (s, 6H), 2.96-2.92 (m, 2H), 2.74-2.72 (m, 1H), 2.50-2.47 (m, 1H), 2.44-2.43 (m, 1H), 2.22-2.21 (m, 1H), 1.99-1.98 (m, 1H), 1.93-1.86 (m, 2H), 1.83-1.82 (m, 1H), 1.65-1.63 (m, 1H), 1.60-1.57 (m, 1H).

Step 5: Synthesis of Compounds 47a and 47b

The compound 47 (20 mg) was split by SFC to give 47a (6 mg), LCMS (ESI) m/z: 585.2 [M+H]⁺, HPLC method B: RT=6.72 min, purity: 98.7%, and 47b (8.6 mg), LCMS (ESI) m/z: 585.2 [M+H]⁺, HPLC method B: RT=6.75 min, purity: 99.6%.

Example 48: Synthesis of Compound 48

Step 1: Synthesis of Compound 48-1

The substrate 27-2 (100 mg, 456.12 μmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (2 mL), then added with 1-Bromo-2-fluoroethane (86.86 mg, 684.18 μmol), K₂CO₃ (88.25 mg, 638.57 μmol) and KI (8 mg, 48.19 μmol) to react for 7.5 hours at 100° C. and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, extracted three times with ethyl acetate, the organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 48-1 (60 mg, 226.17 mol). LCMS (ESI) m/z: 266.2 [M+H]⁺.

Step 2: Synthesis of Compound 48-2

The compound 48-1 (60 mg, 226.17 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 1 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 48-2 (45 mg, crude). LCMS (ESI) m/z: 236.2 [M+H]⁺.

Step 3: Synthesis of Compound 48

The substrate IM-6 (42 mg, 112.47 μmol) and tetrahydrofuran (4 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (72.68 mg, 562.36 μmol) and 48-2 (42 mg, 112.47 μmol) were added to react for 4 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 48 (45 mg, 74.45 μmol). LCMS (ESI) m/z: 545.2 [M+H]⁺, HPLC method B: R_T=6.81 min, purity: 90.1%. ¹H NMR (600 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.86-7.84 (m, 1H), 7.78-7.77 (m, 1H), 7.48 (s, 2H), 7.33 (d, J=7.8 Hz, 1H), 6.73 (d, J=9.0 Hz, 2H), 5.73-5.67 (m, 1H), 5.04 (d, J=10.2 Hz, 1H), 4.94 (d, J=16.8 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 4.62-4.60 (m, 1H), 4.54-4.52 (m, 1H), 3.99 (s, 1H), 3.92 (d, J=4.8 Hz, 2H), 3.64 (d, J=10.8 Hz, 2H), 3.39 (d, J=10.8 Hz, 2H), 2.78-2.70 (m, 3H), 1.68 (d, J=8.4 Hz, 1H), 1.58 (s, 6H).

Example 49: Synthesis of Compound 49

Step 1: Synthesis of Compound 49-1

The substrate 27-2 (100 mg, 456.12 μmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (2 mL), then added with Cyclobutyl bromide (92.37 mg, 684.18 μmol), K₂CO₃ (158 mg, 1.14 mmol) and KI (8 mg, 48.19 μmol) to react for 32 hours at 100° C. and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, extracted three times with ethyl acetate, the organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 49-1 (32 mg, 117.07 mol). LCMS (ESI) m/z: 274.2 [M+H]⁺.

Step 2: Synthesis of Compound 49-2

The compound 49-1 (32 mg, 117.07 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (10 mg), stirred for 1 hour at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 49-2 (28 mg, crude). LCMS (ESI) m/z: 244.1 [M+H]⁺.

Step 3: Synthesis of Compound 49

The substrate IM-6 (35.7 mg, 95.60 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (61.78 mg, 478.00 μmol) and 49-2 (25.59 mg, 105.16 μmol) were added to react for 4 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 49 (20.8 mg, 33.31 μmol). LCMS (ESI) m/z: 553.2 [M+H]⁺, HPLC method B: R_T=7.50 min, purity: 88.5%. ¹H NMR (600 MHz, Chloroform-d) δ 8.82 (s, 1H), 7.86-7.84 (m, 1H), 7.78-7.77 (m, 1H), 7.48 (s, 2H), 7.33 (d, J=7.8 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.74-5.67 (m, 1H), 5.04 (d, J=10.2 Hz, 1H), 4.94 (d, J=19.4 Hz, 1H), 4.67 (d, J=5.4 Hz, 2H), 3.94-3.88 (m, 3H), 3.47 (d, J=10.2 Hz, 2H), 3.35 (d, J=10.2 Hz, 2H), 3.21 (s, 1H), 2.81-2.72 (m, 1H), 2.00-1.90 (m, 5H), 1.78-1.74 (m, 1H), 1.69-1.64 (m, 1H), 1.58 (s, 6H).

Example 50: Synthesis of Compound 50

Step 1: Synthesis of Compound 50-2

The substrate 50-1 (2 g, 14.91 mmol) was added to a dry single-necked flask and dissolved in methanol (40 mL), added with formaldehyde (358.09 mg, 11.92 mmol) and acetic acid (89.51 mg, 1.49 mmol), stirred for 15 min at room temperature, then added with Sodium triacetoxyborohydride (15.80 g, 74.53 mmol) to react for 3 hours at room temperature, concentrated under reduced pressure after the reaction and extracted three times with dichloromethane. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 50-2 (200 mg, 1.35 mmol). LCMS (ESI) m/z: 149.1[M+H]⁺.

Step 2: Synthesis of Compound 50-3

The substrate 50-2 (138 mg, 0.93 mmol), p-fluoronitrobenzene (282 mg, 1.4 mmol), Pd₂(dba)₃ (85 mg, 0.093 mmol), XantPhos (108 mg, 0.18 mmol), t-BuOK (358 mg, 3.72 mmol) and 1,4-Dioxane (3 mL) were added to a dry single-necked flask under N₂ protection. The reaction mixture was stirred for 3 hours at 110° C. under N₂ atmosphere and monitored by LC-MS. The reaction system was cooled to room temperature after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 50-3 (20 mg, 0.074 mmol). LCMS (ESI) m/z: 270.1 [M+H]⁺.

Step 3: Synthesis of Compound 50-4

The compound 50-3 (20 mg, 74 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (10 mg), stirred for 1 hour at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 50-4 (7.80 mg, 32.59 μmol). LCMS (ESI) m/z: 240.2 [M+H]⁺.

Step 4: Synthesis of Compound 50

The substrate IM-1 (13.98 mg, 39.11 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (24.75 mg, 143.41 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (42.12 mg, 325.93 μmol) and 50-4 (7.80 mg, 32.59 μmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 50 (2 mg, 3.65 μmol). LCMS (ESI) m/z: 549.2 [M+H]⁺, HPLC method B: R_T=9.17 min, purity: 95.7%. 1H NMR (600 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.87 (s, 1H), 8.03-7.99 (m, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.70-6.60 (m, 2H), 6.53 (d, J=8.4 Hz, 1H), 6.49-6.42 (m, 1H), 5.71-5.62 (m, 1H), 5.32 (s, 1H), 5.02-4.96 (m, 1H), 4.85-4.79 (m, 1H), 4.68 (d, J=6.0 Hz, 2H), 3.68-3.65 (m, 2H), 3.30 (d, J=1.8 Hz, 2H), 2.87 (s, 3H), 1.46 (s, 6H), 1.24 (s, 1H).

Example 51: Synthesis of Compound 51

Step 1: Synthesis of Compound 51-2

The substrate 51-1 (44 mg, 195.48 μmol), IM-1-4 (44 mg, 197.96 μmol), CuI (37.70 mg, 197.96 mol), K₂CO₃ (38.3 mg, 227.14 μmol) and N,N′-Dimethylethylenediamine (34.90 mg, 395.92 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (2 mL), heated up to 120° C. to react for 4 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure to remove the solvents. The residue was purified by MPLC to give the compound 51-2 (26 mg, 70.95 μmol). LCMS (ESI) m/z: 367.1[M+H]⁺.

Step 2: Synthesis of Compound 51

The substrate 51-2 (56 mg, 152.82 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (4 mL) to dissolve, then added with M-chloroperoxybenzoic acid (42.06 mg, 244.52 μmol) to react for 2 hours at 50° C., then N,N-diisopropylethylamine (98.75 mg, 764.11 μmol) and 27-4 (37.28 mg, 183.39 μmol) were added to the reaction solution to react for 16 hours at 50° C. and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 51 (11 mg, 21.09 μmol). LCMS (ESI) m/z: 522.2 [M+H]⁺, HPLC method B: R_T=8.05 min, purity: 96.8%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.80 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.64-7.59 (m, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.56 (d, J=3.6 Hz, 1H), 5.75-5.65 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.86 (d, J=17.4 Hz, 1H), 4.64 (s, 2H), 4.30-4.26 (m, 2H), 3.57 (d, J=6.0 Hz, 2H), 3.41 (d, J=10.8 Hz, 2H), 3.25 (d, J=11.4 Hz, 2H), 2.42-2.41 (m, 1H), 1.98 (s, 3H), 1.52 (d, J=8.4 Hz, 1H), 1.40-1.38 (m, 3H).

Example 52: Synthesis of Compound 52

Step 1: Synthesis of Compound 52-2

The substrate 52-1 (1 g, 3.94 mmol) was added in a dry single-necked flask and dissolved in N,N-diisopropylethylamine (10 mL), added with CH₃I (1.40 g, 9.84 mmol) and Cs₂CO₃ (5.13 g, 15.74 mmol) to react for 2 hours at 50° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, then diluted with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 52-2 (1 g, 3.54 mmol). LCMS (ESI) m/z: 283.1 [M+H]⁺.

Step 2: Synthesis of Compound 52-3

The substrate 52-2 (167.55 mg, 593.88 μmol), IM-1-4 (110 mg, 494.90 μmol), CuI (9.43 mg, 49.49 μmol), K₂CO₃ (95.76 mg, 692.86 μmol) and N,N′-Dimethylethylenediamine (8.73 mg, 98.98 mol) were added to a dry microwave tube under N₂ protection, then added with N,N-diisopropylethylamine (2 mL), heated up to 110° C. to react for 12 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure to remove the solvents. The residue was purified by MPLC to give the compound 52-3 (16 mg, 37.78 μmol). LCMS (ESI) m/z: 425.1 [M+H]⁺.

Step 3: Synthesis of Compound 52

The substrate 52-3 (18.00 mg, 42.50 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (0.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (11.00 mg, 63.76 μmol) to react for 10 min at room temperature, then N,N-diisopropylethylamine (27.47 mg, 212.52 μmol) and 27-4 (8.64 mg, 42.50 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 52 (7.2 mg, 12.44 μmol). LCMS(ESI) m/z: 579.1[M+H]⁺, HPLC Method B R_T=7.30 min, purity >98.0%. ¹H NMR (600 MHz, DMSO-d₆) δ 9.92 (s, 1H), 8.77 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.19 (s, 1H), 6.59 (s, 3H), 5.68-5.66 (m, 1H), 5.09 (s, 1H), 4.93 (s, 1H), 4.24 (s, 2H), 3.81 (s, 3H), 3.80 (s, 2H), 3.60 (s, 3H), 3.56 (d, J=5.4 Hz, 2H), 3.37 (d, J=10.8 Hz, 2H), 3.24-3.18 (m, 2H), 2.39 (d, J=2.4 Hz, 1H), 1.96 (s, 3H), 1.50 (d, J=8.4 Hz, 1H).

Example 53: Synthesis of Compound 53

Step 1: Synthesis of Compound 53-2

The substrate 53-1 (2.1 g, 10.66 mmol) was added in a dry single-necked flask and dissolved in N,N-diisopropylethylamine (25 mL), added with C₂H₅I (4.99 g, 31.97 mmol) and K₂CO₃ (4.22 g, 31.97 mmol) to react for 12 hours at 90° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, then diluted with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 53-2 (1.38 g, 6.13 mmol). LCMS (ESI) m/z: 226.0 [M+H]⁺.

Step 2: Synthesis of Compound 53-3

The substrate 53-2 (849 mg, 8.66 mmol), B (pin)₂ (1.61 g, 6.35 mmol), Pd(dppf)Cl₂ (236 mg, 0.29 mmol), t-BuOK (845 mg, 8.66 mmol) and 1,4-Dioxane (30 mL) were added to a dry single-necked flask under N₂ protection. The reaction mixture was stirred for 16 hours at 110° C. under N₂ atmosphere and monitored by LC-MS, then cooled to room temperature after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 53-3 (680 mg, 2.5 mmol). LCMS (ESI) m/z: 274.2[M+H]⁺.

Step 3: Synthesis of Compound 53-4

The substrate 53-3 (0.47 g, 1.73 mmol) was added to a dry single-necked flask and dissolved in ethanol (12 mL), added with 6M HCl (0.3 mL, 1.73 mmol) to react for 7 hours at 90° C. and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 53-4 (180 mg, 0.95 mmol). LCMS (ESI) m/z: 192.1[M+H]⁺.

Step 4: Synthesis of Compound 53-5

The substrate 53-4 (217.99 mg, 1.15 mmol) was added to a dry single-necked flask and dissolved in CH₂Cl₂ (20 mL), added with IM-1-4 (170 mg, 764.85 μmol), pyridine (242.00 mg, 3.06 mmol) and Cu(Ac)₂ (277.84 mg, 1.53 mmol), stirred for 24 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 53-5 (31 mg, 84.60 μmol). LCMS (ESI) m/z: 368.1[M+H]⁺.

Step 5: Synthesis of Compound 53

The substrate 53-5 (39 mg, 106.43 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (6 mL) to dissolve, then added with M-chloroperoxybenzoic acid (20.20 mg, 117.07 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (137.55 mg, 1.06 mmol) and 27-4 (23.80 mg, 117.07 μmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 53 (8.3 mg, 15.91 μmol). LCMS (ESI) m/z: 523.3[M+H]⁺, HPLC method B: R_T=7.18 min, purity: 98.3%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.80 (s, 1H), 8.14 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.56-7.43 (m, 2H), 7.28 (s, 1H), 6.60 (s, 2H), 5.76-5.62 (m, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.95 (d, J=17.4 Hz, 1H), 4.51-4.47 (m, 2H), 4.35 (s, 1H), 3.56 (d, J=5.4 Hz, 2H), 3.38 (d, J=10.8 Hz, 2H), 3.22 (d, J=11.2 Hz, 2H), 2.45-2.38 (m, 1H), 1.96 (s, 3H), 1.50 (d, J=8.4 Hz, 1H), 1.44-1.37 (m, 3H).

Example 54: Synthesis of Compound 54

Step 1: Synthesis of Compound 54-2

The substrate 54-1 (300 mg, 1.60 mmol) was added in a dry single-necked flask and dissolved in tetrahydrofuran (3 mL), added with N,N′-Carbonyldiimidazole (344.52 mg, 2.39 mmol) to react for 2 hours at 80° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, then diluted with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 54-2 (260 mg, 1.22 mmol). LCMS (ESI) m/z: 213.9 [M+H]⁺.

Step 2: Synthesis of Compound 54-3

The substrate 54-2 (620 mg, 2.90 mmol) was added in a dry single-necked flask and dissolved in N,N-diisopropylethylamine (6 mL), added with CH₃I (451.83 mg, 2.90 mmol) and Cs₂CO₃ (1.12 g, 3.19 mmol) to react for 12 hours at room temperature and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, then diluted with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 54-3 (279 mg, 1.15 mmol). LCMS (ESI) m/z: 242.0 [M+H]⁺.

Step 3: Synthesis of Compound 54-4

The substrate 54-3 (220 mg, 908.83 μmol), B (pin)₂ (346.18 mg, 1.36 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (74.22 mg, 90.88 μmol), K₂CO₃ (408.20 mg, 2.95 mmol) and 1,4-Dioxane (7 mL) were added to a dry single-necked flask under N₂ protection. The reaction mixture was stirred for 16 hours at 90° C. under N₂ atmosphere and monitored by LC-MS, then cooled to room temperature after the reaction, added with water, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 54-4 (140 mg, 484.20 μmol). LCMS (ESI) m/z: 290.2[M+H]⁺.

Step 4: Synthesis of Compound 54-5

The substrate 54-4 (140 mg, 484.20 μmol) was added to a dry single-necked flask and dissolved in acetonitrile (2 mL), added with 6M HCl (80.70 μL) to react for 4 hours at 80° C. and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 54-5 (33 mg, 159.43 μmol). LCMS (ESI) m/z: 208.1[M+H]⁺.

Step 5: Synthesis of Compound 54-6

The substrate 54-5 (30 mg, 144.93 μmol) was added to a dry single-necked flask and dissolved in CH₂Cl₂ (3 mL), added with IM-1-4 (32.2 mg, 222.27 μmol), pyridine (11.46 mg, 144.93 μmol) and Cu(Ac)₂ (52.65 mg, 289.87 μmol), stirred for 24 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 54-6 (30 mg, 78.24 μmol). LCMS (ESI) m/z: 384.1[M+H]⁺.

Step 6: Synthesis of Compound 54

The substrate 54-6 (30 mg, 78.24 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (2 mL) to dissolve, then added with M-chloroperoxybenzoic acid (20.25 mg, 117.36 mol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (50.56 mg, 391.21 mol) and 27-4 (19.09 mg, 93.89 μmol) were added to the reaction solution to react for 1.5 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 54 (4.3 mg, 6.99 μmol). LCMS (ESI) m/z: 539.1 [M+H]⁺, HPLC method A: R_T=7.01 min, purity: 89.4%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.01 (s, 1H), 8.79 (s, 1H), 7.53-7.48 (m, 4H), 7.26-7.24 (m, 1H), 6.63-6.62 (m, 2H), 5.71-5.66 (m, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.98-4.95 (m, 1H), 4.28-4.19 (m, 2H), 3.89-3.86 (m, 2H), 3.56 (d, J=4.8 Hz, 2H), 3.38 (d, J=10.8 Hz, 2H), 3.22 (d, J=10.8 Hz, 2H), 2.41-2.38 (m, 1H), 1.96 (s, 3H), 1.50 (d, J=8.4 Hz, 1H), 1.27-1.24 (m, 3H).

Example 55: Synthesis of Compound 55

Step 1: Synthesis of Compound 55-2

The substrate 55-1 (0.83 g, 4.28 mmol) was added to a dry single-necked flask, added with N,N-diisopropylethylamine (6 mL) to dissolve, added with t-BuOK (960.29 mg, 8.56 mmol) and Triphenylchloromethane (1.43 g, 5.13 mmol) to react overnight at room temperature and monitored by LC-MS, then cooled to room temperature after the reaction, added with water and extracted three times with CH₂Cl₂. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was recrystallized to give the compound 55-2 (1.53 g, 3.51 mmol). LCMS (ESI) m/z: 437.1[M+H]⁺.

Step 2: Synthesis of Compound 55-3

The substrate 55-2 (0.88 g, 2.02 mmol), Tetrahydropyrrole (573.81 mg, 8.07 mmol), CuI (38.41 mg, 201.70 μmol), t-BuOK (452.67 mg, 4.03 mmol) and 2-Acetylcyclohexanone (56.55 mg, 403.40 mol) were added to a dry microwave tube under N₂ protection, then added with N,N-diisopropylethylamine (5 mL), heated up to 80° C. to react for 24 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure to remove the solvents. The residue was purified by MPLC to give the compound 55-3 (250 mg, 658.77 μmol). LCMS (ESI) m/z: 380.2[M+H]⁺.

Step 3: Synthesis of Compound 55-4

The compound 55-3 (140 mg, 368.91 μmol) was added to a dry single-necked flask and dissolved in CH₂Cl₂ (2 ml), added with trifluoroacetic acid (1 ml) to react for 30 min at room temperature and monitored by LC-MS. The solvents were removed by distillation under reduced pressure after the disappearance of the raw materials to give the compound 55-4 (22 mg, 160.37 mol). LCMS (ESI) m/z: 138.1 [M+H]⁺.

Step 4: Synthesis of Compound 55-5

The substrate 55-4 (250 mg, 1.82 mmol) was added in a dry single-necked flask and dissolved in dimethyl sulfoxide (5 ml), added sequentially with p-fluoronitrobenzene (282.85 mg, 2.00 mmol) and K₂CO₃ (2.52 g, 18.22 mmol). The reaction mixture was stirred for 12 hours at 100° C. and monitored by LC-MS, then diluted with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 55-5 (200 mg, 774.37 μmol). LCMS (ESI) m/z: 259.1[M+H]⁺.

Step 5: Synthesis of Compound 55-6

The compound 55-5 (9 mg, 34.85 μmol) was dissolved tetrahydrofuran (0.5 mL) and acetic acid (0.1 mL) in a dry single-necked flask, added with zinc powder (45.57 mg, 696.93 μmol), stirred for 30 min at room temperature and monitored by LC-MS, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure to give the compound 55-6 (6 mg, 26.28 μmol). LCMS (ESI) m/z: 229.2[M+H]⁺.

Step 6: Synthesis of Compound 55

The substrate IM-1 (42.27 mg, 118.27 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (30.61 mg, 177.40 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (76.43 mg, 591.35 μmol) and 55-6 (27 mg, 118.27 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 55 (2 mg, 3.72 μmol). LCMS(ESI) m/z: 538.2[M+H]⁺, HPLC Method B R_T=8.23 min, purity >97.9%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.90 (s, 1H), 8.10 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.78-7.77 (m, 2H), 7.74-7.69 (m, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.35 (s, 1H), 5.72-5.64 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.69 (d, J=6.0 Hz, 2H), 3.08-3.06 (s, 4H), 1.92-1.89 (m, 4H), 1.47 (s, 6H).

Example 56: Synthesis of Compound 56

Step 1: Synthesis of Compound 56

The substrate 52 (2 mg, 3.46 μmol) was added to a dry single-necked flask and dissolved in methanol (1 mL), added with 1M NaOH (5 μl, 5.18 μmol), stirred for 30 min at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 56 (1.2 mg, 2.13 μmol). LCMS(ESI) m/z: 565.3[M+H]⁺, HPLC Rt=4.68 min, purity >83.3%. ¹H NMR (600 MHz, Methanol-d₄) δ 8.65 (s, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.37 (d, J=8.6 Hz, 3H), 7.10 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.52 (d, J=14.6 Hz, 2H), 5.67-5.59 (m, 1H), 5.06-5.00 (m, 1H), 4.87 (d, J=17.4 Hz, 1H), 4.26 (d, J=5.5 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 2H), 3.50 (d, J=2.8 Hz, 2H), 3.39 (d, J=11.0 Hz, 2H), 2.46 (s, 1H), 1.84 (s, 2H), 1.79 (s, 3H), 1.27 (d, J=2.9 Hz, 1H).

Example 57: Synthesis of Compound 57

Step 1: Synthesis of Compound 57-2

The substrate 57-1 (546.59 mg, 2.39 mmol), IM-1-4 (444 mg, 2.00 mmol), CuI (762 mg, 4.00 mmol), K₂CO₃ (552 mg, 2.00 mmol) and N,N′-Dimethylethylenediamine (705 mg, 2.00 mmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (10 mL), heated up to 110° C. to react for 16 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, filtered, the filterate was concentrated under reduced pressure. The residue was purified by MPLC to give the compound 57-2 (140 mg, 377.94 μmol). LCMS (ESI) m/z: 371.1[M+H]⁺.

Step 2: Synthesis of Compound 57

The substrate 57-2 (7.4 mg, 19.98 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (0.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (7.64 mg, 44.27 μmol) to react for 10 min at room temperature, then N,N-diisopropylethylamine (5.72 mg, 44.27 μmol) and 27-4 (6 mg, 29.52 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 57 (8 mg, 15.22 μmol). LCMS (ESI) m/z: 526.3[M+H]⁺, HPLC R_T=6.38 min, purity >94.2%. ¹H NMR (600 MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.76 (s, 1H), 7.54 (s, 2H), 7.38 (d, J=9.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.64 (d, J=8.6 Hz, 2H), 5.69-5.67 (m, 1H), 5.62 (d, J=18.0 Hz, 1H), 5.10 (d, J=10.2 Hz, 1H), 4.94 (d, J=17.4 Hz, 1H), 4.55 (s, 1H), 4.41 (d, J=9.6 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H), 4.22 (s, 1H), 3.55 (d, J=6.0 Hz, 2H), 3.39 (d, J=11.2 Hz, 2H), 3.22 (d, J=11.2 Hz, 2H), 2.43-2.38 (m, 1H), 1.96 (s, 3H), 1.57 (s, 3H), 1.50 (d, J=8.4 Hz, 1H).

Example 58: Synthesis of Compound 58

Step 1: Synthesis of Compound 58-1

The substrate 38-1 (65.29 mg, 297.82 μmol) was added to a dry single-necked flask and dissolved in 1,2-Dichloroethane (5 mL), added with 3-Oxetanone (108 mg, 1.5 mmol) and acetic acid (0.5 mL), stirred for 15 min at room temperature, then added with Sodium triacetoxyborohydride (315.60 mg, 1.49 mmol) to react for 10 hours at room temperature, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 58-1 (60 mg, 217.94 μmol). LCMS (ESI) m/z: 276.1[M+H]⁺.

Step 2: Synthesis of Compound 58-2

The compound 58-1 (60 mg, 217.94 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 1 hour at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 58-2 (45 mg, 183.43 μmol). LCMS (ESI) m/z: 246.2 [M+H]⁺.

Step 3: Synthesis of Compound 58

The substrate IM-6 (41.84 mg, 112.04 μmol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (72.40 mg, 560.20 μmol) and 58-2 (30.23 mg, 123.24 μmol) were added to react for 2 hour at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 58 (35 mg, 62.16 μmol). LCMS (ESI) m/z: 555.2 [M+H]⁺, HPLC method B: R_T=6.27 min, purity: 98.5%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.61-7.47 (m, 3H), 6.67 (d, J=7.8 Hz, 2H), 5.70-5.63 (m, 1H), 5.32 (s, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.83 (d, J=16.8 Hz, 1H), 4.68 (d, J=2.4 Hz, 2H), 4.58-4.56 (m, 2H), 4.28-4.26 m, 2H), 3.75 (d, J=6.0 Hz, 2H), 3.62-3.60 (m, 1H), 3.28-3.26 (m, 4H), 2.48-2.47 (m, 1H), 1.54 (d, J=8.4 Hz, 1H), 1.47 (s, 6H). D₂O: ¹H NMR (600 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.62-7.45 (s, 3H), 6.69 (d, J=8.4 Hz, 2H), 5.70-5.63 (m, 1H), 5.03 (d, J=10.2 Hz, 1H), 4.83 (d, J=16.8 Hz, 1H), 4.69 (d, J=3.0 Hz, 2H), 4.60-4.58 (m, 2H), 4.32-4.29 (m, 2H), 3.76 (d, J=5.4 Hz, 2H), 3.63-3.62 (m, 1H), 3.26-3.24 (m, 4H), 2.52-2.51 (m, 1H), 1.53 (d, J=8.4 Hz, 1H), 1.48 (s, 6H).

Example 59: Synthesis of Compound 59

Step 1: Synthesis of Compound 59-1

The substrate 46-6 (250 mg, 975.27 μmol) was added to a dry single-necked flask and dissolved in methanol (2 mL), added with formaldehyde (16 mg, 469.76 μmol) and acetic acid (0.5 mL), stirred for 30 min at room temperature, then added with Sodium cyanoborohydride (306.43 mg, 4.88 mmol) to react for 2 hours at 50° C. and monitored by TLC, then concentrated under reduced pressure after the reaction. The residue was purified by column chromatography to give the compound 59-1 (130 mg, 480.83 μmol). LCMS (ESI) m/z: 262.2[M+H]⁺.

Step 2: Synthesis of Compound 59-2

The compound 59-1 (54 mg, 199.73 μmol) was added to a dry single-necked flask and dissolved in CH₂Cl₂ (2 ml), added with trifluoroacetic acid (1 ml) to react for 30 min at room temperature and monitored by LC-MS. The solvents were removed by distillation under reduced pressure after the disappearance of the raw materials to give the compound 59-2 (30 mg, 176.21 mol).

Step 3: Synthesis of Compound 59-3

The compound 59-2 (30 mg, 176.21 μmol) was added in a dry single-necked flask and dissolved in dimethyl sulfoxide (2 ml), added sequentially with p-fluoronitrobenzene (24.86 mg, 176.21 μmol) and NaH (21.15 mg, 881.05 μmol). The reaction mixture was stirred for 3 hours at 100° C. and monitored by LC-MS, then quenched with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 59-3 (35 mg, 120.13 μmol). LCMS (ESI) m/z: 234.1[M+H]⁺.

Step 4: Synthesis of Compound 59-4

The compound 59-3 (35 mg, 120.13 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 59-4 (30 mg, 114.78 μmol). LCMS (ESI) m/z: 262.2 [M+H]⁺.

Step 5: Synthesis of Compound 59

The substrate IM-6 (42.86 mg, 114.78 μmol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (74.17 mg, 573.92 μmol) and 59-4 (30 mg, 114.78 μmol) were added to react for 2 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 59 (3 mg, 4.75 μmol). LCMS (ESI) m/z: 571.2 [M+H]⁺, HPLC method B: R_T=7.61 min, purity: 90.3%. ¹H NMR (600 MHz, Chloroform-d) δ 8.82 (s, 1H), 7.89-7.76 (m, 2H), 7.45-7.44 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 6.97 (s, 2H), 5.73-5.67 (m, 1H), 5.04 (d, J=10.2 Hz, 1H), 4.94 (d, J=16.8, 1.2 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.97-3.83 (m, 3H), 3.25-3.11 (m, 3H), 2.58-2.33 (m, 6H), 1.93 (s, 1H), 1.78 (s, 1H), 1.61 (s, 3H), 1.58 (s, 6H).

Example 60: Synthesis of Compound 60

Step 1: Synthesis of Compound 60-1

The substrate IM-1-5 (250 mg, 1.16 mmol) was dissolved in tetrahydrofuran (2 ml) in a dry single-necked flask, cooled to 0° C. and added with NaH (83.30 mg, 3.47 mmol), stirred for 10 min at 0° C., added with CH₃I (492.7 mg, 3.47 mmol), then heated to room temperature, stirred for 6 h and monitored by LC-MS, then quenched with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 60-1 (210 mg, 912.64 μmol). LCMS (ESI) m/z: 230.1[M+H]⁺.

Step 2: Synthesis of Compound 60-2

The substrate 60-1 (207.05 mg, 899.82 μmol), IM-1-4 (200 mg, 899.82 μmol), CuI (342.74 mg, 1.80 mmol), K₂CO₃ (174.10 mg, 1.26 mmol) and N,N′-Dimethylethylenediamine (705 mg, 2.00 mmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (4 mL), heated up to 110° C. to react for 2 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, added with ammonia (2 mL), filtered, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 60-2 (80 mg, 215.37 μmol). LCMS (ESI) m/z: 372.2[M+H]⁺.

Step 3: Synthesis of Compound 60

The substrate 60-2 (46 mg, 123.84 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (0.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (32 mg, 185.76 μmol) to react for 10 min at room temperature, then N,N-diisopropylethylamine (80.02 mg, 619.19 μmol) and 27-4 (30.21 mg, 148.60 μmol) were added to the reaction solution to react for 6 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 60 (14.08 mg, 26.74 μmol). LCMS (ESI) m/z: 527.2 [M+H]⁺, HPLC method B: R_T=5.86 min, purity: 97.6%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.80 (s, 1H), 8.07-8.05 (m, 1H), 7.83-7.82 (m, 1H), 7.59 (s, 2H), 7.46 (d, J=7.8 Hz, 1H), 6.72 (d, J=7.8 Hz, 2H), 5.70-5.63 (m, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.84-4.81 (m, 1H), 4.69 (d, J=4.2 Hz, 2H), 3.59 (d, J=3.6 Hz, 2H), 3.43 (d, J=10.8 Hz, 2H), 3.28 (d, J=10.8 Hz, 2H), 3.09 (s, 3H), 2.43 (s, 1H), 1.99 (s, 3H), 1.54 (d, J=7.8 Hz, 1H), 1.49 (s, 6H).

Example 61: Synthesis of Compound 61

Step 1: Synthesis of Compound 61-2

The substrate 61-1 (200 mg, 1.30 mmol) was added in a dry single-necked flask and dissolved in N,N-diisopropylethylamine (2.5 mL), added with C₂H₅I (406.24 mg, 2.60 mmol) and K₂CO₃ (5.4 g, 3.91 mmol) to react for 1 hour at 75° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, then filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 61-2 (140 mg, 770.83 μmol). LCMS (ESI) m/z: 266.2 [M+H]⁺.

Step 2: Synthesis of Compound 61-3

The substrate 61-2 (130 mg, 715.77 μmol) was added to a dry single-necked flask and dissolved in acetonitrile (2 mL), added with Bromotrimethylsilane (109.58 mg, 715.77 μmol) to react for 4 hours at 90° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, then concentrated under reduced pressure. The residue was purified by MPLC to give the compound 61-3 (60 mg, 265.40 μmol). LCMS (ESI) m/z: 266.2 [M+H]⁺.

Step 3: Synthesis of Compound 61-4

The substrate 61-3 (36.99 mg, 163.60 μmol), IM-1-4 (40 mg, 179.96 μmol), CuI (62.32 mg, 327.21 μmol), K₂CO₃ (31.65 mg, 229.05 μmol) and N,N′-Dimethylethylenediamine (57.69 mg, 654.42 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (4 mL), heated up to 110° C. to react for 3 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 61-4 (19 mg, 51.71 μmol).

Step 4: Synthesis of Compound 61

The substrate 61-4 (19 mg, 51.71 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (0.7 mL) to dissolve, then added with M-chloroperoxybenzoic acid (13.39 mg, 77.57 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (33.42 mg, 258.55 μmol) and 27-4 (10.51 mg, 51.71 μmol) were added to the reaction solution to react for 10 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 61 (3.89 mg, 7.44 μmol). LCMS (ESI) m/z: 523.3 [M+H]⁺, HPLC method A: R_T=4.98 min, purity: 98.6%. ¹H NMR (600 MHz, CDCl3) δ 8.76 (s, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.44 (s, 2H), 6.67 (d, J=8.4 Hz, 2H), 5.63-5.59 (m, 1H), 4.93-4.90 (m, 3H), 4.87-4.84 (m, 1H), 4.46-4.42 (m, 2H), 3.95 (s, 2H), 3.58 (d, J=8.4 Hz, 2H), 3.46 (d, J=8.4 Hz, 2H), 2.93-2.87 (m, 1H), 2.25 (s, 3H), 1.71 (d, J=6.0 Hz, 1H), 1.61-1.59 (m, 3H).

Example 62: Synthesis of Compound 62

Step 1: Synthesis of Compound 62

The substrate 62-1 (36.99 mg, 163.60 μmol), 62-2 (40.39 mg, 123.75 μmol), CuI (47.14 mg, 247.50 μmol), K₂CO₃ (68.41 mg, 495.01 μmol) and N,N′-Dimethylethylenediamine (21.78 mg, 247.50 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (2 mL), heated up to 110° C. to react for 16 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 62 (0.7 mg, 1.23 μmol). LCMS (ESI) m/z: 569.3 [M+H]⁺, HPLC method A: R_T=6.03 min, purity: 73.2%. ¹H NMR (600 MHz, DMSO-d6) δ 8.93-8.92 (m, 1H), 8.07-8.03 (m, 1H), 7.92-7.87 (m, 4H), 7.88 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 5.76-5.71 (m, 1H), 5.03-5.01 (m, 1H), 4.92-4.89 (m, 1H), 4.83-4.82 (m, 2H), 4.66-4.63 (m, 1H), 4.43-4.41 (m, 1H), 4.29-4.26 (m, 1H), 3.57 (d, J=11.4 Hz, 2H), 3.04-3.00 (m, 2H), 2.95 (s, 3H), 2.19 (d, J=14.4 Hz, 1H), 2.16-1.51 (m, 4H), 1.58-1.53 (m, 7H).

Example 63: Synthesis of Compound 63

Step 1: Synthesis of Compound 63-2

The substrate 38-1 (44 mg, 200.69 μmol) was added to a dry single-necked flask and dissolved in 1,2-Dichloroethane (5 mL), added with 63-1 (171.79 mg, 1.00 mmol) and acetic acid (0.5 mL), stirred for 15 min at room temperature, then added with Sodium triacetoxyborohydride (211.94 mg, 1 mmol) to react for 12 hours at room temperature, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 63-2 (350 mg, 934.75 μmol). LCMS (ESI) m/z: 375.2[M+H]⁺.

Step 2: Synthesis of Compound 63-3

The compound 63-2 (60 mg, 160.24 μmol) was added to a dry single-necked flask and dissolved in CH₂Cl₂ (2 ml), added with trifluoroacetic acid (1 ml) to react for 30 min at room temperature and monitored by LC-MS. The solvents were removed by distillation under reduced pressure after the disappearance of the raw materials to give the compound 63-3 (43 mg, 156.75 mol). LCMS (ESI) m/z: 275.2[M+H]⁺.

Step 3: Synthesis of Compound 63-4

The substrate 63-3 (43 mg, 156.75 μmol) was added to a dry single-necked flask and dissolved in methanol (3 mL), added with formaldehyde (26.69 mg, 783.76 μmol) and acetic acid (0.2 mL), stirred for 10 min at room temperature, then added with Sodium cyanoborohydride (19.70 mg, 313.51 μmol) to react for 6 hours at 50° C. and monitored by LC-MS, then concentrated under reduced pressure after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 63-4 (35 mg, 121.38 μmol). LCMS (ESI) m/z: 289.2[M+H]⁺.

Step 4: Synthesis of Compound 63-5

The compound 63-4 (35 mg, 120.13 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 1 hour at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 63-5 (28 mg, 71.90 μmol). LCMS (ESI) m/z: 259.2 [M+H]⁺.

Step 5: Synthesis of Compound 63

The substrate IM-6 (16.89 mg, 65.36 μmol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (42.24 mg, 326.82 μmol) and 63-5 (28 mg, 71.90 μmol) were added to react for 4 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 63 (11 mg, 18.49 μmol). LCMS (ESI) m/z: 568.4 [M+H]⁺, HPLC method B: R_T=5.21 min, purity: 97.5%. ¹H NMR (600 MHz, DMSO-d₆) δ 8.82-8.79 (m, 1H), 7.99-7.91 (m, 1H), 7.79-7.71 (m, 1H), 7.59-7.55 (m, 1H), 7.51-7.47 (m, 2H), 6.71-6.69 (m, 2H), 5.71-5.69 (m, 1H), 5.67-5.61 (m, 1H), 5.00-4.98 (m, 1H), 4.83-4.56 (m, 3H), 4.25-4.13 (m, 2H), 4.02-3.89 (m, 4H), 3.75-3.57 (m, 5H), 3.28-3.21 (m, 3H), 2.42-2.38 (m, 1H), 1.80-1.72 (m, 1H), 1.46-1.42 (m, 6H). D₂O: ¹H NMR (600 MHz, 333K, DMSO-d₆) δ 8.77 (s, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.47 (s, 2H), 6.72 (d, J=9.0 Hz, 2H), 5.68-5.62 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.85 (d, J=17.4 Hz, 1H), 4.67 (s, 2H), 4.17-3.62 (m, I0H), 3.39-3.37 (m, 1H), 3.18 (s, 3H), 2.45 (s, 1H), 1.77 (s, 1H), 1.47 (s, 6H).

Example 64: Synthesis of Compound 64

Step 1: Synthesis of Compound 64-1

The substrate 38-1 (109 mg, 497.17 μmol) was added to a dry single-necked flask and dissolved in acetone (3 mL), then added with allyl bromide (90.1 mg, 745.76 μmol) and K₂CO₃ (207 mg, 745.76 μmol) to react under N₂ atmosphere for 2 hours at room temperature and monitored by LC-MS, concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 64-1 (128 mg, 497.03 μmol). LCMS (ESI) m/z: 260.2 [M+H]⁺.

Step 2: Synthesis of Compound 64-2

The compound 64-1 (128 mg, 497.03 μmol) was added to a dry single-necked flask and dissolved in ethanol (10 mL), added with iron powder (138.92 mg, 2.49 mmol) and NH₄Cl (399 mg, 7.46 mmol), heated up to 80° C. to react and stirred for 30 min, monitored by LC-MS, then cooled to room temperature after the reaction, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure. The residue was purified by MPLC to give the compound 64-2 (25 mg, 109.02 μmol). LCMS (ESI) m/z: 230.2[M+H]⁺.

Step 3: Synthesis of Compound 64

The substrate IM-1 (18 mg, 50.36 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (13 mg, 137.36 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (9.7 mg, 75.05 μmol) and 64-2 (21 mg, 91.58 μmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 64 (6.2 mg, 11.51 μmol). LCMS (ESI) m/z: 539.2 [M+H]⁺, HPLC method B: R_T=5.59 min, purity: 92.7%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.05-8.03 (m, 1H), 7.79-7.77 (m, 2H), 7.61 (d, J=7.8 Hz, 3H), 6.72 (d, J=8.4 Hz, 2H), 6.01-5.72 (m, 1H), 5.72-5.54 (m, 1H), 5.25-4.96 (m, 4H), 4.83 (d, J=17.4 Hz, 1H), 4.68 (d, J=6.0 Hz, 2H), 3.44 (d, J=11.2 Hz, 2H), 3.30 (d, J=11.2 Hz, 2H), 3.18 (s, 2H), 2.93 (d, J=6.0 Hz, 2H), 1.55 (d, J=8.4 Hz, 1H), 1.47 (s, 6H).

Example 65: Synthesis of Compound 65

Step 1: Synthesis of Compound 65-1

The substrate 38-1 (87 mg, 396.83 μmol) was added in a dry single-necked flask and dissolved in acetone (3 mL), added with C₂H₅I (92.84 mg, 595.25 μmol) and K₂CO₃ (83 mg, 1.19 mmol) to react under N₂ atmosphere for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 65-1 (87 mg, 351.81 μmol). LCMS (ESI) m/z: 248.1 [M+H]⁺.

Step 2: Synthesis of Compound 65-2

The compound 65-1 (94 mg, 380.12 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (5 mL), added with a catalytic amount of Pd/C (10 mg), stirred for 2 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 65-2 (80 mg, 368.14 μmol). LCMS (ESI) m/z: 218.2 [M+H]⁺.

Step 3: Synthesis of Compound 65

The substrate IM-1 (18 mg, 50.36 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (13 mg, 137.36 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (9.7 mg, 75.05 μmol) and 65-2 (19.9 mg, 91.58 μmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 65 (6.2 mg, 11.77 μmol). LCMS (ESI) m/z: 527.2[M+H]⁺, HPLC method B: R_T=6.27 min, purity: 76.2%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.80 (s, 1H), 8.06-8.02 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz, 3H), 6.70 (d, J=8.4 Hz, 2H), 5.74-5.55 (m, 1H), 5.31 (s, 1H), 5.04-4.94 (m, 1H), 4.83 (d, J=17.2 Hz, 1H), 4.68 (d, J=6.0 Hz, 2H), 3.67 (d, J=5.6 Hz, 2H), 3.42 (d, J=11.2 Hz, 2H), 3.26 (d, J=11.2 Hz, 2H), 2.42 (d, J=6.8 Hz, 1H), 2.28 (d, J=7.2 Hz, 2H), 1.55 (s, 1H), 1.46 (s, 6H), 0.93-0.91 (m, 3H).

Example 66: Synthesis of Compound 66

Step 1: Synthesis of Compound 66-1

The substrate 38-1 (80 mg, 364.90 μmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (3 mL), then added with 2-Bromoethanol (68 mg, 544.16 μmol), K₂CO₃ (99 mg, 716.35 μmol) and KI (5 mg, 30.12 μmol) to react for 2 hours at 100° C. and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 66-1 (70 mg, 265.86 μmol). LCMS (ESI) m/z: 264.1 [M+H]⁺.

Step 2: Synthesis of Compound 66-2

The compound 66-1 (70 mg, 265.86 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 3 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 66-2 (35 mg, 150 μmol). LCMS (ESI) m/z: 234.2 [M+H]⁺.

Step 3: Synthesis of Compound 66

The substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (4 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 66-2 (32 mg, 57.32 μmol) were added to react for 4 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 66 (45 mg, 74.45 μmol). LCMS (ESI) m/z: 543.2 [M+H]⁺, HPLC method B: R_T=5.69 min, purity: 97.2%. ¹H NMR (600 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.87-7.84 (m, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.47 (s, 2H), 7.34 (d, J=7.8 Hz, 1H), 6.72 (d, J=9.0 Hz, 2H), 5.73-5.67 (m, 1H), 5.04 (d, J=10.2 Hz, 1H), 4.94 (d, J=16.8 Hz, 1H), 4.73 (d, J=6.0 Hz, 2H), 3.97 (d, J=5.4 Hz, 2H), 3.67-3.63 (m, 4H), 3.44 (d, J=10.8 Hz, 2H), 2.82-2.80 (m, 1H), 2.64 (s, 2H), 1.72 (d, J=8.4 Hz, 1H), 1.59 (s, 6H).

Example 67: Synthesis of Compound 67

Step 1: Synthesis of Compound 67-1

The substrate 38-1 (80 mg, 364.90 μmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (3 mL), then added with 2-Bromoethyl methyl ether (76 mg, 546.80 mol), K₂CO₃ (99 mg, 716.35 μmol) and KI (5 mg, 30.12 μmol) to react for 6 hours at 100° C. and monitored by LC-MS, then the reaction solution was cooled to room temperature after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 67-1 (75 mg, 270.45 μmol). LCMS (ESI) m/z: 264.1 [M+H]⁺.

Step 2: Synthesis of Compound 67-2

The compound 67-1 (75 mg, 270.45 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 3 hours at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 67-2 (53 mg, 214.28 μmol). LCMS (ESI) m/z: 234.2 [M+H]⁺.

Step 3: Synthesis of Compound 67

The substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 67-2 (53 mg, 214.28 μmol) were added to react for 4 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 67 (40 mg, 67.11 μmol). LCMS (ESI) m/z: 557.3 [M+H]⁺, HPLC method B: R_T=6.43 min, purity: 93.4%. ¹H NMR (600 MHz, Chloroform-d) δ 8.82 (s, 1H), 7.88-7.84 (m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.46 (s, 2H), 7.34-7.32 (m, 1H), 6.72 (d, J=8.4 Hz, 2H), 5.76-5.66 (m, 1H), 5.06-5.03 (m, 1H), 4.97-4.92 (m, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.95-3.93 (m, 2H), 3.65 (d, J=10.8 Hz, 2H), 3.52-3.50 (m, 2H), 3.39 (d, J=10.8 Hz, 2H), 3.35 (s, 3H), 2.83-2.81 (m, 1H), 2.66-2.64 (m, 2H), 1.68 (d, J=8.4 Hz, 1H), 1.59 (s, 6H).

Example 68: Synthesis of Compound 68

Step 1: Synthesis of Compound 68-1

Acetic acid (18 mg, 299.74 μmol) and N,N-Diisopropylethylamine (42.61 mg, 329.72 μmol) were dissolved in tetrahydrofuran (2 mL) in a dry single-necked flask, cooled to 0° C. and added with HATU (49.93 mg, 131.39 umol), stirred for 10 min, added with 38-1 (65.72 mg, 299.74 μmol) then stirred for 30 min, quenched with water after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 68-1 (45 mg, 172.23 μmol). LCMS (ESI) m/z: 262.1[M+H]⁺.

Step 2: Synthesis of Compound 68-2

The compound 68-1 (45 mg, 172.23 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (20 mg), stirred for 1 hour at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 68-2 (29 mg, 214.28 μmol). LCMS (ESI) m/z: 236.2 [M+H]⁺.

Step 3: Synthesis of Compound 68

The substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 68-2 (29 mg, 125.38 μmol) were added to react for 4 hour at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 68 (51.3 mg, 89.10 μmol). LCMS (ESI) m/z: 541.3[M+H]⁺, HPLC method B: R_T=6.04 min, purity: 93.9%. ¹H NMR (600 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.87-7.83 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.45 (d, J=7.2 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 5.75-5.65 (m, 1H), 5.05-5.03 (m, 1H), 4.94 (d, J=17.4 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 4.61-4.54 (m, 2H), 4.09 (brs, 1H), 3.97-3.95 (m, 1H), 3.68-3.58 (m, 2H), 3.43 (d, J=9.0 Hz, 1H), 2.78-2.73 (m, 1H), 1.94 (s, 3H), 1.79 (brs, 1H), 1.71 (d, J=8.4 Hz, 1H), 1.59 (s, 6H).

Example 69: Synthesis of Compound 69

Step 1: Synthesis of Compound 69-1

The substrate 38-1 (241.29 mg, 1.10 mmol) was added to a dry single-necked flask and dissolved in N,N-dimethylformamide (5 mL), then added with methyl chloroformate (104 mg, 1.10 mmol), K₂CO₃ (194 mg, 1.40 mmol) to react for 5 hours at room temperature and monitored by LC-MS, then extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 69-1 (60 mg, 216.39 mol). LCMS (ESI) m/z: 278.1 [M+H]⁺.

Step 2: Synthesis of Compound 69-2

The compound 69-1 (75 mg, 270.45 μmol) was added to a 50 mL round-bottomed flask and dissolved in methanol (3 mL), added with a catalytic amount of Pd/C (15 mg), stirred for 1 hour at room temperature under H₂ atmosphere and monitored by LC-MS. After the reaction, the reacton solution was filtered with diatomaceous earth, washed two times with methanol, the filterate was concentrated under reduced pressure to give the compound 69-2 (38 mg, 153.66 μmol). LCMS (ESI) m/z: 248.1 [M+H]⁺.

Step 3: Synthesis of Compound 69

The substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (3 mL) were added to a dry single-necked flask, stirred to dissolve, then N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 69-2 (38 mg, 153.66 μmol) were added to react for 4 hours at room temperature and monitored by LC-MS, then the solvents were removed by distillation under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 69 (35 mg, 62.88 μmol). LCMS (ESI) m/z: 557.2[M+H]⁺, HPLC method B: R_T=7.13 min, purity: 98.7%. ¹H NMR (600 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.87-7.84 (m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.44 (s, 2H), 7.33 (d, J=7.2 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 5.75-5.65 (m, 1H), 5.05-5.02 (m, 1H), 4.96-4.91 (m, 1H), 4.74 (d, J=6.0 Hz, 2H), 4.39 (d, J=5.4 Hz, 2H), 3.93-3.83 (m, 2H), 3.65 (s, 3H), 3.37 (d, J=10.2 Hz, 2H), 2.74-2.69 (m, 1H), 1.60-1.59 (m, 7H).

Example 70: Synthesis of Compound 70

Step 1: Synthesis of Compound 70-2

The compound 70-1 (100 mg, 507.53 μmol) was dissolved in tetrahydrofuran (3 ml) in a dry single-necked flask, cooled to 0° C. and added with NaH (14.62 mg, 609.04 μmol), stirred for 10 min at 0° C., added with C₂H₅I (94.99 mg, 609.04 μmol), warmed to room temperature and stirred for 2 hours, monitored by LC-MS, quenched with water after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 70-2 (65 mg, 288.78 mol). LCMS (ESI) m/z: 225.0[M+H]⁺.

Step 2: Synthesis of Compound 70-3

The compound 70-2 (65 mg, 288.78 μmol) was dissolved in trifluoroacetic acid (1 ml) in a dry single-necked flask, added with acetic anhydride (30.62 mg, 288.78 μmol, 0.5 mL), warmed to 70° C. and stirred for 4 hours, monitored by LC-MS, cooled to room temperature after the reaction, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 70-3 (40 mg, 149.74 μmol). LCMS (ESI) m/z: 267.0[M+H]⁺.

Step 2: Synthesis of Compound 70-4

The substrate 70-3 (32.78 mg, 122.70 μmol), IM-1-4 (30 mg, 134.97 μmol), CuI (46.74 mg, 245.41 μmol), K₂CO₃ (23.74 mg, 171.78 μmol) and N,N′-Dimethylethylenediamine (43.27 mg, 490.81 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (2 mL), heated up to 110° C. to react for 3 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure to remove the solvents. The residue was purified by MPLC to give the compound 70-4 (33 mg, 74.26 μmol). LCMS (ESI) m/z: 409.1[M+H]⁺.

Step 3: Synthesis of Compound 70

The substrate 70-4 (59.71 mg, 146.17 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (45.40 mg, 263.10 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (94.45 mg, 730.83 μmol) and 1-5 (33.55 mg, 175.40 μmol) were added to the reaction solution to react for 12 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 70 (23 mg, 40.40 μmol). LCMS (ESI) m/z: 552.2 [M+H]⁺, HPLC method B: R_T=6.81 min, purity: 97.6%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.84 (s, 1H), 8.64 (d, J=10.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.56 (s, 2H), 6.91-6.89 (m, 2H), 5.71-5.66 (m, 1H), 4.50-4.99 (m, 1H), 4.85 (d, J=17.4 Hz, 1H), 4.66-4.59 (m, 2H), 4.35-4.32 (m, 2H), 3.09-3.08 (m, 4H), 2.49 (s, 3H), 2.48-2.46 (m, 4H), 2.23 (s, 3H), 1.47-1.45 (m, 3H).

Example 71: Synthesis of Compound 71

Step 1: Synthesis of Compound 71-1

The compound 70-1 (600 mg, 2.67 mmol) was dissolved in 1,4-Dioxane (1 ml) in a dry single-necked flask, added with Pyridine tribromide (3.41 g, 10.66 mmol), stirred for 16 hours at room temperature and monitored by LC-MS, added with water after the reaction, extracted three times with CH₂Cl₂. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 71-1 (230 mg, 576.62 μmol). LCMS (ESI) m/z: 398.8[M+H]⁺.

Step 2: Synthesis of Compound 71-2

The compound 71-1 (230 mg, 576.62 μmol) was dissolved in tetrahydrofuran (1.5 mL) in a dry single-necked flask, added with zinc powder (45.57 mg, 696.93 μmol) and saturated NH₄Cl solution (1.5 mL), stirred for 10 min at room temperature, monitored by LC-MS, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure The residue was purified by MPLC to give the compound 71-2 (44 mg, 182.51 μmol). LCMS (ESI) m/z: 241.0[M+H]⁺.

Step 3: Synthesis of Compound 71-3

The compound 71-2 (250 mg, 1.16 mmol) was dissolved in tetrahydrofuran (2 ml) in a dry single-necked flask, cooled to 0° C. and added with NaH (83.30 mg, 3.47 mmol), stirred for 10 min at 0° C., added with CH₃I (492.7 mg, 3.47 mmol), warmed to room temperature and stirred for 6 hours, monitored by LC-MS, quenched with water after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 71-3 (210 mg, 912.64 μmol). LCMS (ESI) m/z: 269.0[M+H]⁺.

Step 4: Synthesis of Compound 71-4

The substrate 71-3 (17.61 mg, 65.44 μmol), IM-1-4 (16 mg, 71.99 μmol), CuI (24.93 mg, 130.88 μmol), K₂CO₃ (12.66 mg, 91.62 μmol) and N,N′-Dimethylethylenediamine (23.07 mg, 261.77 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (1 mL), heated up to 110° C. to react for 3 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 71-4 (2.01 mg, 4.91 μmol). LCMS (ESI) m/z: 411.2[M+H]⁺.

Step 3: Synthesis of Compound 71

The substrate 71-4 (2.01 mg, 4.91 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (2 mL) to dissolve, then added with M-chloroperoxybenzoic acid (1.52 mg, 8.83 μmol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (3.17 mg, 24.54 μmol, 4.27 μL) and 1-5 (938.70 g, 4.91 μmol) were added to the reaction solution to react for 8 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 71 (2.3 mg, 3.45 μmol). LCMS (ESI) m/z: 554.3 [M+H]⁺, HPLC method B: R_T=5.89 min, purity: 83.2%. ¹H NMR (600 MHz, CDCL3) δ 8.77 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.42 (d, J=1.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 6.87-6.84 (m, 2H), 5.70-5.63 (m, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.92 (d, J=16.8 Hz, 1H), 4.63 (d, J=5.4 Hz, 2H), 3.80-3.77 (m, 2H), 3.36-3.24 (m, 4H), 2.87-2.80 (m, 4H), 2.49-2.45 (m, 3H), 1.36 (s, 6H), 1.23-1.21 (m, 3H).

Example 72: Synthesis of Compound 72

Step 1: Synthesis of Compound 72-2

The substrate 72-1 (88 mg, 395.92 μmol) was added to a dry single-necked flask, and dissolved in CH₂Cl₂ (20 mL), then added with IM-1-4 (170 mg, 764.85 μmol), pyridine (0.4 mL), Cu(Ac)₂ (146 mg, 803.83 μmol), stirred for 24 hours at 30° C. and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by MPLC to give the compound 72-2 (28 mg, 79.00 μmol). LCMS (ESI) m/z: 354.95 [M+H]⁺.

Step 2: Synthesis of Compound 72

The substrate 72-2 (28 mg, 79.00 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (2 mL) to dissolve, then added with M-chloroperoxybenzoic acid (27.26 mg, 157.99 mol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (16 mg, 83.65 μmol) and 1-5 (938.70 μg, 4.91 μmol) were added to the reaction solution to react for 2 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 72 (9 mg, 17.72 μmol). LCMS (ESI) m/z: 498. 1[M+H]⁺, HPLC method B: R_T=8.01 min, purity: 98%. ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.85-7.81 (m, 2H), 7.48-7.41 (m, 5H), 6.86 (d, J=8.4 Hz, 2H), 5.79-5.72 (m, 1H), 5.18-5.09 (m, 2H), 4.47 (d, J=6.0 Hz, 2H), 3.32 (s, 4H), 2.86 (s, 4H), 2.55 (s, 3H).

Example 73: Synthesis of Compound 73

Step 1: Synthesis of Compound 73-2

The compound 73-1 (0.5 g, 3.28 mmol) was dissolved in acetonitrile (5 mL) in a dry single-necked flask, added with pyridine (1.5 mL) and Selectfluor reagent (1.05 g, 2.95 mmol), stirred for 16 hours at 15° C. and monitored by LC-MS, added with water after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC to give the compound 73-2 (112 mg, 656.62 μmol). LCMS (ESI) m/z: 171.0 [M+H]⁺.

Step 2: Synthesis of Compound 73-3

The compound 73-2 (0.112 g, 656.62 μmol) was dissolved in N,N-Dimethylformamide (3 ml) in a dry single-necked flask, cooled to 0° C. and added with NaH (39.40 mg, 984.93 μmol, 60% purity), stirred for 30 min at 0° C., added with C₂H₅I (153.65 mg, 984.93 μmol, 78.79 μL), warmed to room temperature and stirred for 16 hours, monitored by LC-MS, quenched with saturated NH₄Cl solution after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 73-3 (120 mg, 604.16 μmol). LCMS (ESI) m/z: 199.2 [M+H]⁺.

Step 3: Synthesis of Compound 73-4

The substrate 73-3 (0.04 g, 201.39 μmol), IM-1-4 (44.76 mg, 201.39 μmol), CuI (76.71 mg, 402.77 μmol), NaI (60.37 mg, 402.77 μmol), K₂CO₃ (69.58 mg, 503.46 μmol) and N,N′-Dimethylethylenediamine (114.58 mg, 805.54 μmol) were added to a dry microwave tube under N₂ protection, then added with anisole (1.5 mL), microwave heated up to 130° C. to react for 4 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, added with water and ammonia (1 mL), extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 73-4 (20 mg, 52.03 μmol). LCMS (ESI) m/z: 385.0 [M+H]⁺.

Step 4: Synthesis of Compound 73

The substrate 73-4 (20 mg, 52.03 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (19.01 mg, 93.65 μmol, 85% purity) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (67.24 mg, 520.25 μmol, 90.62 μL) and 1-5 (11.94 mg, 62.43 μmol) were added to the reaction solution to react for 5 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 73 (20.7 mg, 37.39 μmol). LCMS (ESI) m/z: 528.3 [M+H]⁺, HPLC method B: R_T=8.09 min, purity: 95.3%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.16 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 7.67 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.61 (s, 2H), 6.92 (d, J=8.4 Hz, 2H), 5.74-5.68 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.86 (d, J=17.4 Hz, 1H), 4.65 (s, 2H), 4.26-4.22 (m, 2H), 3.12-3.09 (m, 4H), 2.47-2.45 (m, 4H), 2.22 (s, 3H), 1.39-1.36 (m, 3H).

Example 74: Synthesis of Compound 74

Step 1: Synthesis of Compound 74-2

The compound 74-1 (1.01 g, 3.99 mmol) was dissolved in N,N-Dimethylformamide (30 mL) in a dry single-necked flask, added with isobutylene oxide (345.57 mg, 4.79 mmol) and K₂CO₃ (1.66 g, 11.98 mmol), warmed up to 120° C. to react for 8 hours and monitored by LC-MS, cooled to room temperature after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 74-2 (680 mg, 2.09 mmol). LCMS (ESI) m/z: 311.9 [M+H]⁺.

Step 2: Synthesis of Compound 74-3

The compound 74-2 (98 mg, 301.54 μmol) was dissolved in tetrahydrofuran (4 ml) in a dry single-necked flask, cooled to 0° C. and added in batches with NaH (24.12 mg, 603.08 μmol, 60% purity), warmed up to 60° C. and stirred for 30 hours, monitored by LC-MS, quenched with saturated NH₄Cl solution after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 74-3 (48 mg, 196.65 μmol). LCMS (ESI) m/z: 244.0[M+H]⁺.

Step 3: Synthesis of Compound 74-4

The substrate 74-3 (47 mg, 192.56 μmol), IM-1-4 (31.77 mg, 142.96 μmol), CuI (36.67 mg, 192.56 μmol), K₂CO₃ (38.30 mg, 277.14 μmol) and N,N′-Dimethylethylenediamine (33.95 mg, 385.11 μmol) were added to a dry microwave tube under N₂ protection, then added with 1,4-Dioxane (3 mL), microwave heated up to 120° C. to react for 4 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 74-4 (12 mg, 31.13 μmol). LCMS (ESI) m/z: 386.1[M+H]⁺.

Step 4: Synthesis of Compound 74

The substrate 74-4 (12 mg, 31.13 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (21.49 mg, 124.53 mol) to react for 0.5 hour at room temperature, then N,N-diisopropylethylamine (20.22 mg, 156.46 mol, 27.25 μL) and 1-5 (20 mg, 104.56 μmol) were added to the reaction solution to react for 8 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 74 (7.2 mg, 12.56 μmol). LCMS (ESI) m/z: 529.2[M+H]⁺, HPLC method B: R_T=7.08 min, purity: 92.2%. ¹H NMR (600 MHz, Chloroform-d) δ 8.80 (s, 1H), 7.47 (d, J=7.8 Hz, 2H), 7.37-7.30 (m, 2H), 6.90 (d, J=8.4 Hz, 2H), 5.74-5.68 (m, 1H), 5.05 (d, J=10.2 Hz, 1H), 4.98 (d, J=16.8 Hz, 1H), 4.69 (s, 2H), 4.11 (s, 2H), 3.24 (s, 4H), 2.69 (s, 4H), 2.43 (s, 3H), 1.41 (s, 6H).

Example 75: Synthesis of Compound 75

Step 1: Synthesis of Compound 75-2

The compound 75-1 (965 mg, 5.00 mmol) was dissolved in N,N-Dimethylformamide (20 mL) in a dry single-necked flask, added with C₂H₅I (383 mg, 4.70 mmol) and N,N-Diisopropylethylamine (1.29 g, 10.00 mmol) to 120° C. to react for 1 hour at room temperature and monitored by TLC, extracted three times with ethyl acetate after the reaction. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 75-2 (650 mg, 3.22 mmol). LCMS (ESI) m/z: 202.0 [M+H]⁺.

Step 2: Synthesis of Compound 75-3

The compound 75-2 (308 mg, 1.53 mmol) was dissolved in tetrahydrofuran (5 mL) in a dry single-necked flask, added with zinc powder (1.6 g, 24.62 mmol) and NH₄Cl (642 mg, 12.00 mmol), warmed up to 70° C. and stirred for 3 hours, monitored by LC-MS, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure The residue was purified by MPLC to give the compound 75-3 (248 mg, 1.44 mmol). LCMS (ESI) m/z: 172.1 [M+H]⁺.

Step 3: Synthesis of Compound 75-4

The substrate 75-3 (248 mg, 1.44 mmol) was dissolved in triethyl orthoacetate (4 ml) in a dry single-necked flask, stirred for 1 hour at 100° C., added with acetic acid (1.05 g, 17.47 mmol, 1 mL), continue to be stirred for 8 hours, monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure, extracted three times with ethyl acetate after the reaction. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by MPLC to give the compound 75-4 (220 mg, 1.12 mmol). LCMS (ESI) m/z: 196.1 [M+H]⁺.

Step 4: Synthesis of Compound 75-5

The substrate 75-4 (64 mg, 327.12 μmol), IM-1-4 (72.71 mg, 327.12 μmol), CuI (124.60 mg, 654.23 μmol), NaI (98.06 mg, 654.23 μmol), K₂CO₃ (38.30 mg, 277.14 μmol) and N,N′-Dimethylethylenediamine (186.12 mg, 1.31 mmol) were added to a dry microwave tube under N₂ protection, then added with anisole (2 mL), microwave heated up to 130° C. to react for 10 hours under N₂ atmosphere and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, added with water and ammonia (1 mL), extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 75-5 (15 mg, 39.32 μmol). LCMS (ESI) m/z: 382.2 [M+H]⁺.

Step 5: Synthesis of Compound 75

The substrate 75-5 (15 mg, 39.32 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (2 mL) to dissolve, then added with M-chloroperoxybenzoic acid (20.36 mg, 117.97 mol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (25.36 mg, 196.25 mol, 34.18 μL) and 1-5 (18.77 mg, 98.12 μmol) were added to the reaction solution to react for 8 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 75 (3.2 mg, 5.12 μmol). LCMS (ESI) m/z: 525.2[M+H]⁺, HPLC method B: R_T=6.16 min, purity: 84.0%. ¹H NMR (600 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 5.75-5.68 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.89 (d, J=17.4 Hz, 1H), 4.73 (d, J=3.6 Hz, 2H), 4.32-4.28 (m, 2H), 3.25 (s, 4H), 2.71-2.68 (m, 7H), 2.45 (s, 3H), 1.47-1.42 (m, 3H).

Example 76: Synthesis of Compound 76

Step 1: Synthesis of Compound 76

The substrate 51-2 (26 mg, 70.95 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (2 mL) to dissolve, then added with M-chloroperoxybenzoic acid (35 mg, 202.82 mol) to react for 2 hours at 50° C., then N,N-diisopropylethylamine (45.62 mg, 353.00 μmol) and IM-2 (22 mg, 108.22 μmol) were added to the reaction solution to react for 8 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 76 (15 mg, 28.76 μmol). LCMS (ESI) m/z: 522.3[M+H]⁺, HPLC method B: R_T=7.68 min, purity: 94.4%. ¹H NMR (600 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.53-7.43 (m, 3H), 7.28 (d, J=3.6 Hz, 1H), 6.54-6.52 (m, 3H), 5.75-5.69 (m, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.90 ((d, J=17.4 Hz, 1H), 4.76 (s, 2H), 4.34-4.28 (m, 3H), 3.78 (s, 1H), 3.51-3.45 (m, 2H), 3.21 (s, 1H), 2.84 (s, 1H), 2.53 (s, 3H), 2.21 (s, 1H), 2.06 (d, J=9.6 Hz, 1H), 1.51-1.46 (m, 3H).

Example 77: Synthesis of Compound 77

Step 1: Synthesis of Compound 77

The substrate 51-2 (26 mg, 70.95 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (2 mL) to dissolve, then added with M-chloroperoxybenzoic acid (35 mg, 202.82 mol) to react for 6 hours at 55° C., then N,N-diisopropylethylamine (45.62 mg, 353.00 μmol) and 77-1 (17 mg, 89.34 μmol) were added to the reaction solution to react for 8 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 77 (5 mg, 9.83 μmol). LCMS (ESI) m/z: 509.6[M+H]⁺, HPLC method B: R_T=8.50 min, purity: 98.2%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.87 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.67 (d, J=3.0 Hz, 3H), 7.53 (d, J=7.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.58 (d, J=3.6 Hz, 1H), 5.74-5.68 (m, 1H), 5.00 (d, J=7.2 Hz, 1H), 4.86 (d, J=16.8 Hz, 1H), 4.61 (s, 2H), 4.30-4.26 (m, 2H), 2.86 (d, J=11.4 Hz, 2H), 2.41-2.39 (m, 1H), 2.19 (s, 3H), 1.97-1.93 (m, 2H), 1.71-1.62 (m, 4H), 1.41-1.38 (m, 3H).

Example 78: Synthesis of Compound 78

Step 1: Synthesis of Compound 78-1

3,4-Difluoronitrobenzene (159 mg, 999.43 μmol) was dissolved in dimethyl sulfoxide (3 mL) in a dry single-necked flask and, added sequentially with 27-1 (237.78 mg, 1.20 mmol) and K₂CO₃ (137.92 mg, 999.43 μmol). The reaction mixture was stirred overnight at 100° C. and monitored by LC-MS, then diluted with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 78-1 (302 mg, 890 μmol). LCMS (ESI) m/z: 338.2[M+H]⁺.

Step 2: Synthesis of Compound 78-2

The substrate 78-1 (337.35 mg, 1 mmol) was added to a dry single-necked flask, and dissolved in CH₂Cl₂ (2 mL), then added slowly with trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) to react for 0.5 hour at room temperature and monitored by LC-MS, then concentrated by distillation under reduced pressure to remove the solvents to give the compound 78-2 (223 mg, 0.94 mmol). LCMS (ESI) m/z: 238.1[M+H]⁺.

Step 3: Synthesis of Compound 78-3

The substrate 78-2 (223 mg, 0.94 mmol) was added to a dry single-necked flask, and dissolved in 1,2-Dichloroethane (3 mL), added with formaldehyde (150.13 mg, 5.00 mmol), stirred for 10 min at room temperature, added with sodium triacetoxyborohydride (1.06 g, 5.00 mmol), stirred for 1 hour at room temperature, cooled to room temperature after the reaction, added with water for dilution, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 78-3 (198 mg, 0.78 mmol). LCMS (ESI) m/z: 252.1[M+H]⁺.

Step 4: Synthesis of Compound 78-4

The compound 78-3 (251.26 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and acetic acid (0.5 mL) in a dry single-necked flask, added with zinc powder (1.95 g, 30.00 mmol), stirred for 30 min at room temperature, monitored by LC-MS, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure to give the compound 78-4 (200 mg, 903.86 μmol). LCMS (ESI) m/z: 222.1[M+H]⁺.

Step 5: Synthesis of Compound 78

The substrate IM-1 (42.27 mg, 118.27 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (30.61 mg, 177.40 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (76.43 mg, 591.35 μmol) and 78-4 (27 mg, 118.27 μmol) were added to the reaction solution to react for 4 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 78 (2 mg, 3.72 μmol). LCMS (ESI) m/z: 531.7 [M+H]⁺. HPLC: R_T=7.53 min, purity: 85.0%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.85 (s, 1H), 8.002-7.99 (m, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.71-7.67 (m, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.95-6.91 (m, 1H), 5.70-5.64 (m, 1H), 5.34 (s, 1H), 5.00 (d, J=10.2 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.68 (d, J=6.0 Hz, 2H), 3.63 (d, J=11.1 Hz, 2H), 3.50 (d, J=5.9 Hz, 2H), 3.43 (s, 2H), 3.17 (s, 2H), 2.04 (s, 3H), 1.46 (s, 6H).

Example 79: Synthesis of Compound 79

Step 1: Synthesis of Compound 79-1

3,4-Difluoronitrobenzene (354.16 mg, 2 mmol) was dissolved in dimethyl sulfoxide (5 mL) in a dry single-necked flask and, added sequentially with 27-1 (475.83 mg, 2.40 mmol) and K₂CO₃ (276.00 mg, 2.00 mmol). The reaction mixture was stirred for 1 hour at 100° C., then diluted with water after the reaction and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 79-1 (635 mg, 1.79 mmol). LCMS (ESI) m/z: 356.1 [M+H]⁺.

Step 2: Synthesis of Compound 79-2

The substrate 79-1 (635 mg, 1.79 mmol) was added to a dry single-necked flask, and dissolved in CH₂Cl₂ (5 mL), then added slowly with trifluoroacetic acid (2 mL) to react for 0.5 hour at room temperature and monitored by LC-MS, then concentrated by distillation under reduced pressure to remove the solvents to give the compound 79-2 (300 mg, 1.18 mmol). LCMS (ESI) m/z: 256.1[M+H]⁺.

Step 3: Synthesis of Compound 79-3

The substrate 79-2 (150 mg, 587.73 μmol) was added to a dry single-necked flask, and dissolved in 1,2-Dichloroethane (2 mL), added with formaldehyde (88.24 mg, 2.94 mmol), stirred for 10 min at room temperature, added with sodium triacetoxyborohydride (622.81 mg, 2.94 mmol), stirred for 1 hour at room temperature, cooled to room temperature after the reaction, added with water for dilution, extracted three times with CH₂Cl₂. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the compound 79-3 (131 mg, 487 mol). LCMS (ESI) m/z: 270.1[M+H]⁺.

Step 4: Synthesis of Compound 79-4

The compound 79-3 (131 mg, 487 μmol) was dissolved in tetrahydrofuran (3 mL) and acetic acid (0.2 mL) in a dry single-necked flask, added with zinc powder (0.96 g, 14.61 mmol), stirred for 30 min at room temperature, monitored by LC-MS, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure to give the compound 79-4 (123 mg, 515 μmol). LCMS (ESI) m/z: 240.1[M+H]⁺.

Step 5: Synthesis of Compound 79

The substrate IM-1 (15 mg, 42.20 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1 mL) to dissolve, then added with M-chloroperoxybenzoic acid (14.09 mg, 84.40 μmol) to react for 30 min at room temperature, then N,N-diisopropylethylamine (27.27 mg, 211.00 μmol) and 79-4 (10.10 mg, 42.20 μmol) were added to the reaction solution to react for 3 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 79 (1.5 mg, 2.48 μmol). LCMS (ESI) m/z: 549.3 [M+H]⁺. HPLC: R_T=7.95 min, purity: 90.6%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.95 (s, 1H), 8.03-7.99 (m, 1H), 7.75 (d, J=12.0 Hz, 1H), 7.67 (d, J=12.0 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 5.71-5.64 (m, 1H), 5.70-5.64 (m, 1H), 5.35 (s, 1H), 5.01-4.98 (m, 1H), 4.84 (d, J=1.8 Hz, 1H), 4.80 (d, J=1.8 Hz, 1H), 4.69 (d, J=8.0 Hz, 1H), 3.62 (d, J=15.6 Hz, 2H), 3.17 (d, J=10.2 Hz, 2H), 3.05 (d, J=10.2 Hz, 2H), 2.67 (d, J=2.4 Hz, 1H), 2.33 (d, J=3.0 Hz, 1H), 2.21 (s, 3H), 1.80 (d, J=12.0 Hz, 1H), 1.46 (s, 6H).

Example 80: Synthesis of Compound 80

Step 1: Synthesis of Compound 80-2

The substrate 80-1 (581.98 mg, 3.02 mmol) was added to a dry single-necked flask and dissolved in N,N-Dimethylformamide (10 mL), added with dimethyl malonate (436 mg, 3.30 mmol) and Cs₂CO₃ (3 g, 9.05 mmol), warmed up to 90° C. to react for 2 hours and monitored by LC-MS, then cooled to room temperature after the reaction, extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 80-2 (753 mg, 2.61 mmol). LCMS (ESI) m/z: 289.1 [M+H]⁺.

Step 2: Synthesis of Compound 80-3

The compound 80-2 (753 mg, 2.61 mmol) was dissolved in ethanol (10 mL) and acetic acid (2 mL) in a dry single-necked flask, added with iron powder (582.80 mg, 10.44 mmol), warmed up to 80° C. to react for 2 hours and monitored by LC-MS, filtered with diatomaceous earth after the reaction, the filterate was concentrated under reduced pressure. The residue was purified by MPLC to give the compound 80-3 (417 mg, 1.84 mmol). LCMS (ESI) m/z: 227.1 [M+H]⁺.

Step 3: Synthesis of Compound 80-4

The substrate 80-3 (45 mg, 198.57 μmol) was added to a dry single-necked flask and dissolved in acetonitrile (10 mL), added with CH₃I (0.22 g, 1.99 mmol) and K₂CO₃ (111 mg, 794.29 μmol) to react for 8 hours at 60° C. and monitored by LC-MS. The reaction solution was cooled to room temperature after the reaction, added with water and extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 80-4 (15 mg, 58.90 μmol). LCMS (ESI) m/z: 255.1[M+H]⁺.

Step 4: Synthesis of Compound 80-5

The substrate 80-4 (15 mg, 58.90 μmol), IM-1-4 (13.09 mg, 58.90 μmol), CuI (22.43 mg, 117.80 μmol), NaI (17.66 mg, 117.80 μmol), K₂CO₃ (25 mg, 176.70 μmol) and N,N′-Dimethyl-1,2-cyclohexanediamine (32.2 mg, 235.6 μmol) were added to a dry microwave tube under N₂ protection, then added with anisole (1.5 mL), microwave heated up to 130° C. to react for 4 hours under N₂ atmosphere and monitored by LC-MS. The reaction system was cooled to room temperature after the reaction, added with water and ammonia (1 mL), extracted three times with ethyl acetate. The organic phase was dried with anhydrous Na₂SO₄, filtered, concentrated under reduced pressure. The residue was purified by column chromatography to give the compound 80-5 (10.5 mg, 23.84 μmol). LCMS (ESI) m/z: 441.1[M+H]⁺.

Step 5: Synthesis of Compound 80

The substrate 80-5 (30 mg, 68.11 μmol) was added to a dry single-necked flask, and added with tetrahydrofuran (1.5 mL) to dissolve, then added with M-chloroperoxybenzoic acid (26.39 mg, 152.92 μmol) to react for 1 hour at room temperature, then N,N-diisopropylethylamine (19.76 mg, 152.92 μmol) and 1-5 (19.5 mg, 101.95 μmol) were added to the reaction solution to react for 3 hours at room temperature and monitored by LC-MS, then concentrated under reduced pressure after the reaction. The residue was purified by preparative high-performance liquid chromatography (alkaline) to give the compound 80 (5.7 mg, 9.77 μmol). LCMS (ESI) m/z: 584.2 [M+H]⁺. HPLC: R_T=6.37 min, purity: 98.8%. ¹H NMR (600 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.82 (s, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.67-7.39 (m, 2H), 6.92 (d, J=8.4 Hz, 2H), 5.66-5.63 (m, 1H), 4.99 (d, J=10.2 Hz, 1H), 4.81 (d, J=17.4 Hz, 1H), 4.46 (s, 2H), 3.59 (s, 3H), 3.28 (s, 3H), 3.10 (s, 4H), 2.48-2.43 (m, 4H), 2.23 (s, 3H), 1.58 (s, 3H).

Biological Evaluation Assay:

Unless otherwise specified, some biological evaluation experiments in this part of Example were compared with compound AZD-1775 as control. The structural information of AZD-1775(CAS No.: 955365-80-7) is as follows:

Test Example 1: The Binding of Compound to Wee1 Protein and Tracer 178 was Evaluated by TR-FRET Method

First, solutions of the compounds in different concentration gradients were prepared. The compounds were dissolved in DMSO and the compounds were diluted 4 folds with a total of 10 dose points and 2 parallel replicates for each concentration. DMSO was added as a positive control (maximal signal control) and a negative control (minimal signal control) and a final level of 0.25% DMSO was ensured in each reaction well.

The compound was added to 384-well plates with ECH0665, then added with WEE1 (Thermo Fisher, Cat #PR7373A) protein in buffer (50 mM Hepes pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35) with a final protein concentration of 15 nM, and The substrate Tracer 178 (Invitrogen, PV5593) and MAb Anti-GST-Eu crypate (Cisbio, 61GSTKLA) were added to 384-well plates (Corning, cat #3574), centrifuged at 1000 rpm for 1 min and the 384-well plates were incubated in a constant temperature shaker for 60 min at 25° C. and 300 rpm, wherein Tracer 178 and MAb Anti-GST-Eu crypate were prepared in buffer (50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35) with a final reaction concentration of 50 nM for Tracer 178 and a final concentration of 2 nM for MAb Anti-GST-Eu crypate, where the negative control (minimal signal control) used an equal amount of buffer in place of the protein solution.

After incubation, readings were performed using BMG PHERAStar (excitation light at 337 nm and emission light at wavelength values of 620 nm and 665 nm to read the fluorescence signal values). The ratio of the fluorescence signal was calculated: 665/620*1000 was the final signal value of the enzyme activity, and the TR-FRET signal of the reads obtained from the positive control (maximum signal control) and the negative control (minimum signal control) was normalized to give the inhibition rate for different concentrations of the compound. The IC50 for inhibition of enzyme activity by the compounds was then calculated using GraphPad Prism 6 and fitted with a log (inhibitor) vs. response-Variable slope mode. The fitting equation was: Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope)), wherein Y represents the percentage of residual enzyme activity known and X represents the known concentration of compound after the logarithm.

The Wee1 inhibitory activity of the compounds in the Examples was tested according to the method described above and the results are shown in Table 1, where the IC₅₀ of each compound is categorized as follows:

“−” represents IC₅₀ measured value of more than 10 μM;“+” represents IC₅₀ measured value of less than or equal to 10 μM and more than 1 μM;“++” represents IC₅₀ measured value of less than or equal to 1 μM and more than 100 nM;“+++” represents IC₅₀ measured value of less than or equal to 100 nM and more than 10 nM;“++++” represents IC₅₀ measured value of less than or equal to 10 nM and more than 5 nM;“+++++” represents IC₅₀ measured value of less than or equal to 5 nM.

TABLE 1
The inhibitory activity against Wee1 kinase
of the compounds of the present invention
Compound No.	IC50/nM	Compound No.	IC50/nM	Compound No.	IC50/nM
AZD1775	++++	Compound1	++++	Compound3	+++++
Compound4	+++++	Compound5	+++++	Compound6	+++++
Compound7	+++++	Compound8	++++	Compound9	+++++
Compound10	+++++	Compound11	++++	Compound12	++++
Compound13	++++	Compound14	++++	Compound15	++++
Compound16	+++	Compound17	++++	Compound18	++++
Compound19	+++++	Compound20	++++	Compound21	+++
Compound22	+++	Compound23	+++	Compound24	+++
Compound25	++++	Compound27	++++	Compound28	++++
Compound29	++++	Compound30	+++++	Compound31	+++
Compound32	+++	Compound33	+++	Compound34	+++
Compound35	+++	Compound36	+++	Compound37	+++
Compound38	+++	Compound39	+++++	Compound41	+++
Compound42	+++	Compound43	+++	Compound44	++++
Compound45	+++	Compound46	+++	Compound47	+++++
Compound47a	+++	Compound47b	+++	Compound48	+++++
Compound49	+++++	Compound50	++	Compound51	+++++
Compound52	+++	Compound53	++++	Compound54	++++
Compound55	+++	Compound56	+++	Compound57	+++
Compound58	++++	Compound60	++++	Compound61	+++++
Compound62	++++	Compound63	+	Compound64	+++
Compound65	++++	Compound66	++++	Compound67	++++
Compound68	+++	Compound69	+++	Compound70	++++
Compound71	+++	Compound72	+++	Compound73	+++
Compound74	+++	Compound75	+++	Compound76	+++
Compound77	++++	Compound78	+++	Compound79	+++

The above experiments showed that the disclosed compounds of the present invention have significant inhibitory activity against Wee1 kinase.

Test Example 2: Evaluation of Cell Proliferation Inhibitory Activity

1. Evaluation of the Anti-Proliferative Effect of Compounds on H1299 Cells by the Cell Titer-Glo Method

H1299 cells (ATCC, cat #HTB-96) in culture medium (90%1640 (Hyclone, cat #16600082)+10% FBS (Corning, Cat #35-081-CV)+100 ug/ml Normocin (InvivoGen, cat #Ant-nr-2)) at 750 cells/well were inoculated in 384-well plates, then incubated overnight at 37° C. with 5% CO₂ for cell adhesion.

Compound solutions of different concentration gradients were prepared. DMSO was dissolved to a concentration of 10 mM test compound and 10 mM reference compound AZD1775, and the compounds were serially diluted in culture medium for a total of 9 dose points, with 2 parallel replicates set at each concentration. The cell growth group without compound was used as a positive control (maximum signal control) and the medium was used as a negative control (minimum signal control), while ensuring that the final level of DMSO in each reaction well was 0.2%. After removing the medium from the 384-well plate, 25 ul of the configured compound at different concentrations was transferred into the well plate and the compound and cells were incubated in the cell incubator at 37° C. with 5% CO₂ for 3 days.

The 384-well plates were removed from the cell incubator and allowed to equilibrate for 1h to room temperature. 25 ul of Cell Titer-Glo assay was added to each well, lysed on a shaker for 2 min and then read out (Luminescence) using a BMG PHERAStar after 10 min incubation. Calculate the inhibition rate from the luminescence signal: first calculate the average of the positive control (maximum signal control) and the negative control (minimum signal control).

$\mathrm{Inhibition}\text{⁠}\%=\text{⁠}\text{⁠}1\text{⁠}-\left(\frac{S\left(\mathrm{Compound}\mathrm{signal}\mathrm{value}\right)-S\left(\mathrm{Negative}\mathrm{Control}\mathrm{signal}\mathrm{value}\right)}{\begin{array}{c}S\left(\mathrm{Positive}\mathrm{Control}\mathrm{signal}\mathrm{value}\right)-\\ S\left(\mathrm{Negative}\mathrm{Control}\mathrm{signal}\mathrm{value}\right)\end{array}}\right)\times 100\%$

was used to calculate the rate of inhibition of the cells by different concentrations of the compounds. The IC50 of the compound on cell activity inhibition was calculated by fitting a log(inhibitor) vs. response-Variable slope model to GraphPad Prism 6. The fitted equation was: Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope)), where Y represents the rate of inhibition and X represents the concentration of the known compound after Log.

2. Evaluation of the Anti-Proliferative Effect of Compounds on MIA PaCa2 Cells by the Cell Titer-Glo Method

MIA PaCa2 cells (ATCC, cat #CRL-1420) in culture medium (90%1640 (Hyclone, cat #16600082)+10% FBS (Corning, Cat #35-081-CV)+100 ug/ml Normocin (InvivoGen, cat #Ant-nr-2)) at 750 cells/well were inoculated in 384-well plates (Corning, 3707), then incubated overnight at 37° C. with 5% CO₂ for cell adhesion.

Compound solutions of different concentration gradients were prepared. DMSO was dissolved to a concentration of 10 mM test compound and 10 mM reference compound AZD1775, and the compounds were serially diluted in culture medium for a total of 9 dose points, with 2 parallel replicates set at each concentration. The cell growth group without compound was used as a positive control (maximum signal control) and the medium was used as a negative control (minimum signal control), while ensuring that the final level of DMSO in each reaction well was 0.2%. After removing the medium from the 384-well plate, 25 ul of the configured compound at different concentrations was transferred into the well plate and the compound and cells were incubated in the cell incubator at 37° C. with 5% CO₂ for 3 days.

The 384-well plates were removed from the cell incubator and allowed to equilibrate for 1 h to room temperature. 25 ul of Cell Titer-Glo assay was added to each well, lysed on a shaker for 2 min and then read out (Luminescence) using a BMG PHERAStar after 10 min incubation. Calculate the inhibition rate from the luminescence signal: first calculate the average of the positive control (maximum signal control) and the negative control (minimum signal control).

$\mathrm{Inhibition}\text{⁠}\text{⁠}\%=\text{⁠}\text{⁠}1\text{⁠}-\text{⁠}\left(\frac{S\left(\mathrm{Compound}\mathrm{signal}\mathrm{value}\right)-S\left(\mathrm{Negative}\mathrm{Control}\mathrm{signal}\mathrm{value}\right)}{\begin{array}{c}S\left(\mathrm{Positive}\mathrm{Control}\mathrm{signal}\mathrm{value}\right)-\\ S\left(\mathrm{Negative}\mathrm{Control}\mathrm{signal}\mathrm{value}\right)\end{array}}\right)\times 100\%$

was used to calculate the rate of inhibition of the cells by different concentrations of the compounds. The IC₅₀ of the compound on cell activity inhibition was calculated by fitting a log(inhibitor) vs. response-Variable slope model to GraphPad Prism 6. The fitted equation was: Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((Log IC₅₀−X)*HillSlope)), wherein Y represents the rate of inhibition and X represents the concentration of the known compound after Log.

The results of the in vitro anti-cell proliferation assays of H1299 and MIA Paca-2 for the example compounds according to the method described above are shown in Table 2, wherein the IC50 of each compound was determined and classified according to the description as follows:

“−” represents IC₅₀ measured value of more than 10 μM;“+” represents IC₅₀ measured value of less than or equal to 10 μM and more than 5 μM;“++” represents IC₅₀ measured value of less than or equal to 5 μM and more than 2 μM;“+++” represents IC₅₀ measured value of less than or equal to 2 μM and more than 1 μM;“++++” represents IC₅₀ measured value of less than or equal to 1 μM and more than 0.1 μM;“+++++” represents IC₅₀ measured value of less than or equal to 0.1 μM.

TABLE 2
Inhibitory activity of compounds of the present invention
on the proliferation of H1299 and MIA Paca-2 cells in vitro
Compound		MIA	Compound		MIA
No.	H1299	PaCa 2	No.	H1299	PaCa 2
AZD1775	++++	++++	Compound1	++	ND
Compound3	++++	++++	Compound4	+++	ND
Compound5	++++	ND	Compound6	++++	ND
Compound7	++++	ND	Compound8	+	ND
Compound9	+++	ND	Compound10	++++	ND
Compound11	++++	++++	Compound12	++++	++++
Compound13	+	+	Compound14	+	++
Compound15	−	++	Compound16	−	−
Compound17	++++	+++	Compound18	++	++++
Compound19	−	−	Compound20	++++	+++
Compound21	+++	++++	Compound22	++++	+++
Compound23	−	++	Compound24	+	++++
Compound25	+++	+++	Compound27	++++	++++
Compound28	++++	++++	Compound29	−	−
Compound30	+++	+++	Compound31	+	+
Compound32	++	++	Compound33	+++	++
Compound34	+	++	Compound35	++	+++
Compound36	+++	+++	Compound37	++	++++
Compound38	++	++++	Compound39	++++	+++++
Compound41	++++	++++	Compound42	++++	++++
Compound43	++	++	Compound44	++++	++++
Compound45	−	+	Compound46	++++	++++
Compound47	++++	++++	Compound47a	++++	+++
Compound47b	++	++	Compound48	++++	++++
Compound49	++++	++++	Compound50	+	−
Compound51	++++	++++	Compound52	−	−
Compound53	++++	++	Compound54	++	++
Compound55	+++	+++	Compound56	+	+
Compound57	−	−	Compound58	++++	++++
Compound60	++++	++++	Compound61	++	++
Compound62	+++	++++	Compound63	−	−
Compound64	++++	++++	Compound65	++++	++++
Compound66	++++	++++	Compound67	++++	+++++
Compound68	+++	++++	Compound69	++++	ND
Compound70	++++	ND	Compound71	++	ND
Compound72	+	ND	Compound73	+++	ND
Compound74	−	−	Compound75	+++	ND
Compound76	++++	+++	Compound77	+++	+++
Compound78	−	+++	Compound79	−	ND

As shown in Table 2, most of the compounds of the present invention exhibited strong cell proliferation inhibitory activity against H1299 and MIA Paca-2, some compounds were better than the control compound AZD1775 on cell proliferation inhibitory activity.

Test Example 3: Evaluation of Liver Microsomes (Mouse and Human) In Vitro

1. Preparation of Working Solution:

Microsomes were taken out from the −80° C. refrigerator, rapidly melted in a 37° C. water bath and placed on ice until ready to use. The test article was diluted with DMSO to prepare a 10 mM stock solution, and then diluted with acetonitrile to a 0.5 mM secondary stock solution. The microsomes were diluted to 0.75 mg/ml using Buffer C; the secondary stock solution was then added to a final concentration of 1.5 μM of compound as working solution, based on n=2, 5 time points, 350 μL of each compound was prepared and placed on ice prior to use. NADPH was diluted with Buffer C to a working solution of 6 mM for the starter solution. An acetonitrile solution containing an internal standard was prepared as the precipitant, and Verapamil-HCl was chosen as the internal standard at a concentration of 4 ng/ml.

2. Experimental Procedure:

A round-bottom well plate was taken, noted as the reaction plate, and the prepared working solution for each compound was dispensed into the well plate according to the number of replicates and time points (0 h samples were also added to the reaction plate), 30 μL/well; the plate was incubated at 37° C. for 10 min. A separate plate with pointed bottom wells, noted as a precipitation plate, was added with 135 μL precipitant per well; 0 h samples were transferred to the plate after 10 min incubation and 15 μL of starter solution was added; the plate was placed on ice before centrifugation.

The diluted starter solution was added in sufficient quantity to the dispensing plate to facilitate the multichannel pipette aspiration operation.

The reaction was carried out on a warm incubation shaker and 15 μL of starter solution/sample is added to the plate using a multichannel pipette. The reaction was mixed with a slight shake to initiate the reaction, which was accurately timed and recorded using a timer. In general, samples with shorter reaction times are initiated late and vice versa early, allowing sufficient time for multiple plate manipulation to terminate the reaction. For example, as for the four experiments of 5, 15, 30, and 60 min, the 60 min experiment was started first, and the 5 min experiment was started later, so as to leave sufficient time for the 5 min group.

After the reaction time had elapsed, all the solution in the plate was aspirated using the multichannel pipette and added to the precipitation plate to terminate the reaction at that point in time. After all reactions had been terminated, the plates were shaken for ten minutes on a plate shaker at 600 rpm to precipitate the protein. The plate was centrifuged at 4° C. for 15 minutes at maximum rpm. 80 μL of supernatant was taken, 320 μL of pure water was added and mixed for LC-MS analysis.

3. Test Results: As Shown in Table 3

TABLE 3
Test results of liver microsomes (mouse and human) in vitro
	T1/2/min	T1/2/min		T1/2/min	T1/2/min
Compound	(M)	(H)	Compound	(M)	(H)
AZD1775	25.99	38.12	Compound3	96.25	>120
Compound4	10.08	22.21	Compound6	5.72	5.16
Compound8	>120	untested	Compound9	0.78	2.82
Compound10	1.34	8.31	Compound11	110.0	untested
Compound12	31.50	untested	Compound15	>120	untested
Compound18	>120	untested	Compound19	48.12	untested
Compound23	38.72	untested	Compound24	>120	untested
Compound25	14.09	untested	Compound27	33	105
Compound28	15.03	untested	Compound37	21.72	untested
Compound39	>120	untested	Compound46	13.64	16.82
Compound51	14.65	19.04	Compound54	77	untested
Compound57	43.86	untested	Compound61	>120	untested
Compound62	25.11	untested	/	/	/

As shown in Table 3, the compounds of the present invention have good metabolic stability as evaluated in the model of liver microsomes in vitro.

Test Example 4: Membrane Permeability Study (Caco-2)

Caco-2 cells were purchased from the American Model Tissue Cell Collection (Rockville, MD). The cell culture medium was modified Eagle's medium (MEM) containing 10% inactivated fetal bovine serum and 1% non-essential amino acids. Cells were inoculated on polycarbonate filter membranes (Cat no. 3396) and incubated at 37° C. in a 5% CO₂ incubator.

The cells were incubated for 21-28 days after inoculation for transport experiments and the apparent permeability (Papp) of Lucifer Yellow was used to characterize and verify the compactness of the cell monolayer. A stock solution of 10 mM was prepared by dissolving the compound in DMSO and diluted using Hanks Balanced Salt Solution (HBSS, Invitrogen, Cat #14025-092) containing 25 mM HEPES (pH 7.4) to obtain the working solution. A 10 μM working solution of the compound to be tested was added to the apical side and basolateral side of Caco-2 and incubated at 37° C. for 90 min. After the incubation, dilute the samples on the apical side and basolateral side, and the concentrations of compounds on the apical and basolateral sides were detected by LC-MS/MS, and the concentrations of the compounds were quantified by standard curve.

TABLE 4
Membrane Permeability (Caco-2) data of compounds
		A-B	B-A	Efflux
	Compound	(10−6 cm · s−1)	(10−6 cm · s−1)	Ratio
	AZD1775	15.63	39.83	2.55
	Compound3	2.31	28.92	12.52
	Compound12	2.84	33.55	11.81
	Compound27	3.07	53.53	17.45
	Compound33	9.12	7.56	0.83
	Compound42	6.22	49.70	7.99
	Compound48	13.32	35.26	2.65

According to the test results of Table 4, the compounds of the present invention have the same membrane permeability (Caco-2) as the control compound.

Test Example 5: Evaluation of Plasma Protein Binding (PPB)

1. Experimental Procedure

Sample preparation: The compound was dissolved in DMSO to a stock solution of 10 mM, then the compound was diluted with PBS to a secondary stock solution of 0.02 mM, and then the above 0.02 mM was diluted to 1 μM using blank plasma, which was the sample to be incubated.

Dialysis set-up preparation: 400 μL of blank PBS was first added to the white wells of the equilibrated dialysis plate and 200 μL of the configured plasma sample was added to the red wells, and the dialysis plate was sealed with a sealing film.

Recovery plate preparation: Two 96-well deep-well plates, labelled T0 and T5, were prepared and all plasma samples were added at n=2. 300 μL of acetonitrile (Verapamil-HCl, 4 ng/mL) was added directly to the TO plate, followed by 50 μL of blank PBS mix well for 5 min and left to stand in a 4° C. refrigerator until the end of the incubation.

Experimental Operation: The dialysis device and the T5 plate were incubated together for 5 h in a microplate thermostatic shaker (37° C., using 300 rpm or minimum speed). At the end of the incubation, 300 μL of acetonitrile (Verapamil-HCl, 4 ng/mL) was added and 50 μL of PBS solution was added. At the end of the dialysis incubation, a new 96-well deep well plate was taken. Add 50 μL of plasma well sample to the corresponding position of the 96-well plate, 300 μL of acetonitrile and 50 μL of blank PBS; take 50 μL of buffer well sample to the corresponding position of the 96-well plate, then add 300 μL of acetonitrile and 50 μL of blank plasma. Add 300 μL of acetonitrile (Verapamil-HCl, 4 ng/mL) to the plasma-containing wells of the T5 plate, and then 50 μL of PBS solution was added. Shake for 5 min to fully precipitate the proteins and centrifuge at 20,000 g for 10 min at 4° C. Add 200 μL of supernatant to 200 μL of pure water, mix well and perform LC-MS/MS analysis.

2. Data Processing and Parameter Calculation

$\begin{array}{c}\mathrm{Plasma}\mathrm{protein}\mathrm{binding}\mathrm{rate}=\left[\left(\mathrm{Rpe}-\mathrm{Rb}\right)/\mathrm{Rpe}\right]\times 100\%\\ \mathrm{Recovery}=\left[\left(\mathrm{Rpe}+\mathrm{Rb}\right)/R5h\right]\times 100\%\\ \mathrm{Stability}=\left(R5/R0\right)\times 100\%\end{array}$

Wherein

R_pe=ratio of plasma-side testing sample peak area to internal standard

R_b=ratio of buffer side testing sample peak area to internal standard

R₅=ratio of incubator stability sample peak area to internal standard

R₀=ratio of refrigerator stability sample peak area to internal standard

3. Test Results: As Shown in Table 5

TABLE 5
Plasma protein binding of representative compounds (mouse)
Compound   Mouse plasma PPB(%)
AZD1775    91.3
Compound3  85.8
Compound27 85.9
Compound46 82.1
Compound48 96.9
Compound49 95.8
Compound51 97.0
Compound53 96.5

According to the test results of Table 5, the compounds of the present invention have a good plasma protein binding.

Test Example 6: Evaluation of Enzymatic Inhibitory Activity of CYP450 Isoforms

Enzymatic experiments were performed to quantify the inhibition of CYP450 enzyme activity of each isoform of CYP450 by small molecule inhibitors through fluorescence generated by the oxidation of the The substrate by cytochrome P450. The experiments were performed in 384-well plates (Corning, Cat #3575) using a reaction buffer of 142.86 mM Potassium Phosphate, pH 7.4. The Solution A components used in the experiments were: 26.13 mM NADP+(Sigma-aldrich, Cat #N0505) 65.77 mM G6P (J&K, Cat #968161) and 65.42 mM MgCl2 (Sigma-aldrich, Cat #M2670). The Solution B composition used for the experiment was: 40 U/mL G6PDH (Sigma-aldrich, Cat #G6378). The The substrate mix was 0.05×Solution A, 0.01×Solution B, 50 mM Potassium Phosphate, 0.01 mM BOMCC/0.01 mM EOMCC/0.001 mM DBOMF. For CYP3A4 and CYP2C9, the reaction system was 50 μL or 20 μL, respectively, including 3 nM CYP3A4 or 120 nM CYP2C9, BOMCC The substrate mixed solution and different concentrations of compounds to be tested. For CYP2C19, CYP2D6 and CYP1A2, the reaction system was 20 μL and included 12.5 nM CYP2C19, 80 nM CYP2D6 or 1 nM CYP1A2, EOMCC The substrate mix and various concentrations of the compounds to be tested. For CYP2C8, the reaction system is 50 μL and includes 1.5 nM CYP2C8, DBOMF The substrate mix and various concentrations of compound to be tested. After preincubation with the enzyme for 10 minutes, the The substrate was added and the fluorescence signal was read at different wavelengths (BOMCC/EOMCC Ex430 nm/Em480 nm, DBOMF Ex490 nm/Em520 nm) using BMG PHERAStar depending on the The substrate, with reaction intervals of 30 seconds or more (depending on the actual number of wells) and reaction times of 30 minutes. The data were analyzed and processed using GraphPad Prism 6 software to obtain IC50 values. The results were shown as Table 6.

TABLE 6
Compound inhibition test results on different isoforms of CYPs
	CYP inhibiton/%
Compound	1A2	2C8	2C9	2C19	2D6	3A4	2B6
AZD-1775	1 uM	20.2	7.1	15.4	25.4	3.4	−14.0	ND
	10 uM	17.5	17.3	6.4	71.9	1.5	−32.9	17.39
Compound 3	1 uM	4.5	−9.3	−1.5	1.0	2.6	−19.4	ND
	10 uM	7.8	−16.9	−7.0	16.6	−0.1	−35.3	1.38

According to the test results of Table 6, Compound 3 of the present invention had no significant cytochrome P450 enzymatic inhibitory activity.

Test Example 7: hERG Potassium Channel Inhibition Assay

Experimental Aim: To Detect the Effect of Compounds to be Tested on hERG Potassium Ion Channels by Manual Membrane Clamp Method.

Experimental Procedure:

(I) Experimental Materials:

A. CHO (Chinese Hamster Ovary Cells) Stably Transfected Cell Line Culture

The cell line used for the patch clamp assay was a 10th generation CHO cell overexpressing hERG potassium channel cDNA.

CHO hERG cells were cultured in Petri dishes or flasks at 37° C. in a 5% CO₂ incubator. Cells were dropped onto circular slides 24-48 hours prior to electrophysiological experiments and cultured in cell culture medium and used for experiments after the cells had been adhered.

Cell culture medium (purchased from Invitrogen) Composition:

• • Ham's F12 medium
  • 10% (v/v) heat inactivated FBS
  • 100 μg/ml Hygromycin B (thaumatin)
  • 100 μg/ml Geneticin (Genomycin, G418)

B. Compound Preparation

Compound powders are dissolved in the extracellular solution and are subjected to a routine 5 to 10 minute sonication and shaking to ensure complete dissolution of the compound.

The final concentrations of compounds used for electrophysiological assays were 5, 20 μM and the final concentration of DMSO was 0.1%. (II) Experimental protocol:

A. Experimental Procedure for Electrophysiological Recordings

Cell membrane currents were recorded using a HEKA EPC-10 USB patch-clamp amplifier (HEKA Elektronik, Germany).

• • 1) A coverslip with a large number of uniformly growing individual CHO hERG cells on its surface was taken. Place in a continuous recording cell on an inverted microscope, perfused with extracellular fluid (approximately 1 ml per minute) and recorded continuously, waiting for the current to stabilize.
  • 2) Record HERG channel currents for individual cells using standard whole cell recording mode. The membrane voltage is first clamped at −80 mV and the cell is given a +20 mV stimulus for 5 s to activate the hERG potassium channel, then repolarized to −50 mV for 5 s to generate an outward tail current, which is continuously perfused until the current is stable, at which point the peak tail current is the control current value.
  • 3) The extracellular solution containing the drug to be tested was then perfused and recorded until the inhibitory effect of the drug on the hERG current reached a steady state, at which point the peak tail current was the post-drug current value.
  • 4) The cells are again perfused with the extracellular solution until the hERG current returns to or approaches the level prior to the addition of the drug, then the perfusion can be continued to test other concentrations or drugs. One or more compound or drug concentrations may be tested on each cell.
  • 5) Cisapride (C4740-10 mg, Sigma) is used as a positive control in the experiment to ensure that the cells used respond properly.

(III) Quality Control

The following criteria need to be met for the reported experimental data:

Electrophysiological Recording Parameters

• • a) Sealing resistance >500MΩ
  • b) contact resistance (Ra)<10 MΩ
  • c) Initial tail current amplitude >200 pA
  • d) Current rundown (spontaneous reduction)<2%/min
  • e) Leakage current <200 pA or 10% of peak hERG current (within 90% of recording time)

The test results were shown as Table 7.

TABLE 7
Test results of compound hERG inhibition
	hERG inhibition/%
	Compound	5 μM	20 μM
	AZD1775	21.45	49.98
	Compound 3	3.84	21.56

According to the test results of Table 7, Compound 3 of the present invention had no significant hERG inhibitory activity. It is clear from the results of the tests of the present invention that the compounds of the present invention, especially, the preferred compounds, are superior to the prior art in terms of pharmaceutical activity and toxic side effects.

Test Example 8: Evaluation of Compound Pharmacokinetics on Single Dose in Mice

The present experiment aimed to study the pharmacokinetics in the plasma of male ICR mice after the administration.

1. Experimental Aim:

The present experiment aimed to obtain the pharmacokinetic profile of the subject compounds in ICR mice (both intravenous and oral)

2. Standard Compliance

In this experiment (non-GLP study), the test articles-testing, DMPK animal test, and DMPK analysis were done in Chengdu Hitgen, and all the tests followed the present test protocol, and the relevant SOPs of the related organizations.

3. Test Materials, Instruments and Equipment

3.1 Test Materials

3.1.1 Test Articles

The following test articles were provided by Chengdu Hitgen and their quality was ensured to meet the requirements.

Name/Code                      Test compound
Nature                         solution
Solvent/Dosage form            5% DMSO - 10% Solutol -
                               85% HPBCD (20%, W/V)
preservation condition         room temperature
Concentration of test solution 0.2 mg/ml (intravenous),
                               1 mg/ml (oral)
Volume of test solution        3 ml, 3 ml

3.1.2 Test System

Species: SPF grade male ICR miceBody weight/weekly age: about 30 g

Amount: 6

Experimental animal source: Charles River

4. Experimental Procedure:

4.1 Solvent Preparation

Intravenous solvents: 5% DMSO—10% Solutol-85% HPBCD (20%, W/V)

“Gavage solvent/dosage form: 5% DMSO—10% Solutol-85% HPBCD (20%, W/V)”

4.2 Subjects Given (Route)

Intravenous: 1 mg/kg in a volume of 5 mL/kg

Gavage: 10 mg/kg in a volume of 10 mL/kg

Ultrasound for 5 min before administration

4.3 Subject Preparation (Concentration)

Intravenous: 0.2 mg/mL

Gavage: 1 mg/mL

Fast overnight before administration and feed four hours after administration.

4.4 Sample Collection

Blood samples were collected by orbital venous plexus puncture (40-50 μL) into anticoagulant tubes containing pre-sprayed EDTA-K2 at 5 min (IV only), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h, respectively, and the supernatant, i.e., the plasma, was centrifuged at 10,000 rpm for 20 min within 1 h. The blood samples were stored in a refrigerator at or below −20° C. for LC-MS/MS analysis.

4.5 Biopharmaceutical Analytical Methods and Assays: LC-MS/MS Analytical Detection Used

5. Data Processing

The samples were detected for drug concentration at each time point by LC-MS/MS. Pharmacokinetic parameters terminal elimination half-life (t_1/2), area under the curve (AUC), apparent volume of distribution (Vd), clearance (CL), mean residence time (MRT), and Cmax were calculated using the non-compartmental model of Phoenix WinNonlin 5.2. Bioavailability (F %) was directly from serum concentration results. Mean±standard deviation (X±SD) was used for blood concentration and pharmacokinetic parameters, etc. Specific testing and analytical methods were specified in the form of protocol revisions.

6. The Test Results were Shown as Table 8

TABLE 8
Pharmacokinetic parameters in mice
	Parameters
	Forms of			AUClast
Compound	administration	Dosages	Cmax(ng/mL)	(h*ng/mL)	T1/2 (h)	MRT(h)	F/%
AZD1775	Intravenous	1 mg/kg	250	116	0.5	/	32
	Oral	10 mg/kg	398	396	0.87	/
Compound 3	Intravenous	1 mg/kg	124	145	1.17	0.97	22.4
	Oral	10 mg/kg	247	324	1.07	1.10
Compound 27	Intravenous	1 mg/kg	170	134	0.78	0.66	28.6
	Oral	10 mg/kg	392	285	1.03	1.10
Compound 48	Oral	10 mg/kg	470	482	0.64	0.9	/
Compound 49	Oral	10 mg/kg	388	534	1.03	1.14	/
Compound 51	Oral	10 mg/kg	290	430	0.95	1.18	/
Compound 53	Oral	10 mg/kg	800	1638	1.88	1.92	/

As shown in Table 8, pharmacokinetic assay analysis in mice in vivo indicated that compounds 48 and 49 of the present invention had comparable pharmacokinetic properties to the control compound AZD1775, and compounds 51, 53 had better pharmacokinetic properties than the control compound AZD1775.

Claims

1. A compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

2. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is selected from a group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl,

3. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R2 is selected from a group consisting of

4. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X1 is selected from a group consisting of chemical bond, O, NRN1 or CRC1RC2;RC1, RC2 are independently selected from a group consisting of H, —C1˜3 alkyl, halogen, halogen substituted —C1˜3 alkyl, —C1˜2 alkylene-N(C1˜3 alkyl)(C1˜3 alkyl);RN1 is selected from a group consisting of H, —C1˜3 alkyl, halogen substituted —C1˜3 alkyl, -(3˜10-membered heterocycloalkyl).

5. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 4, wherein: R4 is selected from a group consisting of

6. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 5, wherein: R4 is specifically selected from a group consisting of

7. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R5 is selected from a group consisting of H, halogen, —C1˜3 alkyl, halogen substituted —C1˜3 alkyl, hydroxy-substituted —C1˜3 alkyl, —O(C1˜3 alkyl), —NH(C1˜3 alkyl), —O—C2alkylene-N(C1˜3 alkyl)(C1˜3 alkyl), —O-(3˜10-membered cycloalkyl), —O-(3˜10-membered heterocycloalkyl); wherein said alkyl, alkylene, cycloalkyl, heterocycloalkyl are optionally substituted by one, two, three or four independent R51;R51 is selected from a group consisting of H, —C1˜3 alkyl, halogen substituted —C1˜3 alkyl.

8. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 7, wherein: R5 is selected from a group consisting of methyl, ethyl, ethoxyl, F, hydroxy-substituted methyl,

9. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R6 is selected from a group consisting of H, —C1˜3 alkyl, —NH(C1˜3 alkyl), —N(C1˜3 alkyl)(C1˜3 alkyl).

10. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: A ring is selected from

11. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: B ring is selected from a group consisting of 3˜10-membered heterocyclyl, 5˜12-membered bridged heterocyclyl, 3˜10-membered fused heterocyclyl; wherein said heterocyclyl, bridged heterocyclyl, fused heterocyclyl are optionally substituted by one, two, three or four independent RB1;each RB1 is independently selected from a group consisting of H, —C1˜3 alkyl, halogen substituted —C1˜3 alkyl.

12. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: B ring is selected from a group consisting of

13. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: C ring is selected from a group consisting of

14. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R7, R8 are independently selected from a group consisting of —OH,

15. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R3 is selected from a group consisting of

16. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: the specific compound represented by formula I is

17. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: the specific compound represented by formula I is

18. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: the specific compound represented by formula I is

19. A method of preparing a drug for the treatment of WEE1-mediated disease, comprising incorporating the compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19, wherein the WEE1-mediated disease is one or more of the diseases associated with inflammation, autoimmune disease, infectious disease, cancer, precancer syndrome.

21. A pharmaceutical composition, which is a formulation prepared with the compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as the pharmaceutically active ingredient, together with pharmaceutically acceptable excipients.