Ligand compounds and bifunctional compounds that bind to the trimer 21 protein and uses thereof

Abstract

The application provides a new type of compound capable of forming a combination with an E3 ligase protein TRIM21, and an intermediate for synthesizing a bifunctional compound targeting protein degradation, and further provides a PROTAC bifunctional compound constructed therefrom, and a use thereof in preparation of a medicament for treating a cell abnormal proliferation disease.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a ligand compound that binds to the ternary motif (TRIM) E3 ubiquitin ligase TRIM21 protein and a bifunctional compound that synthesizes protein degradation-targeting chimeric compounds (PROTACs). Background Technology

[0002] Protein degradation is a highly regulated process essential for maintaining cellular homeostasis. The ubiquitin-proteasome pathway (UPP) enables the selective identification and removal of damaged, misfolded, or excess proteins. UPP removes defective proteins and is characterized by ATP dependence, high efficiency, and high selectivity. Its catalytic component is the ubiquitin-derived E3 ligase, but it requires the prior recruitment of the protein to be degraded. PROTACs technology is designed based on the UPP principle, linking the target protein ligand and the E3 ligase ligand with appropriate chemical bonds. This allows for the recognition of the target protein and enhances the binding affinity of the E3 ligase to the target protein, thereby targeting ubiquitination and forcing the degradation of the target protein. It also features high catalytic activity, high efficiency, and high selectivity.

[0003] Multiple ubiquitin molecules are covalently linked to terminal lysine residues via E3 ubiquitin ligase to label proteins for proteasomal degradation. The protein is then digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0004] TRIM21 belongs to the TRIM family of E3 ligases, a multi-member family involved in ubiquitin-dependent proteolytic processes in the cellular NF-κB signaling pathway. Studies have shown that TRIM21 is associated with autoimmune diseases, and others have demonstrated its role in the development and prognosis of various tumors. Based on protein expression databases, TRIM21 is highly expressed in various tumors compared to normal tissues. Therefore, developing TRIM21-based ligand molecules and PROTACs could provide important research tools for the targeted degradation of pathogenic proteins in TRIM21-overexpressing tumors.

[0005] This invention discloses a novel class of compounds that can serve as effective TRIM21 ligands, and further synthesize corresponding bifunctional PROTACs compounds that can target protein degradation chimeras, which can be used to treat various medical conditions, especially abnormal cell proliferation. Summary of the Invention

[0006] This invention provides a compound of Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0007] Formula I The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 alkyl; R 2 Selected from hydrogen, halogens, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR 21 -C 0~4 Alkylene-OC(O)R 21 -C 0~4 Alkylene-SR 21 -C 0~4 Alkylene-S(O)2R 21 -C 0~4 Alkylene-S(O)R 21 -C 0~4 Alkylene-S(O)2NR 21 R 22 -C 0~4 Alkylene-S(O)NR 21 R 22 -C 0~4 Alkylene-C(O)R 21 -C 0~4 Alkylene-C(O)OR 21 -C 0~4 Alkylene-C(O)NR 21 R 22 -C 0~4 Alkylene-NR 21 R 22 -C 0~4 Alkylene-NR 21 C(O)R 22 -C 0~4 Alkylene-NR 21S(O)2R 22 -C 0~4 Alkylene-NR 21 S(O)R 22 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 23 replace; Each R 23 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR 21 -C 0~4 Alkylene-OC(O)R 21 -C 0~4 Alkylene-SR 21 -C 0~4 Alkylene-S(O)2R 21 -C 0~4 Alkylene-S(O)R 21 -C 0~4 Alkylene-S(O)2NR 21 R 22 -C 0~4 Alkylene-S(O)NR 21 R 22 -C 0~4 Alkylene-C(O)R 21 -C 0~4 Alkylene-C(O)OR 21 -C 0~4 Alkylene-C(O)NR 21 R 22 -C 0~4 Alkylene-NR 21 R 22 -C 0~4 Alkylene-NR 21 C(O)R 22 -C 0~4 Alkylene-NR 21 S(O)2R22 -C 0~4 Alkylene-NR 21 S(O)R 22 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 24 replace; R 21 R 22 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Each R 24 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-10 membered cycloalkyl groups, and 3-10 membered heteroalkyl groups; ring A may further be optionally surrounded by one, two, three, or four independent R groups. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 Alkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-OC(O)R A2 -C 0~4 Alkylene-SR A2 -C0~4 Alkylene-S(O)2R A2 -C 0~4 Alkylene-S(O)R A2 -C 0~4 Alkylene-S(O)2NR A2 R A3 -C 0~4 Alkylene-S(O)NR A2 R A3 -C 0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-NR A2 S(O)2R A3 -C 0~4 Alkylene-NR A2 S(O)R A3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace; The R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 Alkyne group.

[0008] As a preferred option: the R 1 Selected from hydrogen, methyl, ethyl, and propyl; More preferably: the R 1 Selected from ethyl.

[0009] As a preferred option: the R 2 Selected from hydrogen, methyl, ethyl, and propyl; More preferably: the R 2 Selected from methyl.

[0010] Preferably, ring A is selected from 6-membered cycloalkyl, 10-membered cycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, and 9-membered aromatic heterocycle; the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further optionally separated by one, two, three, or four independent R... A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, =O, and -C. 1~4 Alkyl, halogen-substituted -C 1~3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-C(O)NR A2 R A3 ; R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, halogen-substituted -C 1~6 alkyl.

[0011] Furthermore: the A ring is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0012] As a preferred embodiment, the compound is specifically: , , , , , , , , , , , , , , , ... , , , , , , , , , , , , , , , , , , , .

[0013] Furthermore, this invention provides a compound of formula V, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0014] Formula V The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 alkyl; Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-10 membered cycloalkyl groups, and 3-10 membered heterocycles; ring A may further be optionally surrounded by one, two, three, or four independent R groups. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 Alkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-OC(O)R A2 -C 0~4 Alkylene-SR A2 -C 0~4 Alkylene-S(O)2R A2 -C 0~4 Alkylene-S(O)R A2 -C 0~4 Alkylene-S(O)2NR A2 R A3 -C 0~4 Alkylene-S(O)NR A2 R A3 -C0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-NR A2 S(O)2R A3 -C 0~4 Alkylene-NR A2 S(O)R A3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace; The R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; T is selected from -(L) T ) q -; q is selected from integers from 1 to 50; each L T Structural fragments composed of any one or more members from the group consisting of the following groups, wherein the group is CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -, -C≡C-, 3~12-membered cycloalkyl, 3~12-membered heterocycloalkyl, 6~10-membered aromatic ring, 5~10-membered heteroaromatic ring, 5~12-membered spirocyclic ring, 5~12-membered spiroheterocyclic ring, 5~12-membered bridged ring, 5~12-membered bridged heterocyclic ring; wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocyclic, spiroheterocyclic, bridged ring, and bridged heterocyclic ring may be further modified by one, two, or three R T1 replace; Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR T2 -C 0~4 Alkylene-OC(O)R T2 -C 0~4 Alkylene-SR T2 -C 0~4 Alkylene-S(O)2R T2 -C 0~4 Alkylene-S(O)R T2 -C 0~4 Alkylene-S(O)2NR T2 R T3 -C 0~4 Alkylene-S(O)NR T2 R T3 -C 0~4 Alkylene-C(O)R T2 -C 0~4 Alkylene-C(O)OR T2 -C 0~4 Alkylene-C(O)NR T2 R T3 -C0~4 Alkylene-NR T2 R T3 -C 0~4 Alkylene-NR T2 C(O)R T3 -C 0~4 Alkylene-NR T2 S(O)2R T3 -C 0~4 Alkylene-NR T2 S(O)R T3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heterocyclic ring); wherein, the alkylene, cycloalkyl, heterocyclic, aromatic ring, or heterocyclic ring may be optionally surrounded by one, two, three, or four independent R... T4 replace; Each R T2 R T3 R T4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); X 2 Selected from -NH2, -NHR X21 -OH, -SH, ethynyl, vinyl, -C(O)H or -C(O)OH-; R X21 Selected from hydrogen, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 Alkyne group.

[0015] Preferably, the T is selected from... , , , , , , , , , , , , , , , , , .

[0016] As a preferred option: the R 1 Selected from hydrogen, methyl, ethyl, and propyl.

[0017] More preferably: the R 1 Selected from ethyl.

[0018] Preferably, ring A is selected from 6-membered cycloalkyl, 10-membered cycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, and 9-membered aromatic heterocycle; the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further optionally separated by one, two, three, or four independent R... A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, =O, and -C. 1~4 Alkyl, halogen-substituted -C 1~3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-C(O)NR A2 R A3 ; R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, halogen-substituted -C 1~6 alkyl.

[0019] Furthermore: the A ring is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0020] Furthermore, this invention provides a compound represented by Formula II, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0021] Formula II The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 alkyl; Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-10 membered cycloalkyl groups, and 3-10 membered heterocycles; ring A may further be optionally surrounded by one, two, three, or four independent R groups. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 Alkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-OC(O)R A2 -C 0~4 Alkylene-SR A2 -C 0~4 Alkylene-S(O)2R A2 -C 0~4 Alkylene-S(O)R A2 -C 0~4 Alkylene-S(O)2NR A2 R A3 -C 0~4 Alkylene-S(O)NR A2 R A3 -C 0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-NR A2 S(O)2R A3 -C 0~4 Alkylene-NR A2 S(O)R A3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace; The R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; The L is selected from TX. 2 ; where T is selected from -(L T ) q -; q is selected from integers from 1 to 50; Each L T Structural fragments composed of any one or more members from the group consisting of the following groups, wherein the group is CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -, -C≡C-, 3~12-membered cycloalkyl, 3~12-membered heterocycloalkyl, 6~10-membered aromatic ring, 5~10-membered heteroaromatic ring, 5~12-membered spirocyclic ring, 5~12-membered spiroheterocyclic ring, 5~12-membered bridged ring, 5~12-membered bridged heterocyclic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocyclic, spiroheterocyclic, bridged ring, and bridged heterocyclic ring may be further divided by one, two, or three R T1 replace; Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C0~4 Alkylene-OR T2 -C 0~4 Alkylene-OC(O)R T2 -C 0~4 Alkylene-SR T2 -C 0~4 Alkylene-S(O)2R T2 -C 0~4 Alkylene-S(O)R T2 -C 0~4 Alkylene-S(O)2NR T2 R T3 -C 0~4 Alkylene-S(O)NR T2 R T3 -C 0~4 Alkylene-C(O)R T2 -C 0~4 Alkylene-C(O)OR T2 -C 0~4 Alkylene-C(O)NR T2 R T3 -C 0~4 Alkylene-NR T2 R T3 -C 0~4 Alkylene-NR T2 C(O)R T3 -C 0~4 Alkylene-NR T2 S(O)2R T3 -C 0~4 Alkylene-NR T2 S(O)R T3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heterocyclic ring); wherein, the alkylene, cycloalkyl, heterocyclic, aromatic ring, or heterocyclic ring may be optionally surrounded by one, two, three, or four independent R... T4 replace; Each R T2 R T3 R T4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); X 2 Selected from -NH2, -NHR X21 -OH, -SH, ethynyl, vinyl, -C(O)H or -C(O)OH-; R X21 Selected from hydrogen, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Z represents a group that binds to the target protein.

[0022] As a preferred option: the R 1 Selected from hydrogen, methyl, ethyl, and propyl.

[0023] More preferably: the R 1 Selected from ethyl.

[0024] Preferably, ring A is selected from 6-membered cycloalkyl, 10-membered cycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, and 9-membered aromatic heterocycle; the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further optionally separated by one, two, three, or four independent R... A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, =O, and -C. 1~4 Alkyl, halogen-substituted -C 1~3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-C(O)NR A2 R A3 ; R A2R A3 Selected independently from hydrogen and -C 1~6 Alkyl, halogen-substituted -C 1~6 alkyl.

[0025] Furthermore: the A ring is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0026] Preferably, the T is selected from... , , , , , , , , , , , , , , , , , .

[0027] Preferably, Z is selected from... , .

[0028] As a preferred embodiment, the compound is specifically: , , , , , , , , .

[0029] The present invention also provides a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or excipient.

[0030] The present invention also provides the use of any of the compounds described above, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts, in the treatment of diseases related to abnormal cell proliferation.

[0031] Furthermore, the disease in question is cancer.

[0032] The present invention also provides the use of any of the compounds described above, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts, in the preparation of targeted protein degradation drugs.

[0033] Furthermore, the use of the said compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, as an intermediate in the preparation of a targeted protein degradation drug is provided.

[0034] Furthermore, the targeted protein degradation drug is a drug that relies on the E3 ligase TRIM21 for protein degradation.

[0035] The TRIM21 ligand and PROTAC bifunctional molecule provided by this invention both have excellent affinity for TRIM21 protein, and the TRIM21 PROTAC bifunctional molecule compound of this invention has excellent BRD4 protein degradation effect in MV-4-11 cells, which is expected to achieve better therapeutic effect and significantly reduce or reduce the toxic side effects associated with traditional treatment methods, and has good clinical application prospects and pharmaceutical development value.

[0036] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems.

[0037] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0038] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules. "Substitution" can also refer to the replacement of lone pairs of electrons in atoms in a molecule by "=O", "=S", etc.

[0039] "Can be further replaced" means that "replacement" can but does not have to happen, and this statement includes situations where it may or may not happen.

[0040] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, 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 an alkyl group containing 1 to 4 carbon atoms.

[0041] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-6 alkoxy groups.

[0042] In this invention, "alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. "C" a ~ b "Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight-chain hydrocarbon groups. For example... "C" 1~6 The term "alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, etc. Therefore, the term "propylene" can be exemplified by the following structures: Similarly, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures. : Or. Furthermore, the term "(C1-6)alkylene" is intended to include such branched hydrocarbon groups, such as cyclopropylmethylene, which can be exemplified by the following structures: For example, -C0~4 alkylene groups can be C0 alkylene, C1 alkylene (e.g., -CH2-), C2 alkylene (e.g., -CH2CH2-), C3 alkylene, or C4 alkylene; C0 alkylene refers to the absence of a group here, which is connected by a chemical bond. For example, A-C0 alkylene-B refers to AB, that is, the A group and the B group are directly connected by a chemical bond.

[0043] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms and, in some embodiments, 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one vinyl unsaturated site (>C=C<). For example, C a-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.

[0044] In this invention, "alkenyl" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valences. For example, (C3-C6) alkenyl groups include >C=CH-CH2-, -CH-CH=CH-CH2-, etc.

[0045] "Alynyl" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, etc.

[0046] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0047] "Halogenated alkyl" or "halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms can be replaced by one or more halogen atoms. For example, C 1～4 Halogenated alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms.

[0048] In this invention, "-OR", "-NRR", etc., refer to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.

[0049] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond.

[0050] In this invention, "cycloalkyl" and "cycloalkane" refer to saturated or partially saturated cyclic groups having multiple carbon atoms and no heterocyclic atoms, and having a single ring or multiple rings (including fused, bridged, spirocyclic, and adamantane systems). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5, 6, 7, 8,-tetrahydronaphthalene-5-yl) is used when the connecting point is located on a non-aromatic carbon atom. 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 polycycloalkyl ring systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. , , Adamantyl groups include, but are not limited to, the following structures: .

[0051] In this invention, "heterocyclic," "heterocyclic alkyl," and "heterocyclic alkane" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; where heteroatoms refer to nitrogen, oxygen, sulfur, etc. Generally, it represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with 3 to 9 ring atoms, containing 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring represents two rings consisting of two ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocyclic alkyl groups are oxobutyl, aziridine, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoalkyl, thiazoalkyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazine, morpholinyl, etc. Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirmonyl, diazarmonyl, periperazinyl, or oxazarmonyl. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl.

[0052] "Spirocycloiden" and "spirocycloheterocycle" are used interchangeably. They refer to non-aromatic saturated rings or non-aromatic unsaturated ring systems with two monocyclic rings sharing a single carbon atom, consisting of a carbon atom and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, "5- to 12-membered spirocycloheterocycles" refer to spirocycloheterocycles with 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.

[0053] "Bridged ring or bridged ring group" refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples include, but are not limited to: , , , .

[0054] "Bridged heterocyclic group" and "bridged heterocycle" are used interchangeably, referring to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms, composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific embodiments include, but are not limited to: , , , , .

[0055] In this invention, "aromatic ring" and "aryl" refer to aromatic hydrocarbon groups having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aryl groups having 5-20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0056] In this invention, "heteroaromatic ring" and "heteroaromatic cyclic group" refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Typically, it refers to an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, one or more of which are selected from O, N, and S heteroatoms. Preferably, it has one to three heteroatoms. Examples of heterocyclic aryl groups include: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiopheneyl, benzofuranyl, benzothiopheneyl, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazoleyl, thiopheneyl, oxadiazolyl, benzimidazoleyl, benzothiazolyl, and benzoxazolyl.

[0057] "Stereoisomers" include enantiomers and diastereomers; The "deuterated compound" of this invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0058] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0059] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds, or their stereoisomers, with an appropriate (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0060] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention. Detailed Implementation

[0061] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0062] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0063] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the optimal reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0064] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker Avance III 400 and a Bruker Avance 600 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated chloroform (CDCl3), deuterated methanol (Methol- d 4The internal standard was tetramethylsilane (TMS). LC-MS was performed using a Shimadzu LC-MS 2020 (ESI) system. HPLC was performed using a Shimadzu LC-20A high-performance liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4 mm to 0.5 mm for product separation and purification. Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0065] The reagents described in the examples are abbreviated as follows: Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DCE: dichloroethane; DMF: N,N-dimethylformamide.

[0066] Example 1: Preparation of compounds T1, T4, T10, T17, T18, T19, T21, T22, T23, T24 and T25

[0067] Step 1: Synthesis of compound T1-e Under ice bath conditions, DMA dissolved in DCE (20 mL) was added to a dry single-necked flask. Tf₂O (2.29 g, 8.13 mmol) was slowly added dropwise, and the mixture was stirred under ice bath conditions for 30 min. Then, a DCE (20 mL) solution of T₁-d and 2,4,6-collidine (985.51 mg, 8.13 mmol) was added dropwise, and the mixture was refluxed and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and DCM (2 mL) and H₂O (2 mL) were added. The mixture was then refluxed and stirred for another 18 hours. The reaction was confirmed to be complete by TLC. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and purified by medium-pressure liquid chromatography to give compound T₁-e (476 mg, 2.22 mmol, 38.3% yield). LCMS (ESI+) m / z: 215.2 [M+H] + .

[0068] Step 2, Synthesis of compound T1-f

[0069] The substrate T1-e (476 mg, 2.22 mmol) was added to a dry single-necked flask, then dissolved in methanol (5 mL). The mixture was cooled to 0°C, and sodium borohydride (100.89 mg, 2.67 mmol) was slowly added. The reaction was carried out at a constant temperature for 1 hour. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the residue was added to water and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound T1-f (500 mg, 2.31 mmol, 104.1% yield). LCMS (ESI+) m / z: 217.2 [M+H]+.

[0070] Step 3, Synthesis of compound T1-g

[0071] The substrate T1-f (500 mg, 2.31 mmol) was added to a dry three-necked flask and dissolved in dichloromethane (5 mL). The mixture was cooled to zero °C under nitrogen protection, followed by the addition of triethylamine (351.03 mg, 3.47 mmol). Finally, MsCl (317.90 mg, 2.78 mmol) was slowly added dropwise. The reaction was carried out at 70 °C for 2 hours. The reaction was monitored by TLC until complete, and the crude product T1-g (647 mg, 2.20 mmol, 95.1% yield) was obtained by concentration under reduced pressure. LCMS (ESI+) m / z: 295.1 [M+H] + .

[0072] Step 4: Synthesis of compound T1-h Under N2 protection, substrate T1-g (647 mg, 2.20 mmol) was added to a dry single-necked flask, followed by the addition of DMF (6 mL), and stirred to dissolve. Then, NaN3 (714.63 mg, 10.99 mmol) was added to the reaction system, and the mixture was stirred overnight. The reaction was monitored by TLC until complete, quenched with water, extracted three times with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid T1-h (434 mg, 1.80 mmol, 81.8% yield). LCMS (ESI+) m / z: 242.2 [M+H]+.

[0073] Step 5: Synthesis of compound T1-i

[0074] Substrate T1-h (434 mg, 1.80 mmol) was added to a dry single-necked flask and dissolved in methanol (5 mL). Palladium on carbon (45 mg) was then added, and the mixture was reacted at room temperature under hydrogen atmosphere for 16 hours. The reaction was monitored for completeness by LC-MS. The reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound T1-i (350 mg, 1.63 mmol, 90.4% yield). LCMS (ESI+) m / z: 216.2 [M+H] + .

[0075] Step 6: Synthesis of compound T1-j Substrate T1-i (70.33 mg, 0.33 mmol) was added to a dry single-necked flask, followed by the addition of DMF (1 mL) and stirring to dissolve. Then, DIPEA (420.36 mg, 3.25 mmol) was added to the reaction mixture, and the mixture was cooled in an ice-water bath. HATU (148.32 mg, 0.39 mmol) was added, and the mixture was stirred at 0°C for 5 minutes. INT-1 (84 mg, 0.39 mmol) was then added to the reaction mixture; the reaction was carried out at 0°C for 20 minutes, and LC-MS was used to monitor the reaction until complete. The mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain a white final product T1 (130 mg, 0.31 mmol, 96.7% yield). LCMS (ESI+) m / z: 414.2 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ 7.82 – 7.15 (m, 10H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m,2H), 3.41 (s, 1H), 2.65 – 2.55 (m, 2H), 2.20 – 1.61 (br, 2H), 1.29 (t, J =12.0 Hz, 3H).

[0076] Step 7: Synthesis of compound T1-b

[0077] Substrate T1-a (600 mg, 2.74 mmol) was added to a dry single-necked flask, followed by the addition of DMF (6 mL), and stirred until dissolved. Next, anhydrous potassium carbonate (757.17 mg, 5.48 mmol) and C2H5I (640.85 mg, 4.11 mmol) were added to the reaction mixture. The mixture was stirred at 25 °C for 2 h, and the reaction was monitored for completeness by LC-MS. The mixture was filtered, the solvent was evaporated, and the solution was purified by medium-pressure liquid chromatography to give a white solid T1-b (215 mg, 870.13 μmol, 31.8% yield). LCMS (ESI+) m / z: 248.2 [M+H]+.

[0078] Step 8: Synthesis of compound T1-c Under N2 protection, substrate T1-b (220 mg, 0.89 mmol), phenylboronic acid (130.27 mg, 1.07 mmol), Pd(dppf)Cl2 (64.61 mg, 0.089 mmol), and K2CO3 (369.17 mg, 2.67 mmol) were added to a microwave-safe tube. Dioxane / H2O (v:v = 3:1) (2 mL) was added, and the mixture was stirred at 100 °C for 2 h. The reaction was monitored by LC-MS to ensure complete reaction. The solvent was evaporated, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid T1-c (171 mg, 0.70 mmol, 78.6% yield). LCMS (ESI+) m / z: 245.1 [M+H]+.

[0079] Step 9: Synthesis of compound INT-1 Substrate T1-c (171 mg, 0.70 mmol) was added to a dry single-necked flask, followed by the addition of MeOH (2 mL) and stirring to dissolve. Then, 2N NaOH (83.99 mg, 2.10 mmol) solution was added to the reaction system, and the mixture was stirred at 60 °C for 2 h. The reaction was monitored for completeness by LC-MS. The methanol was evaporated to dryness, and 3N HCl solution was added to adjust the pH to 5-6. After lyophilization, the solution was purified by medium-pressure liquid chromatography to obtain a light reddish-brown oily liquid INT-1 (97 mg, 0.45 mmol, 64.1% yield). LCMS (ESI+) m / z: 215.2 [MH]-. Step 10: Synthesis of compound IT-1

[0080] Under ice bath conditions, T1-j (15 mg, 36.28 μmol) dissolved in DMF (2 mL) was added to a dry single-necked flask. NaH (7.26 mg, 181.41 μmol, 60% purity) was slowly added, and the mixture was stirred under ice bath conditions for 30 min. Then, iodomethane (25.75 mg, 181.41 μmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. The reaction solution was quenched at 0 °C, and extracted with ethyl acetate (2 mL) and H₂O (2 mL). The organic phase was dried over anhydrous sodium sulfate and purified by medium-pressure liquid chromatography to give the yellow compound T1 (4.00 mg, 9.36 mmol, 25.79% yield, 97.8% purity). LC-MS m / z: [M+H] + calcd. for C24H25F3N3O + : 428.19; found: 428.2. 1 H NMR (400 MHz, DMSO-d6) δ7.82 – 7.15 (m, 10H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H), 3.56 (s,3H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.65 – 2.55 (m, 2H), 2.20 – 1.61(br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0081] Following the synthetic method of compound T1, by replacing compound T1-d with the following raw materials T4-a, T10-a, T17-a, T18-a, T19-a, T21-a, T22-a, T23-a, T24-a and T25a, while keeping other raw materials and operating methods unchanged, compounds T4, T10, T17, T18, T19, T21, T22, T23, T24 and T25 can be obtained.

[0082] raw material: , , , , , , , , , , .

[0083] Compound:

[0084]

[0085] T4 (9.80 mg, 23.58 μmol, 34.17% yield, 98.8% purity). LC-MS m / z: [M+H] + calcd. for C27H34N3O + : 416.27; found: 416.5. 1 H NMR (400 MHz, DMSO-d6) δ 7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.42 – 4.28 (br, 1H), 4.28– 4.12 (m, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.20– 1.62 (br, 2H), 1.36 (s, 9H), 1.28 (t, J = 12.0 Hz, 3H).

[0086]

[0087] T10 (5.20 mg, 13.78 μmol, 24.69% yield, 98.6% purity). LC-MS m / z: [M+H] + calcd. for C23H25FN3O + : 378.20; found: 378.5. 1 H NMR (400 MHz, DMSO-d6) δ 8.00– 7.72 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.42 – 4.28 (br, 1H), 4.28– 4.12 (m, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.20– 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0088]

[0089] T17 (6.80 mg, 17.20 μmol, 33.91% yield, 96.5% purity). LC-MS m / z: [M+H] + calcd. for C23H24F2N3O + : 396.19; found: 396.1. 1 H NMR (400 MHz, DMSO-d6) δ8.00 – 7.72 (m, 1H), 7.64 – 7.44 (m, 7H), 7.28 (s, 1H), 4.42 – 4.28 (br, 1H),4.28 – 4.12 (m, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0090]

[0091] T18 (4.50 mg, 11.04 μmol, 28.89% yield, 95.0% purity). LC-MS m / z: [M+H] + calcd. for C24H27FN3O2 + : 408.21; found: 408.2. 1 H NMR(400 MHz, DMSO-d6) δ 8.00– 7.72 (m, 1H), 7.76 – 7.40 (m, 7H), 7.28 (s, 1H), 4.42 – 4.28 (br, 1H), 4.28– 4.12 (m, 2H), 3.82 (s, 3H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56(m, 2H), 2.20 – 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0092]

[0093] T19 (8.60 mg, 20.80 μmol, 44.78% yield, 99.0% purity). LC-MS m / z: [M+H] + calcd. for C27H32N3O+ : 414.25; found: 414.3. 1 H NMR(400 MHz, DMSO-d6) δ 7.96 –7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.42 – 4.28 (br, 1H), 4.28 –4.12 (m, 2H), 3.41 (s, 1H), 3.12 – 2.72 (m, 7H), 2.64 – 2.56 (m, 2H), 2.20 –1.62 (m, 6H), 1.28 (t, J = 12.0 Hz, 3H).

[0094]

[0095] T20 (8.80 mg, 22.71 μmol, 42.99% yield, 98.8% purity). LC-MS m / z: [M+H] + calcd. for C25H30N3O + : 388.24; found: 388.2. 1 H NMR(400 MHz, DMSO-d6) δ 7.96 –7.68 (m, 1H), 7.56 – 7.40 (m, 7H), 7.28 (s, 1H), 4.42 – 4.28 (br, 1H), 4.28 –4.12 (m, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.38(s, 6H), 2.20 – 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0096]

[0097] T21 (8.20 mg, 19.78 μmol, 42.79% yield, 98.5% purity). LC-MS m / z: [M+H] + calcd. for C25H27N4O2 + : 415.21; found: 415.2. 1H NMR(400 MHz, DMSO-d6) δ 8.82– 8.72 (s, 1H), 7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 7H), 7.28 (s, 1H), 4.42– 4.28 (br, 1H), 4.28 – 4.12 (m, 2H), 3.68 (s, 2H), 3.41 (s, 1H), 3.12 – 2.77(br, 3H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0098]

[0099] T22 (2.30 mg, 6.60 μmol, 19.83% yield, 94.8% purity). LC-MS m / z: [M+H] + calcd.for C21H25N4O + : 349.20; found: 349.2. 1 H NMR(400 MHz, DMSO-d6) δ8.12 (s, 1H),7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 2H), 7.28 (s, 1H), 6.73 (m, 1H), 6.59(m, 1H), 6.12 (m, 1H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12 (m, 1H), 3.68 (s,2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62(br, 2H), 1.28(t, J = 12.0 Hz, 3H).

[0100]

[0101] T23 (2.00 mg, 7.72 μmol, 21.64% yield, 92.3% purity). LC-MS m / z: [M+H] + calcd.for C21H24N3O2 + : 350.19; found: 350.3. 1H NMR(400 MHz, DMSO-d6) 7.96 – 7.68(m, 1H), 7.56 – 7.40 (m, 2H), 7.28 (s, 1H), 7.12 (m, 2H), 6.12 (m, 1H), 4.42– 4.28 (br, 1H), 4.28 – 4.12 (m, 2H), 3.68 (s, 2H), 3.41 (s, 1H), 3.12 – 2.77(br, 3H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0102]

[0103] T24 (2.50 mg, 6.84 μmol, 19.07% yield, 98.8% purity). LC-MS m / z: [M+H] + calcd.for C21H24N3OS + : 366.16; found: 366.2. 1 H NMR(400 MHz, DMSO-d6) 7.96 – 7.68(m, 1H), 7.56 – 7.40 (m, 3H), 7.28 (s, 1H), 6.82 (m, 2H), 4.42 – 4.28 (br,1H), 4.28 – 4.12 (m, 2H), 3.68 (s, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (br, 2H), 1.28 (t, J = 12.0 Hz, 3H).

[0104]

[0105] T25 (4.20 mg, 12.02 μmol, 27.32% yield, 94.4% purity). LC-MS m / z: [M+H] + calcd. for C20H24N5O + : 350.20; found: 350.2. 1H NMR(400 MHz, DMSO-d6) δ8.12(s, 1H), 7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 2H), 7.28 (s, 1H), 6.12 (m,1H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12 (m, 2H), 3.68 (s, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (br, 2H), 1.28 (t, J =12.0 Hz, 3H).

[0106] Example 2: Preparation of compounds T2, T3, T5, T6, T7, T8, T9, T11, T12, T13, T14, T15 and T16

[0107] General Step 1: Synthesis of Compound T2 Substrate INT-1 (12.34 mg, 57.06 μmol) was added to a dry single-necked flask, followed by 3 mL of DMF, and stirred until dissolved. Then, DIPEA (18.43 mg, 142.64 μmol, 24.84 μL) was added to the reaction mixture, and the mixture was cooled in an ice-water bath. HATU (26.02 mg, 68.47 μmol) was added, and the mixture was stirred at 0°C for 5 minutes. T2-a (10 mg, 57.06 μmol) was then added to the reaction mixture; the reaction was carried out at 0°C for 20 minutes, and LC-MS was used to monitor the reaction until complete. The mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain a white final product T2 (8 mg, 21.42 μmol, 37.54% yield, 98.5% purity). LC-MS m / z: [M+H] + calcd. for C24H28N3O + : 374.22; found: 374.2. 1H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H), 3.56 (s, 3H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.65 –2.55 (m, 2H), 2.36 (s, 3H), 2.20 – 1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0108] Following the synthetic method of compound T2, by replacing compound T2-a with the following raw materials T3-a, T5-a, T6-a, T7-a, T8-a, T9-a, T11-a, T12-a, T13-a, T14-a, T15-a, T16-a, T29-a, and T30-a, while keeping other raw materials and operating methods unchanged, compounds T3, T5, T6, T7, T8, T9, T11, T12, T13, T14, T15, T16, T29, and T30 can be obtained.

[0109] raw material: , , , , , , , , , , , , , .

[0110] Compounds:

[0111] T3 (7.50 mg, 18.77 μmol, 37.79% yield, 98.9% purity). LC-MS m / z: [M+H]+calcd. for C26H30N3O+: 400.24; found: 400.5. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 3H), 2.65 – 2.55 (m, 1H), 2.36 (s, 3H), 2.20 – 1.61 (br, 2H), 1.48– 1.40 (m, 2H), 1.29 (t, J = 12.0 Hz, 3H), 0.96 – 0.82 (m, 4H)

[0112] T5 (10.10 mg, 24.42 μmol, 5.259% yield, 99.9% purity). LC-MS m / z: [M+H]+calcd. for C27H32N3O+: 414.25; found: 414.5. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.27 – 4.12 (m, 1H), 3.56(s, 3H), 3.52-3.42 (m, 1H), 2.65 – 2.55 (m, 4H), 2.36 (s, 3H), 2.20 – 1.61(m, 6H), 1.29 (t, J = 12.0 Hz, 3H).

[0113] T6 (7.30 mg, 18.99 μmol, 35.36% yield, 95.5% purity). LC-MS m / z: [M+H]+calcd. for C24H25N4O+: 385.20; found: 385.1. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.56 (s, 3H), 3.41 (s, 1H), 2.65 – 2.55 (m, 2H), 2.20 – 1.61(br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0114] T7 (11.50 mg, 31.99 μmol, 51.59% yield, 98.9% purity). LC-MS m / z: [M+H]+calcd. for C23H26N3O+: 460.21; found: 460.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 9H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.65 – 2.55 (m, 2H), 2.20– 1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0115] T8 (9.10 mg, 22.66 μmol, 46.08% yield, 99.5% purity). LC-MS m / z: [M+H]+calcd. for C26H32N3O+: 402.25; found: 402.3. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.41 (s, 1H), 3.13 – 2.77 (m, 4H), 2.65 – 2.55 (m, 2H), 2.20– 1.61 (br, 2H), , 1.28 (d, J = 6.9 Hz, 6H). 1.24 (t, J = 12.0 Hz, 3H).

[0116] T9 (8.20 mg, 21.16 μmol, 40.06% yield, 98.9% purity). LC-MS m / z: [M+H]+calcd. for C25H30N3O+: 388.24; found: 388.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.41 (s, 1H), 3.13 – 2.77 (m, 3H), 2.65 – 2.55 (m, 4H), 2.20– 1.61 (br, 2H) , 1.28 (t, J = 11.2 Hz, 3H), 1.24 (t, J = 12.0 Hz, 3H).

[0117] T11 (3.20 mg, 8.22 μmol, 15.71% yield, 96.5% purity). LC-MS m / z: [M+H]+calcd. for C25H27N4O2+: 390.22; found: 390.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.86 (s, 3H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.65 – 2.55(m, 2H), 2.20 – 1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0118] T12 (5.50 mg, 13.96 μmol, 27.32% yield, 98.8% purity). LC-MS m / z: [M+H]+calcd. for C23H25ClN3O+: 394.17; found: 394.2. 1H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H), 3.56 (s, 3H), 3.41 (s, 1H), 2.65 – 2.55 (m, 2H), 2.20 –1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0119] T13 (11.20 mg, 27.82 μmol, 56.85% yield, 99.9% purity). LC-MS m / z: [M+H]+calcd. for C25H31N4O+: 403.25; found: 403.3. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.41 (s, 1H), 3.32 (s, 6H), 3.13 – 2.77 (br, 3H), 2.65 – 2.55(m, 2H), 2.20 – 1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0120] T14 (6.20 mg, 14.89 μmol, 32.49% yield, 99.2% purity). LC-MS m / z: [M+H]+calcd. for C25H29N4O2+: 417.23; found: 417.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.41 (s, 1H), 2.65 – 2.55 (m, 2H), 2.36 (s, 3H), 2.20 – 1.61(m, 5H), 1.29 (t, J = 12.0 Hz, 3H).

[0121] T15 (3.50 mg, 8.40 μmol, 18.34% yield, 99.8% purity). LC-MS m / z: [M+H]+calcd. for C25H29N4O2+: 417.23; found: 417.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 4.71 – 4.29 (br, 1H), 4.27– 4.12 (m, 2H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.94 (s, 3H), 2.65 – 2.55(m, 2H), 2.20 – 1.61 (m, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0122] T16 (8.60 mg, 21.00 μmol, 44.37% yield, 96.8% purity). LC-MS m / z: [M+H]+calcd. for C24H26F2N3O+: 410.20; found: 410.2. 1H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 8H), 7.28 (s, 1H), 6.70 (t, JH-F = 56Hz, 1H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H), 3.41 (s, 1H), 3.13 – 2.77(br, 3H), 2.65 – 2.55 (m, 2H), 2.20 – 1.61 (m, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0123] T29 (1.50 mg, 3.94 μmol, 16.98% yield, 96.8% purity). LC-MS m / z: [M+H]+calcd. for C23H33N4O+: 381.26; found: 381.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H), 3.56 (s, 3H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.65 – 2.55 (m, 3H), 2.20 – 1.61 (m, 5H), 1.85 (dt, J= 8.0 Hz, J= 3.2 Hz, 1H), 1.70 (m, 1H), 1.58–1.40 (m, 4H,), 1.28 (t, J = 12.0 Hz, 3H) 1.24–1.10 (m, 2H), 0.95 (d, J= 6.2Hz, 3H).

[0124] T30 (2.30 mg, 6.29 μmol, 30.63% yield, 95.2% purity). LC-MS m / z: [M+H]+calcd. for C23H32N3O+: 366.25; found: 366.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m,2H), 3.82 (m, 1H), 3.56 (s, 3H), 3.41 (s, 1H), 3.13 – 2.77 (br, 3H), 2.65 –2.55 (m, 2H), 2.36 (s, 3H), 2.20 – 1.61 (br, 2H), 1.79 – 1.53(m,6H), 1.29 (t,J = 12.0 Hz, 3H), 1.13 – 0.90 (m, 6H). Example 3: Preparation of compounds T32, T33, T34, T35, T36, T37, T38 and T39.

[0125] Step 1: Synthesis of compound INT-3 Under ice bath conditions, T32-a (1 g, 4.97 mmol) and TEA (1.26 g, 12.42 mmol, 1.73 mL) dissolved in DCM (15 mL) were added to a dry single-necked flask. MsCl (683.00 mg, 5.96 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete as detected by TLC, silica gel was added and the mixture was purified by column chromatography (PE:EA = 5:1) to obtain the target product INT-3 (1.1 g, 3.94 mmol, 79.25% yield). LCMS (ESI+) m / z: 280.1 [M+H] + .

[0126] Step 2, Synthesis of compound T32-b

[0127] Under ice bath conditions, T32-b (27.41 mg, 196.88 μmol) and TEA (1.26 g, 12.42 mmol, 1.73 mL) dissolved in DCM (2 mL) were added to a dry single-necked flask. INT-3 (50 mg, 178.99 μmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete as detected by TLC, silica gel was added and the mixture was purified by column chromatography (PE:EA = 1:1) to obtain the target product T32-b (35 mg, 108.53 μmol, 60.64% yield). LCMS (ESI+) m / z: 323.3 [M+H] + .

[0128] Step 3: Synthesis of compound T32-c

[0129] T32-b (15 mg, 46.51 μmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction system was concentrated to obtain 10 mg of crude product, which was directly used in the next step of the reaction according to the theoretical amount.

[0130] Step 4: Synthesis of compound T32

[0131] Substrate INT-1 (9.72 mg, 44.97 μmol) was added to a dry single-necked flask, followed by 2 mL of DMF, and stirred until dissolved. Then, DIPEA (14.53 mg, 112.43 μmol, 19.58 μL) was added to the reaction system, and the mixture was cooled in an ice-water bath. HATU (20.51 mg, 53.96 μmol) was added, and the mixture was stirred at 0°C for 5 minutes. T32-c (10 mg, 44.97 μmol) was then added to the reaction solution; the reaction was carried out at 0°C for 20 minutes, and LC-MS was used to monitor the reaction until complete. The mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain a white final product T32 (4.0 mg, 9.51 μmol, 21.15% yield, 98.8% purity). LC-MS m / z: [M+H] + calcd. for C26H37N4O + : 421.30; found: 421.2. 1 H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (m, 2H), 4.27 – 4.12(m, 2H), 3.41 (s, 1H), 3.24 (m,1 H), 3.13 – 2.77 (m, 4H), 2.74 (1 m, 1H), 2.65 – 2.55 (m, 2H), 2.43 (dd, 1 H, J1 = 10.3 Hz, J2 = 12.0 Hz), 2.20 – 1.61(m, 4H), 1.42- 1.34 (10 H, m), 1.29 (t, J = 12.0 Hz, 3H).

[0132] Following the synthetic method of compound T32, by replacing compound T32-b with the following raw materials T33-a, T34-a, T35-a, T36-a, T37-a, T38-a, and T39-a, while keeping other raw materials and operating methods unchanged, compounds T33, T34, T35, T36, T37, T38, and T39 can be obtained.

[0133] raw material: , , , , , , .

[0134] compound

[0135] T33 (3.60 mg, 8.56 μmol, 19.56% yield, 98.3% purity). LC-MS m / z: [M+H]+calcd. for C26H37N4O +: 421.30; found: 421.2. 1H NMR (400 MHz, DMSO-d6) δ7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (m, 2H), 4.27 – 4.12 (m,2H), 3.41 (s, 1H), 3.24 (m,1 H), 3.13 – 2.77 (m, 2H), 2.74 (1 m, 2H), 2.65 –2.55 (m, 2H), 2.43 (dd, 1 H, J1 = 10.3 Hz, J2 = 12.0 Hz), 2.20 – 1.61 (m,6H), 1.42- 1.34 (8 H, m), 1.29 (t, J = 12.0 Hz, 3H).

[0136] T34 (3.80 mg, 9.35 μmol, 19.47% yield, 98.8% purity). LC-MS m / z: [M+H]+calcd. for C25H35N4O+: 407.28; found: 407.5. 1H NMR (400 MHz, DMSO-d6) δ 7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12 (m,2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 4H), , 2.20 – 1.62(m, 9H), 1.52 – 1.36 (m, 4H), 1.28 (t, J = 12.0 Hz, 3H)

[0137] T35 (3.90 mg, 10.25 μmol, 18.68% yield, 96.1% purity). LC-MS m / z: [M+H]+calcd. for C23H33N4O+: 381.26; found: 381.1. 1H NMR (400 MHz, DMSO-d6) δ 7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12 (m,2H), 3.41 (s, 1H), 3.12 – 2.77 (m, 7H), 2.64 – 2.56 (m, 2H), 2.20 – 1.58 (br,10H), 1.28 (t, J = 12.0 Hz, 3H)

[0138] T36 (5.10 mg, 12.90 μmol, 25.44% yield, 97.0% purity). LC-MS m / z: [M+H]+calcd. for C22H30N5O2+: 396.24; found: 396.2. 1H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12(m, 2H), 3.47 – 3.25 (m, 5H), 3.12 – 2.77 (m, 5H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (m, 4H), 1.28 (t, J = 12.0 Hz, 3H)

[0139] T37 (3.50 mg, 9.25 μmol, 16.67% yield, 99.3% purity). LC-MS m / z: [M+H]+calcd. for C23H31N4O+: 379.25; found: 379.3. 1H NMR (400 MHz, DMSO-d6) δ 7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12 (m,2H), 3.41 (s, 1H), 3.24 – 2.77 (m, 7H), 2.64 – 2.56 (m, 2H), 2.20 – 1.62 (m,8H), 1.28 (t, J = 12.0 Hz, 3H)

[0140] T38 (5.50 mg, 14.01 μmol, 27.23% yield, 98.5% purity). LC-MS m / z: [M+H]+calcd. for C24H33N4O+: 393.26; found: 393.2. 1H NMR (400 MHz, DMSO-d6) δ 7.96– 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12 (m,2H), 3.41 (s, 1H), 3.22 – 2.77 (br, 7H), 2.64 – 2.56 (m, 2H), 2.20 – 1.40 (m,10H), 1.28 (t, J = 12.0 Hz, 3H)

[0141] T39 (3.20 mg, 7.40 μmol, 14.37% yield, 99.5% purity). LC-MS m / z: [M+H]+calcd. for C25H27N4O2+: 393.26; found: 393.2. 1H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.42 – 4.28 (br, 1H), 4.28 – 4.12(m, 2H), 3.41 (s, 1H), 3.12 – 2.77 (br, 3H), 2.64 – 2.56 (m, 2H), 2.32 – 1.62(m, 6H), 1.58 – 1.24 (m, 8H), 1.28 (t, J = 12.0 Hz, 3H).

[0142] Example 4: Preparation of compounds T26, T28 and T31

[0143] Step 1: Synthesis of compound T26-b Substrate INT-1 (43.99 mg, 203.43 μmol) was added to a dry single-necked flask, followed by 3 mL of DMF, and stirred to dissolve. Then, DIPEA (59.75 mg, 462.33 μmol, 80.53 μL) was added to the reaction system, and the mixture was cooled in an ice-water bath. HATU (20.51 mg, 221.92 μmol) was added, and the mixture was stirred at 0°C for 5 minutes. T26-a (50 mg, 184.93 μmol) was then added to the reaction solution; the reaction was carried out at 0°C for 20 minutes, and LC-MS was used to monitor the reaction until complete. The mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain the white final product T26-b (26 mg, 55.49 μmol, 30.00% yield). LCMS (ESI+) m / z: 469.2 [M+H] + .

[0144] Step 2, Synthesis of Compound T26

[0145] T26-b (26 mg, 55.49 μmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The mixture was reacted at room temperature for 0.5 h. After the reaction was complete, the reaction system was concentrated to obtain a crude product, which was then purified by medium-pressure liquid chromatography to obtain a yellow final product, T26 (12 mg, 32.57 μmol, 58.69% yield, 97.3% purity). LC-MS m / z: [M+H] + calcd.for C21H29N4O2 + : 369.23; found: 369.2. 1 H NMR (400 MHz, DMSO-d6) δ7.96 – 7.68(m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H), 3.74– 3.50 (m, 7H), 3.41 (s, 1H), 2.86 – 2.55 (m, 5H) , 2.20 – 1.61 (br, 2H),1.29 (t, J = 12.0 Hz, 3H).

[0146] Following the synthetic method of compound T26, compounds T28 and T31 can be obtained by replacing compound T26-a with the following raw materials T28-a and T31-a, while keeping other raw materials and operating methods unchanged.

[0147] raw material: , .

[0148] Compounds:

[0149] T28 (3.50 mg, 9.17 μmol, 44.18% yield, 98.8% purity). LC-MS m / z: [M+H] + calcd. for C22H32N5O + : 382.26; found: 382.2. 1H NMR (400 MHz, DMSO-d6) δ7.96 –7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H),3.56 (s, 3H), 3.41 (s, 1H), 2.82 – 2.40 (m, 10H), 2.36 (s, 3H), 2.20 – 1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0150]

[0151] T31 (3.80 mg, 9.32 μmol, 9.32% yield, 94.8% purity). LC-MS m / z: [M+H] + calcd. for C24H34N5O + : 408.28; found: 408.4. 1 H NMR (400 MHz, DMSO-d6) δ7.96 –7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29 (br, 1H), 4.27 – 4.12 (m, 2H),3.56 (s, 3H), 3.41 (s, 1H), 2.82 – 2.54 (m, 6H), 2.36 (s, 3H), 2.30 – 1.42 (m, 7H), 1.29 (t, J = 12.0 Hz, 3H)

[0152] Example 5: Preparation of compound T27

[0153] Step 1: Synthesis of compound T27 In a dry single-necked flask, substrate T26 (10 mg, 27.14 μmol), HCHO (9.24 mg, 271.39 μmol), and AcOH (8.14 mg, 135.70 μmol) were dissolved in methanol (2 mL) and stirred until dissolved. Then, NaBH3CN (8.52 mg, 135.70 μmol) was added, and the reaction was carried out at 20 °C for 3 hours. The reaction was monitored for completeness by LC-MS. The reaction solution was purified by high-performance liquid chromatography to obtain a yellow final product T27 (2 mg, 5.23 μmol, 19.27% ​​yield, 95.8% purity). LC-MS m / z: [M+H] + calcd. for C22H31N4O2 + : 383.24; found: 383.2. 1 HNMR (400 MHz, DMSO-d6) δ7.96 – 7.68 (m, 1H), 7.56 – 7.40 (m, 5H), 4.71 – 4.29(br, 1H), 4.27 – 4.12 (m, 2H), 3.74 – 3.50 (m, 7H), 3.41 (s, 1H), 2.86 – 2.55(m, 5H), 2.26 (s, 3H), 2.20 – 1.61 (br, 2H), 1.29 (t, J = 12.0 Hz, 3H).

[0154] Example 6: General preparation steps for bifunctional compounds:

[0155]

[0156] General Step 1: Synthesis of Compound Intermediate S1 One equivalent of sodium hydride was added to a sealed three-necked flask, and the reaction system was purged with nitrogen three times. Then, an appropriate amount of DMF was added, and the reaction vessel was placed in an ice bath. One equivalent of T1-j was dissolved in an appropriate amount of DMF and slowly added dropwise to the reaction system at low temperature. After stirring at low temperature for 30 minutes, two equivalents of the corresponding linker were dissolved in DMF and slowly added dropwise to the reaction system, and the mixture was stirred again for 30 minutes. The reaction was monitored by LC-MS until completion. The mixture was then quenched with water, extracted three times with excess ethyl acetate, and the organic phases were combined and washed three times with saturated brine. The organic phase was dried over sodium sulfate, the solvent was removed by rotary evaporation, and the mixture was purified by MPLC to obtain the intermediate compound S1.

[0157] General Step 2: Synthesis of Compound Intermediate S2

[0158] One equivalent of intermediate S1 was dissolved in an appropriate amount of dichloromethane, and then three equivalents of trifluoroacetic acid were slowly added dropwise. The mixture was stirred at room temperature for 30 minutes, and the reaction was monitored by LC-MS until complete. Another appropriate amount of dichloromethane was added and the mixture was evaporated to dryness. This step was repeated three times to obtain the crude intermediate S2, which can be used directly in the next reaction without further purification. Note that the crude product may contain a small amount of residual trifluoroacetic acid and should not be stored for extended periods. If necessary, the pH should be adjusted to neutral or weakly alkaline.

[0159] General Step 3, Synthesis of Compounds A1-A9 in Examples

[0160] One equivalent of BRD4 ligand (see patent CN116375717A for the specific synthetic route) was dissolved in an appropriate amount of DMF. The reaction system was placed in an ice bath, and three equivalents of DIPEA and 1.2 equivalents of HATU were added. After stirring at low temperature for 30 minutes, 1.2 equivalents of intermediate S13 were added. The reaction was then raised to room temperature and stirred again for 30 minutes. The reaction was monitored by LC-MS until completion. An appropriate amount of ethyl acetate was added to quench the reaction. The mixture was washed three times with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. After removing the solvent by rotary evaporation, the final product was purified by MPLC.

[0161] Following the above synthetic method, bifunctional compounds A1-A9 can be obtained by using different linkers as described below, while keeping other raw materials and operating methods unchanged.

[0162]

[0163] A1 White Solid (10.81 mg, 0.0144 mmol, 22.5% yield, 97.7% purity). 1HNMR (400 MHz, Chloroform-d, D2O) δ 7.67 (s, 1H), 7.53 (d, J = 3.0 Hz, 1H),7.54 – 7.51 (m, 1H), 7.48 (s, 2H), 7.41 (d, J = 7.2 Hz, 5H), 7.39 (d, J= 2.4Hz, 2H), 7.22 (s, 2H), 6.77 (s, 1H), 4.44 (s, 1H), 4.20 – 4.15 (m, 2H), 3.65(s, 3H), 3.59 – 3.47 (m, 2H), 3.28 (s, 3H), 2.58 (s, 3H), 2.44 (s, 3H), 2.21(s, 3H), 1.58 – 1.42 (m, 4H), 1.33 – 1.29 (m, 2H). LCMS (ESI) m / z: 750.3[M+H]+。

[0164]

[0165] A2 White Solid (5.77 mg, 0.0074 mmol, 35.6% yield, 98.6% purity). 1HNMR (400 MHz, Chloroform-d,D2O) δ 7.69 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H),7.52 – 7.50 (m, 1H), 7.48 (s, 2H), 7.44 (d, J = 6.4 Hz, 5H), 7.41 (d, J = 3.0Hz, 2H), 7.20 (s, 2H), 6.75 (s, 1H), 4.29 (s, 1H), 4.20 – 4.15 (m, 2H), 3.66(s, 3H), 3.58 – 3.44 (m, 2H), 3.31 (s, 3H), 2.58 (s, 3H), 2.44 (s, 3H), 2.21(s, 3H), 1.59 (s, 6H), 1.39 – 1.36 (m, 4H). LCMS (ESI) m / z: 778.4[M+H]+.。

[0166]

[0167] A3 White Solid (1.63 mg, 0.0019 mmol, 23.9% yield, 93.4% purity). 1HNMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.52 (d, J= 2.4 Hz, 1H), 7.50 –7.48 (m, 1H), 7.46 (s, 2H), 7.42 (d, J = 6.4 Hz, 5H), 7.38 (d, J = 2.4 Hz,2H), 7.24 (s, 2H), 6.69 (s, 1H), 4.31 (s, 1H), 4.16 – 4.08 (m, 2H), 3.64 (s,3H), 3.54 – 3.45 (m, 2H), 3.31 (s, 3H), 2.58 (s, 3H), 2.43 (s, 3H), 2.24 (s,3H), 1.59 (s, 8H), 1.38 – 1.33 (m, 7H). LCMS (ESI) m / z: 806.4[M+H]+。

[0168]

[0169] A4 Off-white Solid (6.4 mg, 0.0077 mmol, 16.5% yield, 98.1% purity).1H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.49– 7.45 (m, 3H), 7.41 (d, J = 6.0 Hz, 5H), 7.33 – 7.30 (m, 2H), 7.24 (s, 2H),6.66 (s, 1H), 4.27 (s, 1H), 4.14 – 4.05 (m, 2H), 3.67 (s, 3H), 3.55 – 3.48(m, 2H), 3.28 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 1.77 – 1.55(m, 12H), 1.36 – 1.33 (m, 7H). LCMS (ESI) m / z: 834.4[M+H]+.。

[0170]

[0171] A5 White Solid (7.7 mg, 0.0089 mmol, 8.6% yield, 99.4% purity). 1HNMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.51 –7.47 (m, 3H), 7.43 (d, J = 6.4 Hz, 5H), 7.35 – 7.30 (m, 2H), 7.22 (s, 2H),6.67 (s, 1H), 4.30 (s, 1H), 4.20 – 4.10 (m, 2H), 3.66 (s, 3H), 3.59 – 3.47(m, 2H), 3.22 (s, 3H), 2.40 (s, 3H), 2.31 (s, 2H), 2.21 (s, 3H), 1.80 – 1.50(m, 15H), 1.36 – 1.21 (m, 8H). LCMS (ESI) m / z: 862.4[M+H]+。

[0172]

[0173] A6 White Solid (2.8 mg, 0.0036 mmol, 12.7% yield, 99.1% purity). 1HNMR (400 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.53 –7.50 (m, 1H), 7.47 (s, 2H), 7.45 (d, J = 6.4 Hz, 5H), 7.39 (d, J = 3.0 Hz,2H), 7.21 (s, 2H), 6.88 (s, 1H), 4.41 (s, 1H), 4.29 – 4.22 (m, 2H), 3.69 –3.62 (m, 8H), 3.59 – 3.43 (m, 2H), 3.33 (s, 3H), 2.59 (s, 3H), 2.42 (s, 3H),2.22 – 2.19 (m, 3H), 1.32 (s, 3H). LCMS (ESI) m / z: 780.3[M+H]+。

[0174]

[0175] A7 White Solid (9.9 mg, 0.0120 mmol, 21.9% yield, 95.4% purity). 1HNMR (400 MHz, Chloroform-d, D2O) δ 7.71 (s, 1H), 7.58 (d, J = 2.4 Hz, 1H),7.55 – 7.49 (m, 1H), 7.48 (s, 2H), 7.42 (d, J = 6.4 Hz, 5H), 7.37 (d, J = 3.0Hz, 2H), 7.29 (s, 2H), 6.99 (s, 1H), 4.41 (s, 1H), 4.29 – 4.22 (m, 2H), 3.69– 3.64 (m, 9H), 3.59 – 3.41 (m, 5H), 3.31 – 3.05 (m, 3H), 2.62 (s, 3H), 2.45(s, 3H), 2.27 – 2.22 (m, 3H), 1.55 (s, 3H). LCMS (ESI) m / z: 824.4[M+H]+。

[0176]

[0177] A8 Off-white Solid (12.6 mg, 0.0146 mmol, 34.5% yield, 97.8% purity).1H NMR (400 MHz, Chloroform-d, D2O) δ 7.82 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H),7.57 – 7.47 (m, 3H), 7.45 (d, J = 6.4 Hz, 5H), 7.39 (d, J = 3.2 Hz, 2H), 7.33(s, 2H), 7.03 (s, 1H), 4.54 - 4.41 (m, 5H), 4.39 – 4.33 (m, 4H), 4.26 – 4.23(m, 2H), 3.66 – 3.61 (m, 8H), 3.59 – 3.42 (m, 5H), 3.31 – 3.05 (m, 3H), 2.55(s, 3H), 2.40 (s, 3H), 2.22 – 2.16 (m, 3H), 1.55 (s, 3H). LCMS (ESI) m / z:868.4[M+H]+。

[0178]

[0179] A9 White Solid (9.9 mg, 0.0146 mmol, 10.8% yield, 95.6% purity). 1HNMR (400 MHz, Chloroform-d, D2O) δ 7.80 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H),7.55 – 7.49 (m, 3H), 7.46 (d, J = 6.4 Hz, 5H), 7.36 (d, J = 3.2 Hz, 2H), 7.33(s, 2H), 6.99 (s, 1H), 4.59 - 4.33 (m, 5H), 4.32 - 4.28 (m, 5H), 4.24 - 4.23(m, 2H), 3.64 – 3.61 (m, 8H), 3.55 – 3.49 (m, 5H), 3.31 – 3.05 (m, 3H), 2.57(s, 3H), 2.44 (s, 3H), 2.20 (s, 3H), 1.52 (s, 3H). LCMS (ESI) m / z: 912.4[M+H]+.

[0180] Example 6: Experimental detection of the SPR binding of compound TRIM21 1. Experimental materials and reagents: Biacore 8K Cytiva S series CM5 sensor chip Cytiva Cat#BR-1005-30 Twin strep tag capture kit IBA 2-4370-000 NaOH 50 Cytiva Cat#BR-1003-58 DMSO VETEC V900090 Na2HPO4 Sigma 795410 NaH2PO4 Sigma RDD007 NaCl Sangon Biotech A501218-0005 Tween-20 Sigma 93773 Amino Coupling Kit Cytiva Cat#BR100050 96-hole plate Greener bio-one Cat#650201 2. SPR test method Prepare the running buffers: In protein fixation buffer and running buffer A, the concentrations of NaH2OP4 are 7.6 mM, Na2HOP4 is 12.4 mM, NaCl is 150.0 mM, and Tween 20 is 0.1%, adjusted to pH 7.0. In running buffer B, the concentrations of NaH2OP4 are 7.6 mM, Na2HOP4 is 12.4 mM, NaCl is 150.0 mM, Tween 20 is 0.1%, adjusted to pH 7.0, and DMSO is 1.00%, adjusted to pH 7.0. After preparation, filter the running buffers through a 0.22 μm filter membrane.

[0181] Strep tactin XT fixation: The CM5 chip surface was washed three times with 50 mM NaOH at a flow rate of 60.0 μL / min for 60 seconds each time. Then, an activation reagent was prepared using EDC (75.00 mg / mL) and NHS (11.50 mg / mL) from the amino-conjugation kit at a 1:1 volume ratio. The chip was activated for 420 seconds at a flow rate of 6.0 μL / min. 50.0 μg / mL Strep tactin XT was prepared using the Strep tactin XT fixation buffer provided in the Twin Streptag Capture Kit. The prepared Strep tactin XT was injected at a flow rate of 5.0 μL / min for 600 seconds. After His antibody injection, the chip surface was blocked by injecting 1M ethanolamine from the amino-conjugation kit at a rate of 6.0 μL / min for 7 minutes. The final fixation volume of Strep tactin XT was approximately 12000.0 RU.

[0182] TRIM21 protein fixation: Run buffer A was used as the protein fixation buffer. TRIM21 protein was prepared into a 40.0 μg / mL solution using protein buffer and injected at 5.0 μL / min for 600 seconds to capture the TRIM21 protein onto a CM5 chip using Streptactin XT. The final TRIM21 fixation volume was approximately 2200.00 RU.

[0183] Compound dilution: Dilute the test compound to the desired final concentration 100-fold with 100% DMSO. After mixing, add 4.0 μL to 396 μL of running buffer A and centrifuge at 15000 rpm for 5 minutes to obtain a 1X compound solution containing 1% DMSO for subsequent dilutions. Dilute the compound sequentially 2-fold with running buffer B to eight concentrations starting from the initial concentration. Transfer the diluted compound to a 96-well plate for sample injection.

[0184] Running the program: Open Biacore 8K Control software, and perform the experiment at 25... o The program was run in environment C, using run buffer B at a flow rate of 30.0 μL / min. After three injections of run buffer B to achieve equilibration, compounds were injected sequentially from lowest to highest concentration, with binding and dissociation times both set to 60 seconds. The syringe was rinsed with 50% DMSO after each injection. Solvent differences caused by DMSO were corrected for using 0.50%, 0.75%, 1.00%, 1.25%, and 1.50% DMSO.

[0185] 3. Data Analysis The response values ​​of the compound to TRIM21 were analyzed after subtracting the reference channel and the 0 concentration. The affinity Kd was fitted using Biacore Insight Evaluation Software with a steady state affinity model (1:1 binding model).

[0186] Table 1. Affinity of compounds T1-T39 and A1-A9 of the present invention to TRIM21 protein. Compound numbering TRIM21 Kd measurement (μM) T1 0.327 T2 0.983 T3 0.485 T4 3.055 T5 0.551 T6 2.896 T7 4.203 T8 1.496 T9 3.395 T10 1.652 T11 4.802 T12 2.246 T13 0.918 T14 2.752 T15 4.001 T16 0.786 T17 4.397 T18 1.048 T19 0.423 T20 3.012 T21 1.502 T22 4.617 T23 0.725 T24 1.203 T25 1.947 T26 2.412 T27 3.801 T28 0.628 T29 5.000 T30 0.384 T31 1.581 T32 3.212 T33 2.105 T34 0.336 T35 0.874 T36 1.802 T37 2.598 T38 3.603 T39 1.121 A1 0.373 A2 0.589 A3 0.476 A4 0.304 A5 0.097 A6 0.407 A7 0.459 A8 0.248 A9 0.135 The above results indicate that compounds T1-T39 of the present invention, as TRIM21 ligands, possess excellent affinity for TRIM21 protein, with compound T1 exhibiting the optimal affinity. Compounds A1-A9, obtained using compound T1 as a TRIM21 ligand, also demonstrate excellent affinity for TRIM21 protein as TRIM21 protacodes.

[0187] Example 7: Detection experiment of BRD4 protein degradation of compounds A1-A9 Assay Method: This invention utilizes High Content Imaging (HCA) to evaluate the expression of BRD4 protein in MV-4-11 pancreatic cancer cells. Cell samples were collected and fixed with PFA solution for 15 min. 0.1% Triton X-100 solution was added, and the cells were incubated at room temperature for 15 min. 3% BSA was added, and the cells were incubated at room temperature for 90 min. Then, primary antibody BRD4 rabbit mAb (Abcam, ab128874, 1:1000 dilution) was incubated overnight at 4°C. Secondary antibody working solution was prepared by adding goat anti-rabbit IgG (H+L) secondary antibody, Alexa Fluor 594, and Hoechst 33342 (all diluted 1:1000) to 1% BSA solution and incubating at 37°C in the dark for 2 h. After elution, BRD4 and nuclear fluorescence were captured using In Cell Analyzer 2200, and intensity analysis was performed using workstation software.

[0188] The compounds prepared in the examples were subjected to BRD4 protein degradation detection according to the above method. The test results are shown in Table 2. Table 2. Degradation of BRD4 by compounds A1–A9 in MV-4-11 cells compound <![CDATA[BRD4 DC 50 (μM)]]> <![CDATA[BRD4 D max (%)]]> A1 5.418 50.97 A2 0.5866 53.16 A3 0.5411 61.73 A4 0.4431 76.82 A5 0.1943 90.48 A6 2.989 57.37 A7 0.3104 80.48 A8 0.3657 80.66 A9 0.3235 80.04 The above results indicate that the compound A1-A9 of the present invention, as a TRIM21 PROTAC, has excellent BRD4 protein degradation effect in MV-4-11 cells.

Claims

1. The compound represented by Formula II, or its stereoisomer, its deuterated compound, or its pharmaceutically acceptable salt: Formula II The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 alkyl; Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-10 membered cycloalkyl groups, and 3-10 membered heteroalkyl groups; ring A may further be optionally surrounded by one, two, three, or four independent R groups. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 Alkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-OC(O)R A2 -C 0~4 Alkylene-SR A2 -C 0~4 Alkylene-S(O)2R A2 -C 0~4 Alkylene-S(O)R A2 -C 0~4 Alkylene-S(O)2NR A2 R A3 -C 0~4 Alkylene-S(O)NR A2 R A3 -C 0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-NR A2 S(O)2R A3 -C 0~4 Alkylene-NR A2 S(O)R A3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene rings (5-10 membered heteroaryl rings); wherein, The alkylene, cycloalkyl, heterocycloalkyl, aromatic, and heteroaromatic rings may be optionally further divided by one, two, three, or four independent R... A4 replace; The R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; The L is selected from TX. 2 ; where T is selected from -(L T ) q -; q is selected from integers from 1 to 50; Each L T Structural fragments composed of any one or more members from the group consisting of the following groups, wherein the group is CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -, -C≡C-, 3~12-membered cycloalkyl, 3~12-membered heterocycloalkyl, 6~10-membered aromatic ring, 5~10-membered heteroaromatic ring, 5~12-membered spirocyclic ring, 5~12-membered spiroheterocyclic ring, 5~12-membered bridged ring, 5~12-membered bridged heterocyclic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocyclic, spiroheterocyclic, bridged ring, and bridged heterocyclic ring may be further divided by one, two, or three R T1 replace; Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR T2 -C 0~4 Alkylene-OC(O)R T2 -C 0~4 Alkylene-SR T2 -C 0~4 Alkylene-S(O)2R T2 -C 0~4 Alkylene-S(O)R T2 -C 0~4 Alkylene-S(O)2NR T2 R T3 -C 0~4 Alkylene-S(O)NR T2 R T3 -C 0~4 Alkylene-C(O)R T2 -C 0~4 Alkylene-C(O)OR T2 -C 0~4 Alkylene-C(O)NR T2 R T3 -C 0~4 Alkylene-NR T2 R T3 -C 0~4 Alkylene-NR T2 C(O)R T3 -C 0~4 Alkylene-NR T2 S(O)2R T3 -C 0~4 Alkylene-NR T2 S(O)R T3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heterocyclic ring); wherein, the alkylene, cycloalkyl, heterocyclic, aromatic ring, or heterocyclic ring may be optionally surrounded by one, two, three, or four independent R... T4 replace; Each R T2 R T3 R T4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); X 2 Selected from -NH2, -NHR X21 -OH, -SH, ethynyl, vinyl, -C(O)H or -C(O)OH-; R X21 Selected from hydrogen, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Z represents a group that binds to the target protein.

2. The compound according to claim 1, characterized in that: The R 1 Selected from hydrogen, methyl, ethyl, and propyl.

3. The compound according to claim 1, characterized in that: The A ring is selected from 6-membered cycloalkyl, 10-membered cycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, and 9-membered aromatic heterocycle; the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further optionally separated by one, two, three, or four independent R rings. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, =O, and -C. 1~4 Alkyl, halogen-substituted -C 1~3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-C(O)NR A2 R A3 ; R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, halogen-substituted -C 1~6 alkyl.

4. The compound according to claim 3, characterized in that: The A ring is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

5. The compound according to claim 1, characterized in that: The T is selected from , , , , , , , , , , , , , , , , , .

6. The compound according to claim 1, characterized in that: Z is selected from , .

7. The compound according to any one of claims 1 to 6, characterized in that: The compound is specifically: , , , , , , , , .

8. The compound represented by Formula I, or its stereoisomer, its deuterated compound, or its pharmaceutically acceptable salt: Equation I The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 alkyl; R 2 Selected from hydrogen, halogens, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR 21 -C 0~4 Alkylene-OC(O)R 21 -C 0~4 Alkylene-SR 21 -C 0~4 Alkylene-S(O)2R 21 -C 0~4 Alkylene-S(O)R 21 -C 0~4 Alkylene-S(O)2NR 21 R 22 -C 0~4 Alkylene-S(O)NR 21 R 22 -C 0~4 Alkylene-C(O)R 21 -C 0~4 Alkylene-C(O)OR 21 -C 0~4 Alkylene-C(O)NR 21 R 22 -C 0~4 Alkylene-NR 21 R 22 -C 0~4 Alkylene-NR 21 C(O)R 22 -C 0~4 Alkylene-NR 21 S(O)2R 22 -C 0~4 Alkylene-NR 21 S(O)R 22 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene rings (5-10 membered heteroaryl rings); wherein, The alkylene, cycloalkyl, heterocycloalkyl, aromatic, and heteroaromatic rings may be optionally further divided by one, two, three, or four independent R... 23 replace; Each R 23 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR 21 -C 0~4 Alkylene-OC(O)R 21 -C 0~4 Alkylene-SR 21 -C 0~4 Alkylene-S(O)2R 21 -C 0~4 Alkylene-S(O)R 21 -C 0~4 Alkylene-S(O)2NR 21 R 22 -C 0~4 Alkylene-S(O)NR 21 R 22 -C 0~4 Alkylene-C(O)R 21 -C 0~4 Alkylene-C(O)OR 21 -C 0~4 Alkylene-C(O)NR 21 R 22 -C 0~4 Alkylene-NR 21 R 22 -C 0~4 Alkylene-NR 21 C(O)R 22 -C 0~4 Alkylene-NR 21 S(O)2R 22 -C 0~4 Alkylene-NR 21 S(O)R 22 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 24 replace; R 21 R 22 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Each R 24 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-10 membered cycloalkyl groups, and 3-10 membered heteroalkyl groups; ring A may further be optionally surrounded by one, two, three, or four independent R groups. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 Alkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-OC(O)R A2 -C 0~4 Alkylene-SR A2 -C 0~4 Alkylene-S(O)2R A2 -C 0~4 Alkylene-S(O)R A2 -C 0~4 Alkylene-S(O)2NR A2 R A3 -C 0~4 Alkylene-S(O)NR A2 R A3 -C 0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-NR A2 S(O)2R A3 -C 0~4 Alkylene-NR A2 S(O)R A3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace; The R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 Alkyne group.

9. The compound according to claim 8, characterized in that: The R 1 Selected from hydrogen, methyl, ethyl, and propyl.

10. The compound according to claim 8, characterized in that: The R 2 Selected from hydrogen, methyl, ethyl, and propyl.

11. The compound according to claim 8, characterized in that: The A ring is selected from 6-membered cycloalkyl, 10-membered cycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, and 9-membered aromatic heterocycle; the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further optionally separated by one, two, three, or four independent R rings. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, =O, and -C. 1~4 Alkyl, halogen-substituted -C 1~3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-C(O)NR A2 R A3 ; R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, halogen-substituted -C 1~6 alkyl.

12. The compound according to claim 8, characterized in that: The A ring is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

13. The compound according to any one of claims 8-12, characterized in that: The compound is specifically: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 14. The compound represented by formula V, or its stereoisomer, its deuterated compound, or its pharmaceutically acceptable salt: Formula V The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 alkyl; Ring A is selected from 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 3-10 membered cycloalkyl groups, and 3-10 membered heteroalkyl groups; ring A may further be optionally surrounded by one, two, three, or four independent R groups. A1 replace; The R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 -C substituted with alkynyl or hydroxyl groups 1~6 Alkyl, -C 0~4 Alkylene-OR A2 -C 0~4 Alkylene-OC(O)R A2 -C 0~4 Alkylene-SR A2 -C 0~4 Alkylene-S(O)2R A2 -C 0~4 Alkylene-S(O)R A2 -C 0~4 Alkylene-S(O)2NR A2 R A3 -C 0~4 Alkylene-S(O)NR A2 R A3 -C 0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2 C(O)R A3 -C 0~4 Alkylene-NR A2 S(O)2R A3 -C 0~4 Alkylene-NR A2 S(O)R A3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); R A2 R A3 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene rings (5-10 membered heteroaryl rings); wherein, The alkylene, cycloalkyl, heterocycloalkyl, aromatic, and heteroaromatic rings may be optionally further divided by one, two, three, or four independent R... A4 replace; The R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; T is selected from -(L) T ) q -; q is an integer selected from 1 to 50; Each L T Structural fragments composed of any one or more members from the group consisting of the following groups, wherein the group is CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -, -C≡C-, 3~12-membered cycloalkyl, 3~12-membered heterocycloalkyl, 6~10-membered aromatic ring, 5~10-membered heteroaromatic ring, 5~12-membered spirocyclic ring, 5~12-membered spiroheterocyclic ring, 5~12-membered bridged ring, 5~12-membered bridged heterocyclic ring; wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocyclic, spiroheterocyclic, bridged ring, and bridged heterocyclic ring may be further modified by one, two, or three R T1 replace; Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR T2 -C 0~4 Alkylene-OC(O)R T2 -C 0~4 Alkylene-SR T2 -C 0~4 Alkylene-S(O)2R T2 -C 0~4 Alkylene-S(O)R T2 -C 0~4 Alkylene-S(O)2NR T2 R T3 -C 0~4 Alkylene-S(O)NR T2 R T3 -C 0~4 Alkylene-C(O)R T2 -C 0~4 Alkylene-C(O)OR T2 -C 0~4 Alkylene-C(O)NR T2 R T3 -C 0~4 Alkylene-NR T2 R T3 -C 0~4 Alkylene-NR T2 C(O)R T3 -C 0~4 Alkylene-NR T2 S(O)2R T3 -C 0~4 Alkylene-NR T2 S(O)R T3 -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene (5-10 membered heterocyclic ring); wherein, the alkylene, cycloalkyl, heterocyclic, aromatic ring, or heterocyclic ring may be optionally surrounded by one, two, three, or four independent R... T4 replace; Each R T2 R T3 R T4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene (3- to 10-membered cycloalkyl), -C 0~4 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 Alkylene rings (5-10 membered heteroaryl rings); X 2 Selected from -NH2, -NHR X21 -OH, -SH, ethynyl, vinyl, -C(O)H or -C(O)OH-; R X21 Selected from hydrogen, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 Alkyne group.

15. The compound according to claim 14, characterized in that: The T is selected from , , , , , , , , , , , , , , , , , ...

16. Use of the compound according to any one of claims 1 to 15, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, in the treatment of diseases related to abnormal cell proliferation.

17. The use according to claim 16, characterized in that: The disease in question is cancer.

18. Use of the compound according to any one of claims 1 to 15, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, in the preparation of a drug for targeting protein degradation.

19. The use according to claims 16 and 18, characterized in that: The use of the compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt as an intermediate in the preparation of a drug targeting protein degradation.

20. The use according to claim 19, characterized in that: The targeted protein degradation drug is a drug that relies on the E3 ligase TRIM21 for protein degradation.

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