Novel substituted heterocyclic compound as GSPTs / CK1alpha double-target degradation agent

Abstract

The invention discloses a novel substituted heterocyclic compound with GSPTs / CK1a double-target degradation activity, and particularly discloses a compound which has the GSPTs / CK1a double-target degradation activity and is shown in a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, isotope substitute or isomer of the compound. The compound can be used for preventing or treating diseases related to GSPTs / MYC / CK1a / WNT targets or signal pathways.

Description

[0001] This application requires the applicant to have:

[0002] Priority rights to the earlier application filed with the China National Intellectual Property Administration on April 30, 2024, with patent application number 202410538295.1 and entitled "Novel Substituted Heterocyclic Compounds as GSPTs / MYC Signal Flux Regulation";

[0003] Priority rights to the earlier application filed with the China National Intellectual Property Administration on July 19, 2024, with patent application number PCT / CN2024 / 106549 and title "Novel Substituted Heterocyclic Compounds as GSPTs / MYC Signal Flux Modulation";

[0004] Priority rights to the earlier application filed with the China National Intellectual Property Administration on February 14, 2025, with patent application number 202510168120.0 and title "Novel Substituted Heterocyclic Compounds as GSPTs / CK1α Dual-Target Degraders";

[0005] The full text of the prior application is incorporated herein by reference. Technical Field

[0006] This invention belongs to the field of pharmaceutical chemistry, specifically including novel substituted heterocyclic compounds with dual-target degradation activity of GSPTs / CK1α, compositions containing such compounds, and methods for applying such compounds to prepare medicaments for treating or preventing diseases related to the GSPTs / MYC / CK1α / WNT signaling pathway. Background Technology

[0007] The transcription factor family, composed of c-MYC, L-MYC, and N-MYC, are major regulators of cellular processes such as cell proliferation, cell differentiation, cell cycle, and metabolism. However, when these proteins are overactive, they can accelerate these processes, leading to tumorigenesis. Therefore, MYC is one of the most commonly dysregulated proteins in cancer. MYC overexpression or amplification occurs in various cancers, contributing to tumor development and progression: for example, approximately 70% of small cell lung cancers and about 15% of non-small cell lung cancers exhibit MYC overexpression. Other neuroendocrine tumors such as ovarian cancer, triple-negative breast cancer, bladder cancer, and prostate cancer also widely show MYC overexpression.

[0008] However, MYC has long been considered "difficult to drug." Structurally, it lacks a defined binding pocket, and its function is achieved through protein-protein interactions, offering fewer opportunities for active drug development. Furthermore, MYC also functions in the cell nucleus, regulating a range of signaling pathways, and blocking these pathways could lead to numerous toxicity issues.

[0009] GSPT1 is a post-transcriptional modifying factor that binds to and stabilizes the structure of the MYC protein, thereby enhancing its transcriptional activity. Therefore, degrading GSPT1 is a strategy to inhibit the MYC signaling pathway.

[0010] Although several GSPT1 degraders are under development, such as CC9009 and MRT-2359, their development generally faces numerous challenges, including low maximum degradation, weak efficacy, and poor safety. CC9009's clinical trials have been terminated due to low efficacy and significant side effects. Preclinical and preliminary clinical results for MRT-2359 showed that maximum target degradation was only around 60%, and severe hematological side effects occurred even at a clinical dose of 2 mg / day. Therefore, there is an urgent need to develop GSPT1 degraders with higher efficacy, better drug-like properties, and superior safety.

[0011] Casein kinase CK1α is a widely expressed serine / threonine protein kinase in the CK1 kinase family, involved in regulating a variety of physiological and pathological processes in cells, including regulating WNT / β-catenin signaling activation, promoting β-catenin phosphorylation, recruiting proteasome degradation, and regulating the MDM2 / MDMXE3 ligase complex to regulate the stability of the tumor suppressor p53 protein.

[0012] Studies have shown that CK1α is overexpressed in various human cancers. Glucose degraders targeting this protein can induce ubiquitination of CK1α by the CUL4 / DDB1 / CRBN / RBX1 E3 ubiquitin ligase complex (CRL4CRBN), leading to CK1α degradation and subsequent activation of p53 signaling. This results in cell cycle arrest and apoptosis in tumor cells, thus inhibiting tumor growth. Therefore, CK1α has become a potential target for the treatment of various solid tumors and hematological diseases.

[0013] However, despite the great therapeutic potential of the CK1α target, the development of therapeutic drugs targeting this target has been very challenging. On the one hand, the CK1α target lacks a pocket for inhibitor design and binding, and on the other hand, current CK1α degraders generally have weak efficacy and poor drug-likeness. To date, no inhibitors or degraders with good drug-likeness have entered clinical trials. Therefore, there is an urgent need to develop new candidate molecules with good drug-likeness.

[0014] To address the shortcomings of weak efficacy and significant side effects associated with single-target therapy, this invention designs a series of novel dual-target, bifunctional molecular adhesive degraders with a dual-target synergistic structure based on the principle of dual-target synergy. Summary of the Invention

[0015] The object of this invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isotopic substitute or isomer thereof.

[0016]

[0017] Wherein, A is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0018] The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures:

[0019]

[0020]

[0021]

[0022]

[0023] in, "Any" represents a single or double bond, and when When it is a single bond, X, X1, and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X, X1, and X2 are arbitrarily and independently selected from C(R) d1 ) or N; X3 is arbitrarily and independently selected from C(R) d1 ) or N;

[0024] Z is independently selected from -C(R) d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d6 )S(=O)2-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 P(=Y)–, -OS(=Y)-, -S(=O)2-, alkene bond, alkyne bond, 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0025] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-OC(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、-N(R d7 )C(R d1 (R) d2 -, -O-, -S-, -N(R) d3)C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bond, alkyne bond, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group and 3-8 saturated or partially saturated heterocyclic group; wherein the aryl group, heteroaryl group, cycloalkyl group and heterocyclic group are connected to ring A or B at one end and connected to Z at the other end;

[0026] Y is independently selected from O, S, or =NR0;

[0027] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0028] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0029] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0030] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0031] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0032] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0033] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0034] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0035] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0036] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0037] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (IA).

[0038]

[0039] in,

[0040] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0041] The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures:

[0042]

[0043]

[0044]

[0045]

[0046] in, "Any" represents a single or double bond, and when When it is a single bond, X, X1, and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X, X1, and X2 are arbitrarily and independently selected from C(R)d1 ) or N; X3 is arbitrarily and independently selected from C(R) d1 ) or N;

[0047] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0048] Y is independently selected from O, S, or =NR0;

[0049] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0050] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0051] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0052] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl groups; wherein the hydrogen on R3 is optionally replaced by one to a plurality of groups selected from hydrogen, deuterium, halogen, oxo, CN, pentafluoride sulfide, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0053] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0054] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0055] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0056] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0057] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0058] t is any integer selected from 0, 1, 2, 3, 4, and 5;

[0059] p and q are arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0060] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (IB).

[0061]

[0062] in,

[0063] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0064] The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures:

[0065]

[0066]

[0067]

[0068]

[0069] in, "Any" represents a single or double bond, and when When it is a single bond, X, X1, and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X, X1, and X2 are arbitrarily and independently selected from C(R) d1 ) or N; X3 is arbitrarily and independently selected from C(R) d1 ) or N;

[0070] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -N(R d3 )C(=O)-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0071] Y is independently selected from O, S, or =NR0;

[0072] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0073] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0074] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0075] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0076] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0077] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0078] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0079] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0080] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0081] t is any integer selected from 0, 1, 2, 3, 4, and 5;

[0082] p and q are arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0083] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (IC).

[0084]

[0085] in,

[0086] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0087] L0 is independently selected from non-existent, single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR)-. d5 )-, -O-, -S-, -N(R0)C(=O)-;

[0088] "Any" represents either a single bond or a double bond;

[0089] X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2, C(R d1 ) or N;

[0090] L1, L2, and L3 are independently selected from non-existent, single bonds, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0091] Y is independently selected from O, S, or =NR0;

[0092] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0093] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0094] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0095] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0096] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, pentafluoride sulfide, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0097] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0098] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0099] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0100] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0101] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0102] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (ID).

[0103]

[0104] in,

[0105] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0106] L0 is independently selected from non-existent, single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR)-. d5 )-, -O-, -S-, -N(R0)C(=O)-;

[0107] "Any" represents either a single bond or a double bond;

[0108] X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2, C(R d1 ) or N;

[0109] L1 and L2 are independently selected from non-existent, single bond, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(Rd1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–-(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0110] Y is independently selected from O, S, or =NR0;

[0111] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0112] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0113] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0114] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0115] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, pentafluoride sulfide, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0116] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0117] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0118] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0119] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0120] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0121] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (IE).

[0122]

[0123] in,

[0124] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0125] L0 is independently selected from non-existent, single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR)-. d5 )-, -O-, -S-, -N(R0)C(=O)-;

[0126] "Any" represents either a single bond or a double bond;

[0127] X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4)P(=Y)–, -OS(=Y)-, -S(=O)2, C(R d1 ) or N;

[0128] X3 and X4 are arbitrarily and independently selected from C(R) d1 ) or N;

[0129] L1 and L2 are independently selected from non-existent, single bond, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0130] Y is independently selected from O, S, or =NR0;

[0131] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0132] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0133] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0134] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0135] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0136] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0137] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0138] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0139] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0140] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0141] p is any integer selected from 0, 1, 2, 3, and 4.

[0142] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (IF).

[0143]

[0144] in,

[0145] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0146] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5)-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=X)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-, alkene bond, alkyne bond, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group and 3-8 saturated or partially saturated heterocyclic group;

[0147] X is independently selected from O, S, or =NR0;

[0148] R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0149] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: The hydrogen atom on R1 is preferably selected from one or more groups, including H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0150] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0151] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0152] Each R d1They can be the same or different, and can be arbitrarily and independently selected from deuterium, halogen, CN, sulfonium pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0153] R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 R d10 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0154] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0155] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0156] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0157] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0158] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0159] p is any integer selected from 1, 2, 3, and 4.

[0160] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having a structure of formula (2-IF).

[0161]

[0162] in,

[0163] A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0164] The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures:

[0165]

[0166]

[0167]

[0168]

[0169] in, "Any" represents a single or double bond, and when When it is a single bond, X is arbitrarily and independently selected from -C(R) d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X is arbitrarily and independently selected from C(R) d1 ) or N;

[0170] Z is independently selected from -C(R) d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2)C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 P(=Y)–, -OS(=Y)-, -S(=O)2-, alkene bond, alkyne bond, 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group are optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0171] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bond, alkyne bond, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group and 3-8 saturated or partially saturated heterocyclic group; wherein the aryl group, heteroaryl group, cycloalkyl group and heterocyclic group are connected to ring A or B at one end and connected to Z at the other end;

[0172] Y is independently selected from O, S, or =NR0;

[0173] Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0174] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0175] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0176] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one or more elements selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0177] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 and R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0178] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0179] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0180] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0181] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0182] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0183] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having a structure of formula (IG-1) or (IG-2).

[0184]

[0185] in,

[0186] Each can independently represent a single bond or a double bond;

[0187] X1 and X3 are arbitrarily and independently selected from C(R) d1 ) or N;

[0188] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5)-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0189] Y is independently selected from O, S, or =NR0;

[0190] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0191] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0192] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0193] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0194] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0195] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0196] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0197] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0198] t is any integer selected from 0, 1, 2, 3, 4 and 5.

[0199] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0200] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided, said compound having the structure of formula (IH-1), (IH-2), or (IH-3).

[0201]

[0202]

[0203] in,

[0204] Each can independently represent a single bond or a double bond;

[0205] L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2)C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups;

[0206] Y is independently selected from O, S, or =NR0;

[0207] Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0208] Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0209] Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups;

[0210] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents;

[0211] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0212] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0213] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0214] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0215] t is any integer selected from 0, 1, 2, 3, 4, and 5;

[0216] p is any integer selected from 0, 1, 2, 3, 4 and 5.

[0217] According to an embodiment of the present invention, the carboxyl substitute is:

[0218] According to an embodiment of the present invention, Also selected

[0219]

[0220] In one aspect of the invention, a compound or a pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof is provided having the structure of formula (II).

[0221]

[0222] Among them, ring B is selected from 5-14-membered heterocyclic groups and 5-14-membered heteroaryl groups;

[0223] L2 is selected from unsubstituted or optionally by one, two or more R... L The following groups are substituted: C-16 1-6 Alkyl groups, 3-8 membered heterocyclic groups; each R L Same or different, selected independently from C 1-6 Alkyl, C 1-6 Alkoxy;

[0224] L3 does not exist or is selected from O or NR. L31 C(R) L32 (R) L33 ); R L31 R L32 R L33 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, halogen, CN, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0225] R1 is selected from H, halogens, CN, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0226] R2 is selected from H, halogens, oxometalates (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0227] m is selected from 0, 1, 2, 3, 4, 5;

[0228] n is selected from 0, 1, 2, 3, 4, 5.

[0229] According to an embodiment of the present invention, ring B is selected from 9-12 membered heterocyclic groups and 9-12 membered heteroaryl groups; the heterocyclic group may be a fused ring formed by at least two of the following: a dihydropyrrole ring, a dihydrofuran ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, and a benzene ring; the heteroaryl group may be a fused ring formed by at least two of the following: a benzene ring, a pyrrole ring, and a furan ring.

[0230] According to an embodiment of the present invention, ring B is selected from...

[0231] According to an embodiment of the present invention, Selected from

[0232] According to an embodiment of the present invention, Selected from

[0233] According to embodiments of the present invention, L2 is selected from unsubstituted or optionally replaced by one, two or more R. L The following groups are substituted: methylene, azeticyclic butyl; preferably, R L It is methyl;

[0234] According to an embodiment of the present invention, L2 is selected from CH2, (For example ).

[0235] According to an embodiment of the present invention, L3 is absent or selected from O, NH, CH2.

[0236] According to an embodiment of the present invention, R1 is selected from H, halogen, CN, NH2, and halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0237] According to an embodiment of the present invention, R1 is selected from H, halogen, CN, NH2, and halogenated C. 1-3 Alkoxy;

[0238] According to an embodiment of the present invention, R1 is selected from H, F, Cl, CN, NH2, trifluoromethyl, and trifluoromethoxy.

[0239] According to an embodiment of the present invention, R2 is selected from H, halogens, and oxo (=O).

[0240] According to an embodiment of the present invention, R2 is selected from H, F, and oxo.

[0241] According to an embodiment of the present invention, Selected from For example

[0242]

[0243] In one aspect of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer or isotopic substitute, wherein the compound is a novel compound selected from the structures disclosed in the examples.

[0244] In one aspect of the present invention, the isomers include enantiomers and diastereomers.

[0245] In one embodiment of the present invention, the isomer is selected from enantiomers.

[0246] The present invention also provides a pharmaceutical composition comprising at least one of the following: a therapeutically effective amount of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate, an isomer (preferably an enantiomer), and an isotopic substitute.

[0247] According to embodiments of the present invention, the pharmaceutical composition is formulated for administration via a route selected from the following: oral, injection, rectal, nasal, pulmonary, local, oral and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural.

[0248] According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

[0249] The oral dosage form is not particularly limited and can be any oral dosage form known in the art, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.

[0250] According to embodiments of the present invention, the pharmaceutical composition may further comprise pharmaceutically acceptable excipients selected from at least one of the following: fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, humectants, pH adjusters, solubilizers or co-solvents, and osmotic pressure regulators. Those skilled in the art can readily determine how to select the appropriate excipients and their corresponding amounts based on the specific dosage form requirements.

[0251] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0252] Another object of the present invention is to provide the use of the above-mentioned compounds, their pharmaceutically acceptable salts, solvates, isomers (preferably enantiomers), and isotopic substitutes in the preparation of medicaments for the prevention and / or treatment of diseases related to the MYC / GSPTs signaling pathway. The diseases related to the MYC / GSPTs signaling pathway include, but are not limited to, cancer, metabolic diseases, autoimmune diseases, and inflammatory diseases.

[0253] Another object of the present invention is to provide the above-mentioned compounds, their pharmaceutically acceptable salts, solvates, isomers (preferably enantiomers), and isotopic substitutes, and the use of said pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases associated with or mediated by GSPTs and / or CK1α. The diseases associated with or mediated by GSPTs and / or CK1α include, but are not limited to, cancer, metabolic diseases, autoimmune diseases, inflammatory diseases, etc.

[0254] The present invention also provides the above-mentioned compounds, their pharmaceutically acceptable salts, solvates, isomers (preferably enantiomers) and isotopic substitutes, and the use of the pharmaceutical compositions in the degradation of GSPTs and / or CK1α.

[0255] The present invention also provides the above-mentioned compounds, their pharmaceutically acceptable salts, solvates, isomers (preferably enantiomers) and isotopic substitutes, and the use of the pharmaceutical compositions in the preparation of medicaments for degrading GSPTs and / or CK1α.

[0256] The present invention also provides compounds of formula (I), pharmaceutically acceptable salts, solvates, isomers (preferably enantiomers), and isotopic substitutes thereof, and the use of said pharmaceutical compositions in the prevention and / or treatment of diseases associated with the MYC / GSPTs / CK1α / WNT signaling pathway. The diseases associated with the MYC / GSPTs / CK1α / WNT signaling pathway include, but are not limited to, cancer, metabolic diseases, autoimmune diseases, and inflammatory diseases.

[0257] The present invention also provides the above-described compounds, their pharmaceutically acceptable salts, solvates, isomers (preferably enantiomers), and isotopic substitutes, and the use of said pharmaceutical compositions in the prevention and / or treatment of GSPTs and / or CK1α-related or mediated diseases. The GSPTs and / or CK1α-related or mediated diseases have the definitions described above.

[0258] The present invention also provides a method for preventing and / or treating diseases related to the MYC / GSPTs / CK1α / WNT signaling pathway, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, an isomer (preferably an enantiomer), and an isotopic substitute; or administering to a patient a preventive or therapeutically effective amount of the aforementioned pharmaceutical composition. The diseases related to the MYC / GSPTs / CK1α / WNT signaling pathway have the definitions described above.

[0259] The present invention also provides a method for preventing and / or treating GSPTs and / or CK1α-related or mediated diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the above-described compound, its pharmaceutically acceptable salt, solvate, isomer (preferably enantiomer), and isotopic substitute, or administering to a patient a preventive or therapeutically effective amount of the above-described pharmaceutical composition. The GSPTs and / or CK1α-related or mediated diseases have the definitions described above.

[0260] In some implementations, the GSPTs are preferably GSPT1.

[0261] In some implementations, the patient is a mammal, preferably a human.

[0262] Technical effect

[0263] Unexpectedly, the heterocyclic compounds of this invention were found to be potent degraders not only of GSPTs but also of CK1α. Through synergistic effects, the heterocyclic compounds of this invention can enhance antitumor efficacy by hundreds of times without increasing toxicity, thus providing a wider safety window. Furthermore, some of the heterocyclic compounds of this invention, compared to the reference compound MRT-2359, not only exhibit tens to hundreds of times greater GSPTs and CK1α degradation activity and antitumor cell proliferation activity, but also possess better in vivo antitumor activity, as well as favorable pharmacokinetic properties (including a longer T1 / 2 and higher exposure), bioavailability, and safety. Some representative compounds even caused complete tumor regression, with no recurrence after drug withdrawal, achieving tumor cure. Therefore, they are more suitable as drug candidates for the prevention or treatment of diseases related to the GSPTs / MYC target and / or the CK1α / WNT signaling pathway.

[0264] Definitions and explanations:

[0265] C 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 C 2-10 Selected from C2, C3, C4, C5, C6, C7, C8, C9 and C 10 C3-10 Selected from C3, C4, C5, C6, C7, C8, C9 and C 10 ;

[0266] As used herein, the term "alkyl" should be understood to refer to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms, also denoted as "C". 1-20 Alkyl group. For example, "C 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0267] The term "one or more" as used in this article refers to more than one, such as one, two, three, four, five or more.

[0268] The term "monocyclic or polycyclic structure with 3 to 18 carbon atoms" encompasses various monocyclic or polycyclic structures having 3 to 18 carbon atoms (and may also contain other heteroatoms). The number of carbon atoms in the monocyclic or polycyclic structure can be selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or any combination of these values. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridged ring structures; wherein aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridged rings are defined as follows.

[0269] The term "alkenyl" should be understood to refer to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a linear or branched hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 "Alkenyl". "C" 2-10"Alkenyl" should be understood to preferably represent a linear or branched hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C... 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0270] The term "alkynyl" should be understood to refer to a straight or branched hydrocarbon group containing one or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a linear or branched hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C"). 2-8 "Alkyne group" has 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0271] The term "heteroalkyl" refers to a saturated or partially unsaturated group consisting of 1 to 20 carbon atoms and at least one heteroatom or heterogroup. In some embodiments, the heteroatom is selected from O, N, S, or P and their isotopes, wherein the N, S, or P atom is optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-10 Heteroalkyl, C 1-6Heteroalkyl. Heteroatoms or heteroatomic groups can be located at any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, such as alkoxy, alkylthio, alkamino, or ether. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and at most two heteroatoms can be consecutive, such as -CH2-NH-OCH3.

[0272] The terms "alicylic ring," "carbocyclic (alkyl)," or "cycloalkyl" refer to a saturated or partially unsaturated monocyclic or polycyclic alkyl group, wherein the carbocyclic ring may contain 3 to 20 carbon atoms, preferably C14. 3-12 Cycloalkyl groups comprising 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably C4. 3-10 cycloalkyl, C 3-6 The carbocyclic ring can be monocyclic or polycyclic, and can be a saturated cycloalkyl group or optionally contain one, two or more double and / or triple bonds on its ring, thereby forming so-called cycloalkenyl or cycloynyl groups. In the case of multiple rings, these rings can form spirocyclic, fused, and bridged ring structures. For example, non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, cyclooctyl, cyclooctatetraenyl, etc.; non-limiting examples of polycyclic carbocyclic rings include decahydronaphthyl or isobornyl.

[0273] The term "aryl" or "aromatic ring" refers to, preferably, a monocyclic, bicyclic (e.g., fused, bridged, or spirocyclic) or tricyclic hydrocarbon ring having aromatic or partially aromatic properties with 6 to 20 carbon atoms. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C". 6-14 Aryl. The term "C" 6-14 "Aryl" should be understood to preferably represent an aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0274] The term "spirocyclic" refers to a ring system in which two rings share a single cyclic atom, and it may contain aliphatic rings, heterocyclic rings, aromatic rings, or heteroaromatic rings as described above.

[0275] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms, and it may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as described above.

[0276] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms, and it may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as described above.

[0277] The term "heterocyclic (group)" refers to a saturated or partially unsaturated monocyclic or polycyclic alkyl substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms or groups selected from N, O, NH, S, S(O) or S(O)2, but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, 3-12 membered heterocyclic groups comprising 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms (e.g., 1, 2, 3, and 4); more preferably, 3-6 membered heterocyclic groups comprising 3 to 6 ring atoms (e.g., 3, 4, 5, and 6). The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms, or a nitrogen atom (if present), or an oxygen or sulfur atom (especially in the case of forming ononium salts). The heterocyclic group can include fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclic groups include azirrobutyl, oxacyclobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxacyclopentenyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithiaalkyl, trithiaalkyl, homopiperazinyl, diazacycloheptyl, etc., preferably piperidinyl or pyrrolyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups, and may also be benzofused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group may be bicyclic, and non-limiting examples include hexahydrocyclopenta[c]pyrrolo-2(1H)-yl and hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl. Heterocyclic groups can also be partially unsaturated, meaning they can contain one or more double bonds. Non-limiting examples include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl.

[0278] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0279] In this document, the term "heteroaryl / heteroary ring" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen, and phosphorus. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered. Non-limiting examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[a] derivatives, such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, and indolyl. Isoindolyl, etc.; or pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purineyl, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphridinyl, pteridinyl, carbazoyl, acridineyl, phenazinyl, phenothiazinyl and / or phenotoxazinyl, etc.

[0280] The heteroaryl / heteroaryl ring can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0281] Unless otherwise stated, heterocyclic groups, heteroaryl groups, or heteroaromatic rings include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, forms may include those in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridinoid-2-yl, pyridinoid-3-yl, pyridinoid-3-yl, pyridinoid-4-yl, and pyridinoid-4-yl; thiophene groups or thiophene groups include thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, etc.

[0282] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0283] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0284] Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0285] The term "pharmaceutically acceptable salt" as used herein refers to derivatives of the compounds of this invention, wherein the parent compound is modified by salting with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of anions such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, etc. Conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids, inorganic and organic bases, wherein the inorganic or organic acid is selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohepose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, etc. The inorganic and organic bases mentioned above, such as hydroxyethanesulfonic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid, are selected from Na, potassium, magnesium, calcium, etc., or amines, diethylamine, triethylamine, ethanolamine, etc.

[0286] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0287] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0288] Some compounds of the present invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms.

[0289] In this document, the term "solvate" refers to an association formed by one or more solvent molecules with the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Therefore, the term "hydrate" refers to an association formed by solvent molecules that are water.

[0290] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0291] The illustrations of racemic, ambiscalemic and scalemic, or enantiomerically pure compounds in this document are derived from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, wedge-shaped and dashed lines denote the absolute configuration of a stereocenter. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all tautomers are included within the scope of this invention.

[0292] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0293] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0294] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0295] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0296] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0297] When a substituent can be cross-bonded to two atoms on a ring, it can bond to any atom on that ring. When a listed substituent does not specify which atom it is attached to in a compound included but not specifically mentioned in the general chemical formula, it can bond to any atom of that substituent. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0298] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0299] The present invention is now further described by way of examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many methods known in the field of organic synthesis. The embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by modifications thereof. Preferred methods include, but are not limited to, the methods described below.

[0300] Unless otherwise specified, all solvents used in this invention are commercially available and require no further purification. Reactions are typically carried out in an anhydrous solvent under an inert nitrogen atmosphere. Nuclear magnetic resonance (NMR) spectra were determined using a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts are reported in δ (ppm). Mass spectrometry was performed using an Agilent 1200 series (plus 6110 / and 1956A) LC / MS or a Shimadzu MS (DAD:SPD-M20A(LC)) and a Shimadzu Micromass 2020 detector. The mass spectrometer was equipped with an electrospray ionization (ESI) source operating in both positive and negative modes.

[0301] The abbreviations used are as follows: aq for aqueous solution; TLC for thin-layer chromatography; RT for room temperature; MeOH for methanol; EtOH for ethanol; EtOAc for ethyl acetate; THF for tetrahydrofuran; equivalent (eq); CDI for carbonyl diimidazole; DCM for dichloromethane; PE for petroleum ether; DIAD for diisopropyl azodicarbonate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; CBz for benzyloxycarbonyl; BOC for tert-butyl... Butyl carbonyl; HOAc is acetic acid; Ms is methanesulfonyl; NMP is N-methylpyrrolidone; DMAP is 4-(dimethylamino)pyridine; Boc2O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; DIPEA is diisopropylethylamine; SOCl2 is thionyl chloride; CS2 is carbon disulfide; TsOH is 4-toluenesulfonic acid; MTBE is tert-butyl methyl ether; FA is formic acid; ACN is acetonitrile; i-PrOH is 2-propanol.

[0302] Compounds can be named manually or using... The reaction should be named accordingly; if commercially purchased, the supplier's catalog name can also be used. TLC or LC-MS is typically used to determine whether the reaction is complete. Detailed Implementation

[0303] To illustrate the invention in more detail, the following examples are given, but the scope of the invention is not limited thereto.

[0304] Example 2: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxopiridin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl ester (compound 2):

[0305] 1) Synthesis of methyl 4-bromoindoline-6-carboxylate:

[0306]

[0307] At 0 °C, triethylsilane (13.73 g, 118.05 mmol) was slowly added to a solution of methyl 4-bromo-1H-indole-6-carboxylate (20 g, 78.7 mmol) in 2,2,2-trifluoroacetic acid (200 mL), and the mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (500 mL), and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The collected organic matter was washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give methyl 4-bromoindoline-6-carboxylate (15.0 g, 58.6 mmol, yield: 74.5%), LCMS m / z: 256 [M+H]. + .

[0308] 2) Synthesis of methyl 4-bromo-7-iodoindoline-6-carboxylate:

[0309]

[0310] At 0 °C, N-iodosuccinimide (968 mg, 4.30 mmol) was slowly added to a solution of methyl 4-bromoindoline-6-carboxylate (1.00 g, 3.91 mmol) in acetic acid (40 mL), and the mixture was heated to 80 °C and stirred for 0.5 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 15 / 1) to give methyl 4-bromo-7-iodoindoline-6-carboxylate (700 mg, 1.83 mmol, yield: 46.8%). LCMS m / z: 382 [M+H] + .

[0311] 3) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid:

[0312]

[0313] At room temperature, triethylamine (555 mg, 5.49 mmol), 4-dimethylaminopyridine (112 mg, 0.915 mmol), and di-tert-butyl dicarbonate (598 mg, 2.75 mmol) were added to a solution of methyl 4-bromo-7-iodoindoline-1,6-dicarboxylic acid (15 / 15) in 20 mL of dichloromethane. The mixture was heated to 60 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester (750 mg, 1.56 mmol, yield: 85%) as a yellow solid. LCMS: m / z: 382 [M+H-100] + .

[0314] 4) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylic acid:

[0315]

[0316] At room temperature, to a mixed solution of 1,4-dioxane (10 mL) and water (1.0 mL) containing 1-(tert-butyl)-6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid ester (750 mg, 1.56 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoboropentan (480 mg, 3.12 mmol), potassium carbonate (646 mg, 4.68 mmol), and Pd(dppf)Cl2.CH2Cl2 (600 mg, 0.82 mmol) were added. Under nitrogen protection, the mixture was heated to 70 °C in a sealed tube and stirred for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester (360 mg, 0.942 mmol, yield: 60.4%), LCMS m / z: 326 [M+H-56] + .

[0317] 5) Synthesis of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester):

[0318]

[0319] At room temperature, NaIO4 (1.0 g, 4.71 mmol) and K2OsO4 (17 mg, 0.047 mmol) were added to a solution containing 10 mL of tetrahydrofuran (360 mg, 0.942 mmol) of 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester (360 mg, 0.942 mmol) and water (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) ester (100 mg, 0.26 mmol, yield: 27.7%), LCMS m / z: 328 [M+H-56]. + .

[0320] 6) Synthesis of tert-butyl 4-bromo-7-(2,6-dioxopiridine-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate:

[0321]

[0322] To a solution of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) ester (100 mg, 0.26 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (128 mg, 0.78 mmol), triethylamine (0.5 mL), sodium triacetoxyborohydride (110 mg, 0.52 mmol), and acetic acid (1 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 6) to give compound tert-butyl 4-bromo-7-(2,6-dioxopiridine-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid (80 mg, 0.172 mmol, yield: 66.3%). LCMS m / z: 464 [M+H] + .

[0323] 7) Synthesis of tert-butyl 7-(2,6-dioxopiridine-3-yl)-4-(hydroxymethyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate:

[0324]

[0325] To a solution of tert-butyl 4-bromo-7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid (80 mg, 0.172 mmol) in 1,4-dioxane (8 mL), add (tributyltinyl)methanol (1.1 g, 3.45 mmol) and Pd(PPh3)4 (88 mg, 0.086 mmol). Under nitrogen protection, heat in a sealed tube at 100 °C and stir for 16 hours. Filter the mixture, collect the filtrate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound tert-butyl 7-(2,6-dioxopiridine-3-yl)-4-(hydroxymethyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate (60 mg, 0.144 mmol, yield: 84.0%), LCMS m / z: 416

[0326] [M+H] +

[0327] 8) Synthesis of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid:

[0328]

[0329] At room temperature, a solution of 1,4-dioxane (3.0 mL) containing 7-(2,6-dioxopiridine-3-yl)-4-(hydroxymethyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid tert-butyl ester (60 mg, 0.144 mmol) was added to (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (46 mg, 0.144 mmol) and 4-dimethylaminopyridine (20 mg, 0.158 mmol), and the mixture was heated to 90 °C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-100% B within 15 min; detector: 254 nm). When the content of mobile phase B reached 75%, the fraction containing the product was collected and concentrated under reduced pressure to obtain compound 7-(2,6-dioxopiridine-3-yl)-4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid tert-butyl ester (50 mg, 0.078 mmol, yield: 54.5%), LCMS m / z: 637 [M+H]. +

[0330] 9) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxopiridin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl ester:

[0331]

[0332] To a solution of 7-(2,6-dioxopiperidin-3-yl)-4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid tert-butyl ester (50 mg, 0.078 mmol) in dichloromethane (3.0 mL), 2,2,2-trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) and the pH was adjusted to 6-7 with saturated sodium carbonate solution. The organic phase was collected, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-100% B within 15 min; detector: 254 nm). When the concentration of mobile phase B reached 60%, the fraction containing the product was collected, and the compound (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxopiridine-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl ester (19.09 mg, 0.0356 mmol, yield: 45.6%) was concentrated under reduced pressure. LCMS m / z: 578 [M+41+H] +

[0333] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.89(s,1H),7.84(s,1H),7.38(t,J=9.6H z,1H),7.14-7.12(m,1H),7.05(s,1H),5.95(s,1H),5.17(s,2H),5.11-5.07(m, 1H),4.16(dd,J1=35.2Hz,J2=16.8Hz,2H),3.59(t,J=8.8Hz,2H),3.11-3.06(m, 2H),2.94-2.86(m,1H),2.62-2.51(m,1H),2.40-2.33(m,1H),2.01-1.96(m,1H).

[0334] 19 F NMR(377MHz,DMSO-d6)δ-57.197,-125.995.

[0335] Example 3: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2-(2,6-oxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindole-5-yl)methyl ester (compound 3):

[0336] 1) Preparation of methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate:

[0337]

[0338] 25 g (0.14 mol) of methyl 2,3-dihydrobenzofuran-5-carboxylate was dissolved in acetic anhydride (250 mL), cooled to 0 °C, and nitric acid (26.05 g, 0.28 mol, 68% concentration) was added dropwise. The mixture was stirred at 0 °C for 5 hours. The reaction mixture was poured into ice water (100 mL), and a solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate (100 mL). The solid was collected and dried to give methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate (15 g, 0.067 mol, yield 47.8%).

[0339] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.10(s,1H),4.91(t,J=8.8Hz,2H),3.87(s,3H),3.36(t,J=8.8Hz,2H).

[0340] 2) Synthesis of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate:

[0341]

[0342] 13 g (0.058 mol) of methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate was dissolved in 130 mL of ethanol and 26 mL of water. Ammonium chloride (15.37 g, 0.290 mol) and iron (9.74 g, 0.174 mol) were added, and the reaction mixture was heated to 80 °C and stirred for 3 hours. The mixture was filtered, concentrated under reduced pressure, and diluted with 300 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (11 g, 0.057 mol, yield: 97.7%).

[0343] 1H NMR (400MHz, DMSO-d6) δ8.17(d,J=1.2Hz,1H),8.13(s,1H),4.90(s,2H),4.58(t,J=8.8Hz,2H),3.76(s,3H),3.16(t,J=8.8Hz,2H).

[0344] 3) Preparation of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate:

[0345]

[0346] NBS (11.44 g, 64.24 mmol) was slowly added dropwise to a solution of N,N-dimethylformamide (240 mL) containing methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (12.4 g, 64.24 mmol) over 2 hours until complete. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (800 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (500 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate (14.13 g, 0.052 mol, yield 80.8%).

[0347] 1 H NMR (400MHz, DMSO-d6) δ7.11(s,1H),5.06(s,2H),4.63(t,J=8.8Hz,2H),3.77(s,3H),3.17(t,J=8.8Hz,2H).

[0348] 4) Preparation of methyl 7-amino-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate:

[0349]

[0350] To a mixture of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate (13 g, 47.98 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoboropentan (19.2 g, 143.38 mmol) in 1,4-dioxane (200 mL) and water (20 mL), Pd(dppf)Cl2 (6.98 g, 9.56 mmol) and K2CO3 (19.78 g, 143.35 mmol) were added, and the mixture was heated to 80°C and stirred for 16 hours under nitrogen protection. The reaction mixture was then added to water (100 mL) and extracted with ethyl acetate (120 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 2), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%, 254 nm) to methyl 7-amino-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (8 g, 36.52 mmol, yield: 76.3%), LCMS m / z: 220 [M+H]. + .

[0351] 5) Synthesis of methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate:

[0352]

[0353] To a solution of methyl 7-amino-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (2 g, 9.13 mmol) in H₂O (5 mL), NaNO₂ (661 mg, 9.59 mmol) and HBr (4 mL) were added, and the mixture was stirred at 0 °C for 1 hour. Cuprous bromide (2.6 g, 18.26 mmol) was then added to the mixture, and the mixture was stirred at 0 °C for 3 hours. The mixture was then added to water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and subjected to reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / EA = 0–10%, 254 nm) to give methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (890 mg, 3.14 mmol, yield: 34.4%).

[0354] 1 H NMR(400MHz,DMSO-d6)δ7.84(d,J=3.0Hz,1H),7.12(dd,J=17.9,11.7Hz,1H), 5.58–5.41(m,2H),4.70(t,J=8.8Hz,2H),3.78(s,3H),3.41(t,J=8.8Hz,2H).

[0355] 6) Synthesis of methyl 7-bromo-4-formyl-2,3-dihydrobenzofuran-5-carboxylate:

[0356]

[0357] A solution of tetrahydrofuran (10 mL) and H₂O (2 mL) containing methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (890 mg, 4.06 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, NaIO₄ (3.5 g, 16.26 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 0%–20%, 254 nm) to give methyl 7-bromo-4-formyl-2,3-dihydrobenzofuran-5-carboxylate (300 mg, 1.05 mmol, yield: 33.4%), LCMS m / z: 285 [M+H]. + .

[0358] 7) Synthesis of 3-(5-bromo-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidine-2,6-dione:

[0359]

[0360] At room temperature, triethylamine (659 mg, 6.53 mmol), methyl 7-bromo-4-formyl-2,3-dihydrobenzofuran-5-carboxylate (310 mg, 1.09 mmol), sodium triacetoxyborohydride (STAB, 691 mg, 3.26 mmol), and HOAc (0.2 mL) were added to a solution of 3-aminopiperidine-2,6-dione hydrogen chloride (538 mg, 3.26 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then added to H₂O (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–10%, 254 nm) to give 3-(5-bromo-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidin-2,6-dione (330 mg, 0.90 mmol, yield: 83.1%), LCMS m / z: 367 [M+H]. + .

[0361] 8) Synthesis of 3-(5-(hydroxymethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidine-2,6-dione:

[0362]

[0363] To a solution of 1,4-dioxane (10 mL) containing 3-(5-bromo-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidin-2,6-dione (300 mg, 0.82 mmol), (tributyltinyl)methanol (5.27 g, 16.44 mmol) and Pd(PPh3)4 (474 ​​mg, 0.41 mmol), the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. Potassium fluoride solution (10 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes, followed by extraction with dichloromethane (30 mL × 3). The combined organic extracts were washed with saturated brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–10%, 254 nm) to give 3-(5-(hydroxymethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidin-2,6-dione (60 mg, 0.19 mmol, yield: 23.0%), LCMS m / z: 317 [M+H] + .

[0364] 9) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2-(2,6-oxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindole-5-yl)methyl ester:

[0365]

[0366] To a solution of 1,4-dioxane (2 mL) containing 3-(5-(hydroxymethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidin-2,6-dione (40 mg, 0.13 mmol), 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (47 mg, 0.15 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) were added, and the mixture was heated to 90 °C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (Waters 3767 / QDA, column: SunFireC18 19*250mm, 10µm; mobile phase A: 10mmol / L; A: H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 53%–63%; retention time: 7.4–8.2 min, 17 min) to obtain (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2-(2,6-oxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl ester (8.89 mg, 0.016 mmol, yield: 13.0%), LCMS m / z: 579 [M+H). + .

[0367] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),9.90(s,1H),7.83(s,1H),7.64(s,1H),7.38 (dd,J=10.3,9.1Hz,1H),7.13(d,J=9.1Hz,1H),5.19(s,2H),5.10(dd,J=13.3,5.1H z,1H),4.75(t,J=8.9Hz,2H),4.40(d,J=17.2Hz,1H),4.26(d,J=17.1Hz,1H),3.32( m,2H),3.03-2.82(m,1H),2.63-2.52(m,1H),2.38-2.46(m,1H),2.07-1.85(m,1H).

[0368] 19 F NMR(377MHz,DMSO-d6)δ-57.21(s),-125.94(s).

[0369] Example 5: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxohesperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-yl)methyl ester (compound 5):

[0370] 1) Preparation of methyl 5-bromo-3-hydroxy-2-methylbenzoate:

[0371]

[0372] At 0°C, 1 mL of water containing sodium nitrite (1.40 g 16.4 mmol) was added dropwise to a solution of methyl 3-amino-5-bromo-2-methylbenzoate (4.00 g 16.4 mmol) and sulfuric acid (40 mL, 10% H₂O). Then, sulfuric acid (50% aqueous solution) was added at room temperature, and the mixture was heated to 100°C and stirred for 1 hour. The reaction mixture was diluted with water (250 mL × 2) and extracted with dichloromethane (250 mL × 3). The solution was dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give methyl 5-bromo-3-hydroxy-2-methylbenzoate (2.20 g, 8.98 mmol, yield: 54.7%).

[0373] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,J=2.0Hz,1H),7.31(d,J=2.0Hz,1H),7.14(d,J=2.0Hz,1H),3.81(s,3H),2.23(s,3H).

[0374] 2) Synthesis of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate:

[0375]

[0376] To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (2.20 g, 9.0 mmol) and 2-bromo-1,1-dimethoxyethane (1.98 g, 11.7 mmol) in N,N-dimethylformamide (200 mL), potassium carbonate (2.48 g, 17.9 mmol) and sodium iodide (135 mg, 0.9 mmol) were added. The mixture was heated to 100 °C and stirred for 24 hours under nitrogen protection. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3, 254 nm) to give methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (2.40 g, 7.21 mmol, yield: 80.1%).

[0377] 1H NMR (400MHz, DMSO-d6) δ7.47-7.42(m,2H),4.72-4.70(m,1H),4.06(d,J=4.8Hz,2H),3.82(s,3H)

[0378] 3.36 (s, 6H), 2.27 (s, 3H).

[0379] 3) Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylate:

[0380]

[0381] Xylene (48 mL) was added to a flask containing methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (2.40 g, 7.2 mmol) and PPA (2.40 g), and the mixture was heated to 130 °C and stirred for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5, 254 nm) to give methyl 4-bromo-7-methylbenzofuran-6-carboxylate (1.20 g, 4.46 mmol, yield: 62.0%).

[0382] 1H NMR (400MHz, DMSO-d6) δ 8.34 (d, J = 2.0 Hz, 1H), 7.93 (s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 2.68 (s, 3H).

[0383] 4) Preparation of methyl 4-bromo-7-(bromomethyl)benzofuran-6-carboxylate:

[0384]

[0385] At 0 °C, azobisisobutyronitrile (73 mg, 0.45 mmol) and N-bromosuccinimide (873.5 mg, 4.9 mmol) were added to a carbon tetrachloride (12 mL) solution containing methyl 4-bromo-7-methylbenzofuran-6-carboxylate (1.20 g, 4.46 mmol), and the mixture was heated to 110 °C and stirred for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3, 254 nm) to give methyl 4-bromo-7-(bromomethyl)benzofuran-6-carboxylate (1.40 g, 4.00 mmol, yield: 90.2%).

[0386] 1H NMR (400MHz, DMSO-d6) δ8.44(d,J=2.0Hz,1H),8.00(s,1H),7.10(d,J=2.4Hz,1H),5.22(s,2H),3.87(s,3H).

[0387] 5) Synthesis of 3-(4-bromo-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione:

[0388]

[0389] At room temperature, N,N-diisopropylethylamine (2.23 g, 17.25 mmol) was added to a solution of 1,4-dioxane (1 mL) containing methyl 4-bromo-7-(bromomethyl)benzofuran-6-carboxylate (1.20 g, 3.45 mmol) and 3-aminopiperidine-2,6-dione (855 mg, 5.18 mmol) and heated to 100 °C with stirring for 4 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (150 mL) and extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 3-(4-bromo-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidin-2,6-dione (600 mg, 1.65 mmol, yield: 48.0%), LCMS m / z: 395 [M+Na]. +

[0390] 6) Synthesis of compound 3-(4-(hydroxymethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione:

[0391]

[0392] Under a nitrogen atmosphere, Pd(PPh3)4 (335 mg, 0.29 mmol) was added to a solution of 1,4-dioxane (15 mL) containing 3-(4-bromo-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione (530 mg, 1.46 mmol) and (tributyltinyl)methanol (4.69 g, 14.60 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 95 / 5) to give crude product (200 mg). The crude product was purified by thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give 3-(4-(hydroxymethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidin-2,6-dione (50 mg, 0.16 mmol, yield: 11.0%), LCMS m / z: 315 [M+H]. +

[0393] 7) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxohesperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-yl)methyl ester:

[0394]

[0395] At room temperature, 4-dimethylaminopyridine (23 mg, 0.19 mmol) was added to a solution of 1,4-dioxane (2 mL) containing 3-(4-(hydroxymethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidin-2,6-dione (50 mg, 0.16 mmol) and (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (76 mg, 0.24 mmol). The mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 5) to give 2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxohesperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)methyl ester (30.02 mg, 0.06 mmol, yield: 35.2%), LCMS m / z: 577 [M+MeCN].+ .

[0396] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.96(s,1H),8.28(d,J=2.4Hz,1H),7.84- 7.83(m,1H),7.75(s,1H),7.41-7.36(m,1H),7.33(d,J=2.4Hz,1H),7.15-7.12(m ,1H),5.55(s,2H),5.18-5.14(m,1H),4.76(d,J=17.6Hz,1H),4.56(d,J=17.6Hz, 1H),2.99-2.89(m,1H),2.64-2.60(m,1H),2.50-2.43(m,1H),2.07-2.01(m,1H).

[0397] 19 F NMR(377MHz,DMSO-d6)δ-57.21,-125.94.

[0398] Example 6: Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (compound 6):

[0399] 1) Synthesis of 5-fluoro-7-nitro-2,3-dihydrobenzofuran:

[0400]

[0401] 5-Fluoro-2,3-dihydrobenzofuran (9 g, 65.15 mmol) was dissolved in nitric acid (80 mL) and stirred at -10 °C for 0.5 h. The mixture was then quenched dropwise with water (125 mL) at -10 °C and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 5-fluoro-7-nitro-2,3-dihydrobenzofuran (11.9 g, 65.03 mmol, yield: 99.8%).

[0402] 1 H NMR (400MHz, DMSO-d6) δ7.71-7.68(m,1H),7.63-7.61(m,1H),4.81(t,J=8.0Hz,2H),3.32-3.30(m,2H).

[0403] 2) Synthesis of 5-fluoro-2,3-dihydrobenzofuran-7-amine:

[0404]

[0405] To a solution of ethyl acetate (100 mL) containing 11.9 g (65.03 mmol) of 5-fluoro-2,3-dihydrobenzofuran, Pd and C (15.3 g, 10% content) were added, and the mixture was stirred at 25 °C under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent PE: EA = 0%–50%, R...). f =0.5) Purification yielded 5-fluoro-2,3-dihydrobenzofuran-7-amine (7.5 g, 49.02 mmol, yield: 75.4%).

[0406] 1 H NMR (400MHz, DMSO-d6) δ6.24-6.20(m,2H),4.90(s,2H),4.47(t,J=8.0Hz,2H),3.09(t,J=8.0Hz,2H).

[0407] 3) Synthesis of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine:

[0408]

[0409] Under nitrogen protection, NBS (0.27 g, 1.567 mmol) was added to 30 mL of DMF containing 0.3 g (1.959 mmol) of 5-fluoro-2,3-dihydrobenzofuran-7-amine. The mixture was stirred at 0 °C for 1 hour under nitrogen protection. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic residues were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent PE: EA = 0%–50%) to give 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (347 mg, 1.496 mmol, yield: 76.3%).

[0410] 1 H NMR (400MHz, DMSO-d6) δ6.40(d,J=8.0Hz,1H),5.10(s,2H),4.55(t,J=8.0Hz,2H),3.13(t,J=8.0Hz,2H).

[0411] 4) Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine

[0412]

[0413] Under nitrogen protection, a mixture of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (2.5 g, 10.78 mmol) dissolved in 1,4-dioxane (102 mL) and water (17 mL) was added, followed by the addition of 2,6-bisbenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (5.4 g, 12.93 mmol), Pd(dppf)Cl2 (0.78 g, 1.078 mmol), and Na2CO3 (3.43 g, 32.33 mmol). The mixture was heated to 80 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water (130 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried, filtered, and concentrated to dryness. The crude compound was subjected to normal-phase column chromatography (eluent PE: EA = 0%–50%) to give a yellow solid 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol, yield: 84.8%). LCMS m / z: 443 [M+H] +

[0414] 5) Synthesis of 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine

[0415]

[0416] At 0°C, a mixed solution of MeCN (10 mL), HCl (12 M, 2 M), and water (10 mL) containing 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol) was added to a solution of water (2 mL) containing NaNO2 (820 mg, 11.88 mmol). The mixture was stirred at 0°C for 1 hour under nitrogen protection. Then, an aqueous solution of potassium iodide (3.03 g, 18.28 mmol) (5 mL) was added dropwise to the above mixed solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting PE: EA = 0%–30%) to 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (3.4 g, 6.15 mmol, yield: 67.3%), LCMS m / z: 554 [M+H]. + .

[0417] 6) Synthesis of tert-butyl carbamate (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate

[0418]

[0419] To a toluene (28 mL) solution containing 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (500 mg, 0.904 mmol), tert-butyl aziridine-3-ylcarbamate (778 mg, 4.518 mmol), BINAP (56.3 mg, 0.09 mmol), Pd2(dba)3 (82.8 mg, 0.09 mmol), and t-BuONa (174 mg, 1.808 mmol) were added, and the mixture was heated to 120 °C and stirred for 18 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL c×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent PE: EA = 0%–10%) to give tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate (238 mg, 0.398 mmol, yield: 44.0%).

[0420] 1 H NMR (400MHz, DMSO-d6) δ7.59-7.57(m,1H),7.55-7.47(m,3H),7.43-7.40(m,2H),7.38-7.28(m,5H),6.50(d,J=8.0Hz,1H),6.1 4(d,J=12Hz,1H),5.36-5.34(m,4H),4.44-4.28(m,3H),4.09-4.02(m,2H),3.66-3.56(m,2H),3.01-2.75(m,2H),1.39(s,9H).

[0421] 7) Synthesis of tert-butyl carbamate (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate

[0422]

[0423] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate (200 mg, 0.335 mmol) in ethyl acetate (50 mL), Pd / C (356 mg) and Pd(OH)₂ (470.4 mg) were added. The mixture was heated at 40 °C and stirred for 8 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate (133 mg, 0.317 mmol, yield: 94.7%), LCMS m / z: 420 [M+H].

[0424] 8) Preparation of 3-(7-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione:

[0425]

[0426] To a solution of 133 mg (0.317 mmol) of tert-butyl carbamate in dichloromethane (16 mL), 2,2,2-trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give a yellow solid 3,7-(3-aminoazacyclobutane-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (101 mg, 0.317 mmol, yield: 100%). LCMS m / z: 320 [M+H] + .

[0427] 9) Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea:

[0428]

[0429] To a solution of 1,4-dioxane (20 mL) containing 3-(7-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (101 mg, 0.317 mmol), phenyl (4-chloro-2-fluorophenyl)carbamate (84.32 mg, 0.317 mmol) and DMAP (46.4 mg, 0.380 mmol) were added, and the mixture was heated to 90 °C and stirred for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (system: Waters 3767 / Qda; column: Sunfire C18, 19*250mm, 10µm; mobile phase A: H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 46-56%, retention time: 9.6-10.5min of 16min) to give 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (70mg, 0.143mmol, yield: 45%), LCMS: m / z: 491 [M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.41(s,1H),8.40-8.12(m,1H),8.10 -8.08(m,1H),7.42-7.40(m,1H),7.39-7.16(m,1H),6.13(d,J=12Hz,1H),4 .51-4.43(m,3H),4.14-4.11(m,2H),3.88-3.83(m,1H),3.61-3.57(m,2H), 3.10-2.98(m,2H),2.77-2.69(m,1H),2.48-2.47(m,1H),2.09-1.93(m,2H).

[0430] Example 7. Synthesis of (4-chloro-2-fluorophenyl)carbamate-1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl esters (compounds 7A and 7B):

[0431] 1) Synthesis of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-ol

[0432]

[0433] To a solution of 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (400 mg, 0.723 mmol) in tert-butanol (30 mL), azirmonobutane-3-ol (264 mg, 3.614 mmol), K3PO4 (1.074 g, 5.061 mmol), and Brettphos Pd G3 (66 mg, 0.0723 mmol) were added. The mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 2:1, 254 nm) to 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-ol (215 mg, 0.431 mmol, yield: 59.6%), LCMS m / z: 499 [M+H + .

[0434] 2) Synthesis of 3-(5-fluoro-7-(3-hydroxyazacyclobutane-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0435]

[0436] To a solution of ethyl acetate (60 mL) containing 230 mg (0.461 mmol) of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-ol, Pd / C (491 mg) and Pd(OH)₂ (647 mg, 0.461 mmol) were added, and the mixture was stirred at 25 °C for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain…

[0437] The reaction mixture was concentrated to give 3-(5-fluoro-7-(3-hydroxyazacyclobutan-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (103 mg, 0.322 mmol, yield: 69.8%), LCMS m / z: 321 [M+H] + .

[0438] 3) Synthesis of (4-chloro-2-fluorophenyl)carbamate 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester (compounds 7A and 7B)

[0439]

[0440] To a solution of 1,4-dioxane (20 mL) containing 3-(5-fluoro-7-(3-hydroxyazacyclobutan-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (104 mg, 0.325 mmol), phenyl (4-chloro-2-fluorophenyl)carbamate (86.45 mg, 0.325 mmol) and DMAP (48 mg, 0.39 mmol) were added, and the mixture was heated to 90 °C and stirred for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 5:1, 254 nm) to give (4-chloro-2-fluorophenyl)carbamate-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester (80 mg, 0.163 mmol, yield: 50.0%), LCMS m / z: 492 [M+H] + .

[0441] 4) Separation of enantiomers (compounds 7A and 7B):

[0442] 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl(4-chloro-2-fluorophenyl)carbamate (80 mg, 0.179 mmol) was separated by SFC (conditions: SHIMADZU LC-20AP, column: REGIS(S,S)WHELK-O1, 250*25mm 10μm; mobile phase A: EtOH). , Mobile phase B: acetonitrile; A:B = 80:20; Detection wavelength: 254 nm; Flow rate: 50 mL / min; Column temperature: RT; Column pressure: 100 bar; Injection volume: 10.0 mL; Cycling temperature: 9.0 min) Purification yielded two isomers: C101-N309A and C101-N309B.

[0443] Compound 7A: Peak 1 chiral - HPLC: 3.048 min (4.19 mg, 0.008 mmol, yield: 5.22%); LCMS m / z: 492 [M+H] + .

[0444] 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.70(s,1H),7.68-7.64(m,1H),7.48- 7.45(m,1H),7.27-7.25(m,1H),6.17(d,J=12.4Hz,1H),5.21-5.17(m,1H),4. 49(t,J=9.2Hz,2H),4.22-4.19(m,2H),3.88-3.79(m,1H),3.78-3.77(m,2H) ,3.10-2.99(m,2H),2.77-2.67(m,1H),2.33-2.07(m,1H),2.05-1.96(m,1H).

[0445] Compound 7B: Peak 2-chiral - HPLC: 5.211 min (3.08 mg, 0.006 mmol, yield: 3.85%), LCMS: m / z: 492 [M+H] + .

[0446] 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.70(s,1H),7.68-7.64(m,1H),7.48- 7.45(m,1H),7.27-7.25(m,1H),6.17(d,J=12.4Hz,1H),5.21-5.17(m,1H),4. 49(t,J=9.2Hz,2H),4.22-4.19(m,2H),3.88-3.79(m,1H),3.78-3.77(m,2H) ,3.10-2.99(m,2H),2.77-2.67(m,1H),2.33-2.08(m,1H),2.05-1.97(m,1H).

[0447] Example 8: Synthesis of N-(4-chloro-2-fluorophenyl)-2-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)acetamide (compound 8):

[0448] 1) Synthesis of tert-butyl 3-(2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate:

[0449]

[0450] At room temperature, DIEA (258 mg, 2.00 mmol) and HATU (570 mg, 1.50 mmol) were added to a 2 mL solution of DMF containing 2-(1-(tert-butoxycarbonyl)azacyclobutan-3-yl)acetic acid (215 mg, 1.00 mmol) and 4-chloro-2-fluoroaniline (146 mg, 1.00 mmol). The mixture was stirred at room temperature for 1 hour. LCMS showed 37% product. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EA (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to give tert-butyl 3-(2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate (200 mg, 0.58 mmol, yield: 58.3%), LCMS m / z: 343 [M+H] + .

[0451] 2) Synthesis of 2-(azacyclobutan-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide:

[0452]

[0453] At room temperature, TFA (2 mL) was added to a DCM (6 mL) solution containing tert-butyl 3-(2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate (200 mg, 0.58 mmol). The mixture was stirred at room temperature for 1 hour. LCMS showed 76% product. The mixture was diluted with DCM (20 mL) and concentrated under reduced pressure. The residue was purified by rapid reversed-phase column chromatography (column: spherical C18, 20-40 μm, 130 g; mobile phase A: water (0.1% NH3·H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 20% B-80% B for 25 min; detector: 254 nm). The fraction containing the product was collected and concentrated under reduced pressure at 42% B to give 2-(azacyclobutan-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide (100 mg, 0.41 mmol, yield: 70.9%), LCMS m / z: 243 [M+H]. + .

[0454] 3) Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide:

[0455]

[0456] Under a nitrogen atmosphere, Cs₂CO₃ (880 mg, 2.70 mmol) and Xantphos Pd G₃ (1.02 g, 1.08 mmol) were added to a solution of 1,4-dioxane (5 mL) containing 2,6-bis(benzyloxy)-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (300 mg, 0.54 mmol) and 2-(azacyclobutan-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide (131 mg, 0.54 mmol). The mixture was heated to 110 °C and stirred for 16 hours. LC-MS showed 37% product. The mixture was quenched with saturated NH₄Cl (100 mL) and extracted with EA (30 mL × 2). The combined organic phases were dried over saturated brine (50 mL × 2) and anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide (180 mg, 0.27 mmol, yield: 49.9%), LCMS m / z: 668 [M+H] + .

[0457] 4) Synthesis of N-(4-chloro-2-fluorophenyl)-2-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)acetamide:

[0458]

[0459] Under nitrogen atmosphere at room temperature, PtO2 (14 mg) was added to a 20 mL solution of ethyl acetate containing 70 mg (0.105 mmol) of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide. The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. LC-MS showed a product of 23%. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was collected and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters 2767 / Qda, column: XBridge C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 50%–60%; retention time: 9.2–9.9 min, 16 min) of N-(4-chloro-2-fluorophenyl)-2-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)acetamide (6.60 mg, 0.013 mmol, yield: 12.8%), LCMS m / z: 490 [M+H). + .

[0460] 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.86(s,1H),7.90(t,J=8.8Hz,1H),7.47(dd,J=10. 8Hz,2.4Hz,1H),7.26-7.23(m,1H),6.07-6.04(dd,J=12.4Hz,2.4Hz,1H),4.46(t,J=6.8H z,2H),4.00-3.96(m,2H),3.86-3.82(m,1H),3.57-3.54(m,2H),3.04-2.94(m,2H),2.94- 2.90(m,1H),2.76-2.69(m,3H),2.49-2.46(m,1H),2.10-1.96(m,1H),1.94-1.91(m,1H).

[0461] 19 F NMR(377MHz,DMSO-d6)δ-121.36,132.11.

[0462] Example 9: Synthesis of 1-(4-cyano-2-fluorophenyl)-3-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (compound 9):

[0463]

[0464] To a solution of 1,4-dioxane (2.0 mL) containing 3-(7-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (40 mg, 0.12 mmol) and DMAP (18 mg, 0.15 mmol), phenyl (4-cyano-2-fluorophenyl)carbamate (38 mg, 0.15 mmol) was added, and the mixture was heated to 90 °C and stirred for 3 hours. LC-MS showed that the reaction was complete, and the resulting mixture was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters 3767 / oda, column: XBridge C18, 19*250mm, 10µm; mobile phase A: 10mmol / L% NaHCO3 / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 35%–43%; retention time: 6.5–7.4 min, 17 min) to give 1-(4-cyano-2-fluorophenyl)-3-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (14.53 mg, 0.03 mmol, yield: 25.0%), LCMS m / z: 482 [M+H). + .

[0465] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.82(s,1H),8.35(t,J=8.4Hz,1H),7.82(dd,J=11.6,1.6Hz,1 H),7.59(d,J=9.6Hz,1H),7.45(d,J=7.2Hz,1H),6.14(d,J=12.4Hz,1H),4.47(dd,J=17.6,8.8Hz,3H) ,4.13(dd,J=7.6,5.2Hz,2H),3.85(dd,J=12.4,5.2Hz,1H),3.66-3.58(m,2H),3.05(qd,J=15.6,7.6H z,2H),2.73(ddd,J=22.4,14.0,7.6Hz,1H),2.48-2.42(m,1H),2.05(ddd,J=30.4,17.6,11.6Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-126.264,-128.492.

[0466] Example 10: Synthesis of 1-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)urea (compound 10):

[0467]

[0468] To a solution of 1,4-dioxane (2 mL) containing 3-(7-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (40 mg, 0.12 mmol) and DMAP (18 mg, 0.15 mmol), phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (47 mg, 0.15 mmol) was added, and the mixture was heated to 90 °C and stirred for 3 hours. LC-MS showed that the reaction was complete, and the reaction mixture was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) under the following conditions (Waters 3767 / oda, column: XBridge C18, 19*250mm, 10µm; mobile phase A: 10mmol / L% NaHCO3 / H2O, B: ACN; flow rate: 20mL / min; gradient: 35%–43%; retention time: 6.8–7.4min, 17min) to obtain 1-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)urea (18.86mg, 0.035mmol, yield: 28%), LCMS m / z: 541 [M+H). + .

[0469] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.62(d,J=2.4Hz,1H),8.20(d,J=4.0Hz,1H), 7.51-7.18(m,2H),7.06-6.67(m,1H),6.14(d,J=12.4Hz,1H),4.57-4.36(m,3H),4.1 3(t,J=8.4Hz,2H),3.86(dd,J=12.4,5.6Hz,1H),3.62(dd,J=27.2,20.4Hz,2H),3.1 9-2.94(m,2H),2.73(ddd,J=22.8,14.4,8.0Hz,1H),2.47(s,1H),2.18-1.96(m,2H). 19 FNMR(377MHz,DMSO-d6)δ-57.102,-126.256,-131.483.

[0470] Example 11. Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid(R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester and its enantiomers (MRANK-023-001-1 and MRANK-023-001-2):

[0471] 1) Synthesis of 1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0472]

[0473] To a solution of 1,4-dioxane (5 mL) containing 100 mg (0.31 mmol) of 3-(5-fluoro-7-(3-hydroxyazacyclobutan-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (0.31 mmol), phenyl 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (98.4 mg, 0.31 mmol) and DMAP (45.7 mg, 0.37 mmol) were added. The mixture was heated to 90 °C and stirred for 8 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The residue was subjected to silica gel column chromatography (PE:EA = 5:1) to give (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester (100 mg, 0.18 mmol, yield: 58.1%), LCMS m / z: 542 [M+H] + .

[0474] 2) Preparation of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester and its enantiomers

[0475]

[0476] Dissolved (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid 1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester (100 mg, 0.18 mmol) was subjected to supercritical fluid chromatography (chromatographic conditions: Waters SFC 150, column: IG, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: isopropanol (+0.1% 7.0mol / l MEOH ammonia solution); A:B = 60:40; Wavelength: 214nm; Flow rate: 80mL / min; Column temperature: RT; Back pressure: 100bar; Injection solution: 5.0mL; Cycle time: 7.0min) Purification yielded two isomers: MRANK-023-001-1 and MRANK-023-001-2.

[0477] MRANK-023-001-1: Peak 1 Chiral-HPLC: 1.803 min, (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid(R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester or enantiomer (17.9 mg, 0.033 mmol, yield: 17.9%), LCMS m / z: 542 [M+H] + .

[0478] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.96-9.65(m,1H),7.80-7.78(m,1H),7.41-7.36(m,1H),7.16-7.13(m,1H),6.19-6.16(m,1H),5.24-5.19 (m,1H),4.49(t,J=8Hz,2H),4.22(t,J=8Hz,2H),3.88-3.79(m,3H),3.3 2-3.05(m,2H),2.78-2.73(m,1H),2.49-2.47(m,1H),2.12-1.92(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-57.22,-125.73,-126.12

[0479] MRANK-023-001-2: Peak 2 Chiral HPLC: 2.556 min, (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid(R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester or enantiomer (13.4 mg, 0.025 mmol, yield: 13.4%), LCMS m / z: 542 [M+H] + .

[0480] 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.96-9.65(m,1H),7.80-7.78(m,1H),7.41-7.36(m,1H),7.16-7.13(m,1H),6.19-6.16(m,1H),5.24-5.19 (m,1H),4.49(t,J=8Hz,2H),4.22(t,J=8Hz,2H),3.88-3.79(m,3H),3.3 2-3.05(m,2H),2.78-2.73(m,1H),2.49-2.47(m,1H),2.12-1.92(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-57.22,-125.73,-126.12.

[0481] Example 12, Synthesis of (R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenylacetamide and its enantiomers (MRANK-023-002-1 and MRANK-023-002-2):

[0482] 1) Synthesis of tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate

[0483]

[0484] At room temperature, DIEA (1.20 g, 9.30 mmol) and HATU (2.65 g, 6.98 mmol) were added to a 10 mL solution of DMF containing 1.00 g (1.00 g, 4.65 mmol) and 907 mg (9.65 mmol) of 2-(1-(tert-butoxycarbonyl)azacyclobutan-3-yl)acetic acid (1.00 g, 4.65 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with EA (50 mL × 2). The combined organic phases were dried over saturated brine (50 mL × 2) and anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)amino)-2-oxoethyl)azacyclobutane-1-carboxylate (1.80 g, 4.59 mmol, yield: 98.9%), LCMS m / z: 337 [M+H-56]. + .

[0485] 2) Synthesis of (2-(azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0486]

[0487] At room temperature, TFA (9 mL) was added to a 30 mL solution of DCM containing 900 mg (2.30 mmol) of tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)amino)-2-oxoethyl)azacyclobutane-1-carboxylic acid. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 20 mL of DCM and concentrated under reduced pressure to obtain a crude yellow oily compound (720 mg). The residue was purified by reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH3·H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5% B-100% B for 25 min; detector: 254 nm). The fraction containing the product was collected and concentrated under reduced pressure at 42% B to give (2-(azacyclobutan-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (600 mg, 2.05 mmol, yield: 89.4%), LCMS m / z: 293 [M+H]. +

[0488] 3) Synthesis of 2-(1-(4-bromo-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0489]

[0490] Under a nitrogen atmosphere, Cs₂CO₃ (2.45 g, 7.52 mmol), Pd₂(dba)₃ (174 mg, 0.19 mmol), and BINAP (118 mg, 0.19 mmol) were added to a 1,4-dioxane (10 mL) solution containing (2-(azacyclobutan-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (550 mg, 1.88 mmol) and 4-bromo-5-fluoro-7-iodobenzofuran (641 mg, 1.88 mmol). The mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with 100 mL of water and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 2-(1-(4-bromo-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (500 mg, 0.99 mmol, yield: 52.5%), LCMS m / z: 505 [M+H]. + .

[0491] 4) Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0492]

[0493] To a solution containing 1,4-dioxane (10 mL) and H₂O (2.5 mL) of 2-(1-(4-bromo-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (500 mg, 0.99 mmol) and (2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (621 mg, 1.49 mmol), Pd(dppf)Cl₂ (146 mg, 0.20 mmol) and Na₂CO₃ (315 mg, 2.97 mmol) were added, and the mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was quenched with saturated NH₄Cl (100 mL) and extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (500 mg, 0.70 mmol, yield: 70.5%), LCMS m / z: 716 [M+H] + .

[0494] 5) Synthesis of 2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0495]

[0496] Under nitrogen atmosphere, Pd / C (370 mg) and Pd(OH)₂ (370 mg) were added to a solution of EA (370 mg, 0.52 mmol) containing 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (370 mg, 0.52 mmol), and the mixture was stirred for 16 hours under H₂ atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EA (50 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give 2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (90 mg, 0.17 mmol, yield: 32.3%), LCMS m / z: 540 [M+H] + .

[0497] 6) Preparation of (R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenylacetamide and its enantiomers (MRANK-023-002-1 and MRANK-023-002-2):

[0498]

[0499] Compound 2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (90 mg, 0.17 mmol) was analyzed by SFC (chromatographic titration: Waters SFC 150, column: ... IG, 1250*30mm 10um; and A: supercritical CO2, mobile phase B: MeOH (+0.1% 7.0mol / L methanolamine solution); A:B = 50:50; wavelength: 214nm; flow rate: 140mL / min; column temperature: RT; back pressure: 100bar; injection solution: 2.0mL; circulation time: 7.8min; sample solution preparation: the sample was dissolved in about 20mL of methanol to prepare two isomers: MRANK-023-002-1 and MRANK-023-002-2.

[0500] MRANK-023-002-1: Peak 1, Chiral HPLC: 2.834 min; (R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenylacetamide or enantiomer (32.84 mg, 0.06 mmol, yield: 36.4%), LCMS m / z: 540 [M+H] + .

[0501] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),10.04(s,1H),8.09(d,J=4.0Hz,1H),7.40(t,J=9.2Hz,1H),7.18-7.13(m,1H),6.06(d,J=12.4H z,1H),4.46(t,J=9.2Hz,2H),4.00-3.97(m,2H),3.86-3.82(m,1H),3.56(t,J=6.0Hz,2H),3.10-2.91(m,3H),2.81-2.69(m,3H),2.48 -2.46(m,1H),2.11 -2.00(m,1H),1.97-1.91(m,1H).

[0502] 19 F NMR(377MHz,DMSO-d6)δ-57.20,-126.23.

[0503] MRANK-023-002-2: Peak 2 Chiral HPLC: 4.215 min; (S)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenylacetamide or enantiomer (27.20 mg, 0.05 mmol, yield: 30.2%), LCMS m / z: 540 [M+H] + .

[0504] 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),10.04(s,1H),8.09(d,J=4.0Hz,1H),7.40(t,J=9.2Hz,1H),7.18-7.13(m,1H),6.06(d,J=12.4H z,1H),4.46(t,J=9.2Hz,2H),4.00-3.97(m,2H),3.86-3.82(m,1H),3.56(t,J=6.0Hz,2H),3.10-2.91(m,3H),2.81-2.69(m,3H),2.48 -2.46(m,1H),2.11 -2.00(m,1H),1.97-1.91(m,1H).

[0505] 19 F NMR(377MHz,DMSO-d6)δ-57.20,-126.23.

[0506] Example 13. Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester and its enantiomers (MRANK-023-003SR-1 and MRANK-023-003SR-2):

[0507] 1) Synthesis of (2S,3R)-2-methylazacyclobutane-3-ol

[0508]

[0509] Dissolve tert-butyl (2S,3R)-3-hydroxy-2-methylazacyclobutane-1-carboxylate (1.00 g, 5.35 mmol) in hydrochloric acid / ethyl acetate (10 mL, 4 M) and stir at room temperature for 1 hour. Dilute the mixture with EA (20 mL) and concentrate under reduced pressure to obtain (2S,3R)-2-methylazacyclobutane-3-ol (720 mg, crude product).

[0510] 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),4.14-4.09(m,1H),3.88-3.83(m,1H),3.58-3.56(m,2H),1.45-1.37(m,3H).

[0511] 2) Synthesis of (2S,3R)-1-(4-bromo-5-fluorobenzofuran-7-yl)-2-methylazacyclobutane-3-ol

[0512]

[0513] At room temperature, Cs₂CO₃ (7.25 g, 22.24 mmol), Pd₂(dba)₃ (513 mg, 0.56 mmol), and BINAP (349 mg, 0.56 mmol) were added to a solution of 1,4-dioxane (20 mL) containing (2S,3R)-2-methylazacyclobutane-3-ol (483 mg, 5.56 mmol) and 4-bromo-5-fluoro-7-iodobenzofuran (1.90 g, 5.56 mmol). The mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with water (100 mL), extracted with EA (50 mL), washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to (2S,3R)-1-(4-bromo-5-fluorobenzofuran-7-yl)-2-methylazacyclobutane-3-ol (500 mg, 1.67 mmol, yield: 29.9%), LCMS m / z: 300 [M+H] +

[0514] 3) Synthesis of (2S,3R)-1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)-2-methylazacyclobutane-3-ol

[0515]

[0516] Under a nitrogen atmosphere, at room temperature, a solution of 1,4-dioxane (10 mL) and H₂O (2.5 mL) containing (2S,3R)-1-(4-bromo-5-fluorobenzofuran-7-yl)-2-methylazacyclobutane-3-ol (500 mg, 1.67 mmol) and (2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (1.05 g, 2.51 mmol) was added to Pd(dppf)Cl₂ (241 mg, 0.33 mmol) and Na₂CO₃ (531 mg, 5.01 mmol), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was quenched with saturated NH₄Cl (100 mL) and extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to (2S,3R)-1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)-2-methylazacyclobutane-3-ol (600 mg, 1.17 mmol, yield: 70.4%), LCMS m / z: 511 [M+H] + .

[0517] 4) Synthesis of 3-(5-fluoro-7-((2S,3R)-3-hydroxy-2-methylazacyclobutane-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0518]

[0519] Under a nitrogen atmosphere, Pd / C (580 mg) and Pd(OH)₂ (580 mg) were added to a solution of (2S,3R)-1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)-2-methylazacyclobutane-3-ol (580 mg, 1.14 mmol). The mixture was stirred at room temperature under a H₂ atmosphere for 4 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EA (100 mL). The filtrate was collected and concentrated under reduced pressure to obtain 3-(5-fluoro-7-((2S,3R)-3-hydroxy-2-methylazacyclobutane-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (450 mg, crude product), LCMS m / z: 335 [M+H]. + .

[0520] 5) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester

[0521]

[0522] To a solution of 1,4-dioxane (5 mL) containing 100 mg (0.30 mmol) of 3-(5-fluoro-7-((2S,3R)-3-hydroxy-2-methylazacyclobutan-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione, 95 mg (0.30 mmol) of phenyl carbamate (44, 0.36 mmol) and DMAP were added, and the mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester (60 mg, 0.11 mmol, yield: 36.1%), LCMS m / z: 556 [M+H]+ .

[0523] 6) Preparation of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester and its enantiomers (MRANK-023-003SR-1 and MRANK-023-003SR-2)

[0524]

[0525] The compound (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester (60 mg, 0.11 mmol) was analyzed by SFC (under the following conditions: Waters SFC 150, column: REGIS(S,S)WHELK-O-1, 1250*30 mm). 10µm; A: supercritical CO2, mobile phase B: MeOH (+0.1% 7.0mol / L methanol ammonia solution); A:B = 60:40; wavelength: 214nm; flow rate: 120mL / min; column temperature: RT; back pressure: 100bar; injection solution: 7.0mL; circulation time: 13.44min; sample solution preparation: (dissolve the sample in approximately 35mL of methanol) to prepare two isomers: MRANK-023-003SR-1 and MRANK-023-003SR-2.

[0526] MRANK-023-003SR-1: Peak 1: Chiral HPLC: 1.062 min; (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester or enantiomer (25.39 mg, 0.05 mmol, yield: 42.3%), LCMS m / z: 555.9 [M+H] + .

[0527] 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.91(s,1H),7.78(d,J=3.2Hz,1H),7.38( t,J=10.0Hz,1H),7.17-7.13(m,1H),6.23(d,J=12.4Hz,1H),4.85-4.81(m,1H), 4.50(t,J=8.8Hz,2H),4.33-4.29(m,1H),4.11-4.05(m,1H),3.88-3.84(m,1H), 3.56-3.52(m,1H),3.14-2.97(m,2H),2.78-2.70(m,1H),2.49-2.47(m,1H),2.13 -2.02(m,1H),1.99-1.92(m,1H),1.43(d,J=5.6Hz,3H).

[0528] 19 F NMR(377MHz,DMSO-d6)δ-57.23,-125.79.

[0529] MRANK-023-003SR-2: Peak 2: Chiral HPL: 2.967 min; (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (2S,3R)-1-(4-(((S)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazacyclobutane-3-yl ester or enantiomer (27.85 mg, 0.05 mmol, 46.4% yield), LCMS m / z: 555.9 [M+H] + .

[0530] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.91(s,1H),7.78(d,J=3.2Hz,1H),7.38( t,J=10.0Hz,1H),7.17-7.13(m,1H),6.23(d,J=12.4Hz,1H),4.85-4.81(m,1H), 4.50(t,J=8.8Hz,2H),4.33-4.29(m,1H),4.11-4.05(m,1H),3.88-3.84(m,1H), 3.56-3.52(m,1H),3.14-2.97(m,2H),2.78-2.70(m,1H),2.49-2.47(m,1H),2.13 -2.02(m,1H),1.99-1.92(m,1H),1.43(d,J=5.6Hz,3H).

[0531] 19 F NMR(377MHz,DMSO-d6)δ-57.23,-125.79.

[0532] Example 14. Synthesis of N-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)4-chloro-2-fluoroaniline-1-sulfonamide and its isomers (MRANK-103-003-1 and MRANK-103.003-2):

[0533] 1) Synthesis of 2-oxooxazolidine-3-sulfonyl chloride

[0534]

[0535] At 0°C, chlorosulfonic acid isocyanate (6.0 g, 42.25 mmol) was added to a 30 mL solution of DCM containing 5.3 g (42.25 mmol) of 2-bromoethane-1-ol, and the mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was used directly in the next reaction step.

[0536] 2) Synthesis of N-(4-chloro-2-fluorophenyl)-2-oxoxazolidine-3-sulfonamide

[0537]

[0538] At 0 °C, TEA (2.76 g, 27.4 mmol) and 2-oxooxazolidine-3-sulfonyl chloride (7.6 g, 41.1 mmol) were added to a DCM (40 mL) solution containing 4-chloro-2-fluoroaniline (2 g, 13.7 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (PE / EA = 3:1) to obtain the crude product. The crude product was purified by reverse-phase rapid-phase column chromatography (column: spherical C18, 20-40 μm, 330 g; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeCN; flow rate: 100 mL / min; gradient: 30% B-32% B over 25 min; detector: 254 nm) to N-(4-chloro-2-fluorophenyl)-2-oxooxazolidine-3-sulfonamide (300 mg, 1.01 mmol, yield: 7.42%), LCMS m / z: 295 [M+H). + .

[0539] 3) Synthesis of tert-butyl carbamate (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate

[0540]

[0541] To a solution of EA (100 mL) containing (1 g, 1677 mmol) bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azacyclobutane-3-yl)carbamate, Pd / C (300 mg) and Pd(OH)₂ (300 mg) were added. The mixture was concentrated under reduced pressure to obtain (650 mg, crude) tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate, LCMS m / z: 420 [M+H] + .

[0542] 4) Synthesis of 3-(7-(3-aminoazacyclobutane-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0543]

[0544] Add 4 mL of TFA to a 20 mL solution of DCM containing 650 mg (1.55 mmol) of (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate tert-butyl ester (DCM), and stir at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by reversed-phase column chromatography (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: acetonitrile; flow rate: 70 mL / min; gradient: 10% B-11% B; retention time: 6.5 min of 25 min; detector: 254 nm) to give 3-(7-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (460 mg, 1.44 mmol, yield: 93.03%), LCMS m / z: 320 [M+H). + .

[0545] 5) Synthesis of N-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)4-chloro-2-fluoroaniline-1-sulfonamide

[0546]

[0547] At room temperature, N-(4-chloro-2-fluorophenyl)-2-oxoxazolidine-3-sulfonamide (345 mg, 1.17 mmol) and DMAP (380 mg, 3.12 mmol) were added to a 5 mL solution of 1,4-dioxane containing 250 mg (0.78 mmol) of 3-(7-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (350 mg, 0.78 mmol), and the mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA = 0%–20%) to give compound MRANK-103-003 (50 mg, 0.09 mmol, yield: 12.16%), LCMS m / z: 527 [M+H]. + .

[0548] 6) Preparation of N-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)4-chloro-2-fluoroaniline-1-sulfonamide and its isomers (MRANK-103-003-1 and MRANK-103.003-2):

[0549]

[0550] Compound MRANK-103-003 (50 mg, 0.09 mmol) was purified by SFC (conditions: system: Waters SFC150; column name: AS column dimensions: 250*30mm x 10μm; mobile phase A: supercritical CO2; mobile phase B: MeOH (MeOH + 0.1% 7.0mol / L ammonia), A:B = 55:45; wavelength: 214nm; flow rate: 140mL / min; column temperature: RT; column pressure: 100bar; injection volume: 6.5mL; cycle time: 8.5min. Two isomers were prepared: MRANK-103-003-1 and MRANK-103.003-2.

[0551] MRANK-103-003-1: Peak 1: Chiral HPLC: 3.491 min; MRANK-103-003-1 (8.63 mg, 0.0163 mmol, yield: 17.3%), LCMS m / z: 527 [M+H] + .

[0552] 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.70(s,1H),8.16(s,1H),7.69-7.32(m,2 H),7.31-7.25(m,1H),6.06(d,J=12.0Hz,1H),4.45(t,J=9.2Hz,2H),4.21-4.12 (m,1H),4.05(t,J=8.0Hz,2H),3.84(dd,J=12.8,5.6Hz,1H),3.52(t,J=6.8Hz,2 H),3.14-2.92(m,2H),2.81-2.66(m,1H),2.47-2.44(m,1H),2.09-1.88(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-121.21,-126.18.

[0553] MRANK-103-003-2: Peak 2: Chiral HPLC: 4.549 min; MRANK-103-003-2 (8.80 mg, 0.0167 mmol, yield: 17.6%), LCMS m / z: 527 [M+H] + .

[0554] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.70(s,1H),8.16(s,1H),7.69-7.32(m,2 H),7.31-7.25(m,1H),6.06(d,J=12.0Hz,1H),4.45(t,J=9.2Hz,2H),4.21-4.12 (m,1H),4.05(t,J=8.0Hz,2H),3.84(dd,J=12.8,5.6Hz,1H),3.52(t,J=6.8Hz,2 H),3.14-2.92(m,2H),2.81-2.66(m,1H),2.47-2.44(m,1H),2.09-1.88(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-121.21,-126.18.

[0555] Example 15. Synthesis of (R)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea or its S-enantiomers (MRANK-103-004-1 and MRANK-103-004-2):

[0556] 1) Synthesis of 1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea

[0557]

[0558] To a solution of 1,4-dioxane (5 mL) containing 3-(7-(3-(3-aminoazacyclobutan-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (80 mg, 0.25 mmol), phenyl 5-chloro-2-fluorophenyl)carbamate (80 mg, 0.3 mmol) and DMAP (40 mg, 0.3 mmol) were added. The mixture was rapidly cooled with water (50 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (Waters 3767 / QDA, column: XBridge C18, 19*250 mm, 10 μm; A: 10 mmol / L). NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 42%–52%; retention time: 7.7–8.6 min from 17 min) purification yielded 1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (50 mg, 0.10 mmol, yield: 40.0%), LCMS m / z: 491 [M+H). + .

[0559] 2) Synthesis of (R)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea or its S-enantiomer

[0560]

[0561] The compound 1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (50 mg, 0.101 mmol) was subjected to supercritical fluid chromatography: (Conditions: System: SHIMADZU SHIMADDU) LC-20AP; Column name: REGIS(S,S)WHELK-O1; Column size: 250*25mm, 10μm; Mobile phase A: EtOH (+0.1% 7.0mol / L ammonia in MeOH); Mobile phase B: ACN; A:B = 70:30; Detection wavelength: 214nm; Flow rate: 40mL / min; Column temperature: RT; Back pressure: 100bar; Injection: 4.0mL; Cycle time: 5min) Two isomers were obtained after purification: MRANK-103-004-1 and MRANK-103-004-2.

[0562] MRANK-103-004-1: Peak 1, Chiral HPLC: 3.062 min; (R)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea or enantiomer (0.95 mg, 0.0019 mmol, yield: 1.91%), LCMS m / z: 491 [M+H] + .

[0563] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.52(d,J=2.4,1H),8.21(dd,J=7.2,2 .8Hz,1H),7.37-7.20(m,2H),7.03-6.96(m,1H),6.13(d,J=12.4Hz,1H),4.55 -4.41(m,3H),4.13(t,J=7.2Hz,2H),3.91-3.79(m,1H),3.59(t,J=6.8Hz,2H) ,3.15-2.94(m,2H),2.83-2.64(m,1H),2.47-2.40(m,1H),2.13-1.89(m,2H). 19 F NMR (377MHz, DMSO-d6) δ-126.21, δ-132.21.

[0564] MRANK-103-004-2: Peak 2, Chiral HPLC: 4.868 min; (S)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxadiazin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea or enantiomer (1.30 mg, 0.0026 mmol, yield: 2.62%), LCMS m / z: 491 [M+H] + .

[0565] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.52(d,J=2.4,1H),8.21(dd,J=7.2,2 .8Hz,1H),7.37-7.20(m,2H),7.03-6.96(m,1H),6.13(d,J=12.4Hz,1H),4.55 -4.41(m,3H),4.13(t,J=7.2Hz,2H),3.91-3.79(m,1H),3.59(t,J=6.8Hz,2H) ,3.15-2.94(m,2H),2.83-2.64(m,1H),2.47-2.40(m,1H),2.13-1.89(m,2H). 19 F NMR (377MHz, DMSO-d6) δ-126.21, δ-132.21.

[0566] Example 16. Synthesis of (5-chloro-2-fluorophenyl)carbamic acid (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester and its enantiomers (MRANK-103-005-1 and MRANK-103-005-2):

[0567] 1) Synthesis of (5-chloro-2-fluorophenyl)carbamate 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester

[0568]

[0569] To a solution of 1,4-dioxane (5.0 mL) containing 100 mg (0.31 mmol) of 3-(5-fluoro-7-(3-hydroxyazacyclobutan-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (5.0 mL), phenyl 5-chloro-2-fluorophenyl)carbamate (122 mg, 0.46 mmol) and DMAP (60 mg, 0.46 mmol) were added at room temperature, and the mixture was heated to 90 °C and stirred for 16 hours. LC-MS showed a detection of 12.8% of the target product. The reaction mixture was then concentrated under reduced pressure. The residue was purified by pre-HPLC (Waters 3767 / Oda, column: XBridge C18, 19*250mm, 10µm; mobile phase A: 30mmol / L% TFA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 36%–42%; retention time: 6.8–7.4min, 17min) to obtain (5-chloro-2-fluorophenyl)carbamate 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester).

[0570] (75 mg, 0.15 mmol, yield: 48.8%), LCMS m / z: 492 [M+H] + .

[0571] 2) Synthesis of (5-chloro-2-fluorophenyl)carbamic acid (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester and its enantiomers (MRANK-103-005-1 and MRANK-103-005-2)

[0572]

[0573] The compound (5-chloro-2-fluorophenyl)carbamic acid 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester (75 mg, 0.15 mmol) was purified by SFC (conditions: system: SHIMADZU LC-20AP; column name: Column dimensions: 250*25mm 10μm; Mobile phase A: acetonitrile; Mobile phase B: EtOH, A:B = 20:80; Wavelength: 254nm; Flow rate: 40mL / min; Column temperature: room temperature; Back pressure: 100bar; Injection volume: 4.0mL; Cycle time: 4 minutes) Two isomers were obtained: MRANK-103-005-1 and MRANK-103-005-2.

[0574] MRANK-103-005-1: Peak 1: Chiral HPLC: 2.997 min; Compound (5-chloro-2-fluorophenyl)carbamic acid(R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester or enantiomer (8.45 mg, 0.017 mmol, yield: 11.27%), LCMS m / z: 492 [M+H] + .

[0575] 1 H NMR(400MHz, DMSO-d6)δδ10.83(s,1H),9.84(s,1H),7.78(d,J=4.8Hz,1H),7.30(d d,J=10.0,8.8Hz,1H),7.23-7.12(m,1H),6.17(d,J=12.4Hz,1H),5.29-5.12(m,1H ),4.49(t,J=9.2Hz,2H),4.21(t,J=6.8Hz,2H),3.93-3.73(m,3H),3.16-3.01(m,2 H),2.82-2.64(m,1H),2.47-2.44(m,1H),2.07(d,J=7.2Hz,1H),2.01-1.95(m,1H).

[0576] 19 F NMR(377MHz,DMSO-d6)δ-126.082,-126.436.

[0577] MRANK-103-005-2: Peak 2: Chiral HPLC: 3.210 min: (5-chloro-2-fluorophenyl)carbamic acid (S)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl ester or enantiomer (7.63 mg, 0.016 mmol, yield: 10.17%), LCMS m / z: 492 [M+H] + .

[0578] 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.84(s,1H),7.78(d,J=4.8Hz,1H),7.30(dd ,J=10.0,8.8Hz,1H),7.23-7.12(m,1H),6.17(d,J=12.4Hz,1H),5.29-5.12(m,1H) ,4.49(t,J=9.2Hz,2H),4.21(t,J=6.8Hz,2H),3.93-3.73(m,3H),3.16-3.01(m,2H ),2.82-2.64(m,1H),2.47-2.44(m,1H),2.07(d,J=7.2Hz,1H),2.01-1.95(m,1H).

[0579] 19 F NMR(377MHz,DMSO-d6)δ-126.072,-126.401.

[0580] Example 17: Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydro-2H-furano[2,3-e]isoindol-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate:

[0581] 1) Synthesis of methyl 2,3-dihydrobenzofuran-6-carboxylate

[0582]

[0583] Palladium on carbon (5.90 g) was added to a methanol (100 mL) solution containing methyl benzofuran-6-carboxylate (10.00 g, 56.82 mmol). The mixture was stirred at room temperature for 16 hours under hydrogen protection. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give methyl 2,3-dihydrobenzofuran-6-carboxylate (9.10 g, 51.12 mmol, yield: 90.0%). LCMS: m / z: 179 [M+H] + .

[0584] 2) Synthesis of methyl 7-nitro-2,3-dihydrobenzofuran-6-carboxylate

[0585]

[0586] At 0 °C, fuming nitric acid (3.45 mL) and acetic anhydride (34.5 mL) solutions were slowly added dropwise to a solution of methyl 2,3-dihydrobenzofuran-6-carboxylate (6.90 g, 38.76 mmol) in dichloromethane (69 mL), under a nitrogen atmosphere and stirred at 0 °C for 0.5 h. The mixture was slowly poured into ice water and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 7-nitro-2,3-dihydrobenzofuran-6-carboxylate (4.80 g, 21.52 mmol, yield: 55.5%).

[0587] 1 H NMR (400MHz, DMSO-d6) δ7.58(d,J=7.6Hz,1H),7.38(d,J=7.6Hz,1H),4.81(t,J=8.8Hz,2H),3.81(s,3H),3.40-3.33(m,2H).

[0588] 3) Synthesis of methyl 7-amino-2,3-dihydrobenzofuran-6-carboxylate

[0589]

[0590] Palladium on carbon (3.73 g) was added to a methanol (100 mL) solution containing methyl 7-nitro-2,3-dihydrobenzofuran-6-carboxylate (6.33 g, 28.38 mmol). The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give methyl 7-amino-2,3-dihydrobenzofuran-6-carboxylate (4.87 g, 25.23 mmol, yield: 88.8%), LCMS m / z: 194 [M+H]. + .

[0591] 4) Synthesis of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-6-carboxylate

[0592]

[0593] At 0 °C, N-bromosuccinimide (6.74 g, 37.85 mmol) was added to a carbon tetrachloride (100 mL) solution containing methyl 7-amino-2,3-dihydrobenzofuran-6-carboxylate (4.87 g, 25.23 mmol), and the mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-6-carboxylate (3.22 g, 11.84 mmol, yield: 46.9%). LCMS m / z: 272 [M+H] + .

[0594] 5) Synthesis of methyl 4-bromo-7-iodo-2,3-dihydrobenzofuran-6-carboxylate

[0595]

[0596] At 0°C, a solution of sodium nitrite (355 mg, 5.15 mmol) in water was added to a solution of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-6-carboxylate (1.00 g, 3.68 mmol) in hydrochloric acid (6 mL) and water (30 mL). The mixture was stirred at 0°C for 1 hour. Then, an aqueous solution of potassium iodide (3.05 g, 18.40 mmol) (12 mL) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to methyl 4-bromo-7-iodo-2,3-dihydrobenzofuran-6-carboxylate (594 mg, 1.55 mmol, yield: 42.1%).

[0597] 1 H NMR (400MHz, DMSO-d6) δ7.36 (s, 1H), 4.71 (t, J = 8.4Hz, 2H), 3.83 (s, 3H), 3.65 (t, J = 8.8Hz, 2H).

[0598] 6) Synthesis of methyl 4-bromo-7-vinyl-2,3-dihydrobenzofuran-6-carboxylate

[0599]

[0600] At room temperature, to a solution of methyl 4-bromo-7-iodo-2,3-dihydrobenzofuran-6-carboxylate (790 mg, 2.07 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoboropentane (638 mg, 4.14 mmol), potassium carbonate (857 mg, 4.62 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (171 mg, 0.15 mmol) were added. The mixture was sealed in a tube and heated under nitrogen at 70 °C with stirring for 16 hours. The mixture was then diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to methyl 4-bromo-7-vinyl-2,3-dihydrobenzofuran-6-carboxylate (580 mg, 2.05 mmol, yield: 99%), LCMS m / z: 283 [M+H] + .

[0601] 7) Synthesis of methyl 4-bromo-7-formyl-2,3-dihydrobenzofuran-6-carboxylate

[0602]

[0603] At room temperature, sodium periodate (2.21 g, 10.25 mmol) and potassium osmium tetroxide dihydrate (33 mg, 0.10 mmol) were added to a tetrahydrofuran (10 mL) / water (10 mL) solution containing methyl 4-bromo-7-vinyl-2,3-dihydrobenzofuran-6-carboxylate (580 mg, 2.05 mmol) and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give methyl 4-bromo-7-formyl-2,3-dihydrobenzofuran-6-carboxylate (150 mg, 0.53 mmol, yield: 25.68%), LCMS m / z: 285 [M+H]. + .

[0604] 8) Synthesis of 3-(4-bromo-6-oxo-2,3,6,8-tetrahydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0605]

[0606] At room temperature, triethylamine (600 μL), methyl 4-bromo-7-formyl-2,3-dihydrobenzofuran-6-carboxylate (130 mg, 0.46 mmol), sodium borohydride acetate (195 mg, 0.92 mmol), and glacial acetic acid (1.0 mL) were added to a solution of 3-amino-2,6-piperidinidone hydrochloride (228 mg, 1.38 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 65 mL / min; gradient: 5% B-50% B over 12 min; detector: 254 nm). When the content of mobile phase B reached 45%, the fraction containing the product was collected, and the compound 3-(4-bromo-6-oxo-2,3,6,8-tetrahydro-7H-furano[2,3-e]isoindol-7-yl)piperidin-2,6-dione (70 mg, 0.19 mmol, yield: 42.16%) was concentrated under reduced pressure. LCMS m / z: 365.0 [M+H] + .

[0607] 9) Synthesis of 3-(4-(hydroxymethyl)-6-oxo-2,3,6,8-tetrahydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0608]

[0609] At room temperature, a solution of 1,4-dioxane (5 mL) containing 70 mg (0.19 mmol) of 3-(4-bromo-6-oxo-2,3,6,8-tetrahydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione was added to (1.22 g, 3.80 mmol) methanol and 102 mg (0.10 mmol) tetraphenylphosphine palladium (102 mg, 0.10 mmol). The mixture was heated to 100°C and stirred for 16 hours under nitrogen protection. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 3-(4-(hydroxymethyl)-6-oxo-2,3,6,8-tetrahydro-7H-furano[2,3-e]isoindol-7-yl)piperidin-2,6-dione (50 mg, 0.16 mmol, yield: 82.5%), LCMS m / z: 317 [M+H] +

[0610] 10) Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydro-2H-furano[2,3-e]isoindol-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0611]

[0612] At room temperature, to a solution of 1,4-dioxane (5 mL) containing 3-(4-(hydroxymethyl)-6-oxo-2,3,6,8-tetrahydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione (50 mg, 0.16 mmol), phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (60 mg, 0.192 mmol) and 4-dimethylaminopyridine (23 mg, 0.192 mmol) were added, and the mixture was heated to 90 °C and stirred for 3 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-60% B over 12 min; detector: 254 nm). When the content of mobile phase B reached 50%, the fraction containing the product was collected and concentrated under reduced pressure to give compound (7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydro-2H-furano[2,3-e]isoindol-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (34.03 mg, 0.06 mmol, yield: 40%). LCMS m / z: 538 [M+H] + .

[0613] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.95(s,1H),7.85-7.84(m,1H),7.4 1-7.36(m,2H),7.15-7.12(m,1H),5.24(s,2H),5.12-5.07(m,1H),4.72(t ,J=8.8Hz,2H),4.40-4.36(m,1H),4.24-4.19(m,1H),3.36-3.34(m,2H),2 .95-2.86(m,1H),2.61-2.56(m,1H),2.44-2.40(m,1H),2.01-1.95(m,1H).

[0614] 19 F NMR(377MHz,DMSO-d6)δ-57.23,-126.07.

[0615] Example 18. Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxopiridin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl ester (C101-N110):

[0616] 1) Synthesis of methyl 4-bromoindoline-6-carboxylate

[0617]

[0618] At 0 °C, triethylsilane (13.73 g, 118.05 mmol) was slowly added to a solution of methyl 4-bromo-1H-indole-6-carboxylate (20 g, 78.7 mmol) in 2,2,2-trifluoroacetic acid (200 mL), and the mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (500 mL), and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The collected organic matter was washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give methyl 4-bromoindoline-6-carboxylate (15.0 g, 58.6 mmol, yield: 74.5%), LCMS m / z: 256 [M+H]. + .

[0619] 2) Synthesis of methyl 4-bromo-7-iodoindoline-6-carboxylic acid.

[0620]

[0621] At 0 °C, N-iodosuccinimide (968 mg, 4.30 mmol) was slowly added to a solution of methyl 4-bromoindoline-6-carboxylate (1.00 g, 3.91 mmol) in acetic acid (40 mL), and the mixture was heated to 80 °C and stirred for 0.5 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 15 / 1) to give methyl 4-bromo-7-iodoindoline-6-carboxylate (700 mg, 1.83 mmol, yield: 46.8%). LCMS m / z: 382 [M+H] + .

[0622] 3) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid ester

[0623]

[0624] At room temperature, triethylamine (555 mg, 5.49 mmol), 4-dimethylaminopyridine (112 mg, 0.915 mmol), and di-tert-butyl dicarbonate (598 mg, 2.75 mmol) were added to a solution of methyl 4-bromo-7-iodoindoline-6-carboxylate (700 mg, 1.83 mmol) in 20 mL of dichloromethane. The mixture was heated to 60 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester (750 mg, 1.56 mmol, yield: 85%) as a yellow solid. LCMS: m / z: 382 [M+H-100] + .

[0625] 4) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylic acid ester

[0626]

[0627] At room temperature, to a mixed solution of 1,4-dioxane (10 mL) and water (1.0 mL) containing 1-(tert-butyl)-6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid ester (750 mg, 1.56 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoboropentan (480 mg, 3.12 mmol), potassium carbonate (646 mg, 4.68 mmol), and Pd(dppf)Cl2.CH2Cl2 (600 mg, 0.82 mmol) were added. Under nitrogen protection, the mixture was heated to 70 °C in a sealed tube and stirred for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester (360 mg, 0.942 mmol, yield: 60.4%), LCMS m / z: 326 [M+H-56] + .

[0628] 5) Synthesis of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) ester

[0629]

[0630] At room temperature, NaIO4 (1.0 g, 4.71 mmol) and K2OsO4 (17 mg, 0.047 mmol) were added to a solution containing 10 mL of tetrahydrofuran (360 mg, 0.942 mmol) of 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester (360 mg, 0.942 mmol) and water (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) ester (100 mg, 0.26 mmol, yield: 27.7%), LCMS m / z: 328 [M+H-56]. + .

[0631] 6) Synthesis of tert-butyl 4-bromo-7-(2,6-dioxopiridine-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate

[0632]

[0633] To a solution of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) ester (100 mg, 0.26 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (128 mg, 0.78 mmol), triethylamine (0.5 mL), sodium triacetoxyborohydride (110 mg, 0.52 mmol), and acetic acid (1 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 6) to give compound tert-butyl 4-bromo-7-(2,6-dioxopiridine-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid (80 mg, 0.172 mmol, yield: 66.3%). LCMS m / z: 464 [M+H] + .

[0634] 7) Synthesis of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-4-(hydroxymethyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate

[0635]

[0636] To a solution of tert-butyl 4-bromo-7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid (80 mg, 0.172 mmol) in 1,4-dioxane (8 mL), add (tributyltinyl)methanol (1.1 g, 3.45 mmol) and Pd(PPh3)4 (88 mg, 0.086 mmol). Under nitrogen protection, heat in a sealed tube at 100 °C and stir for 16 hours. Filter the mixture, collect the filtrate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound tert-butyl 7-(2,6-dioxopiperidin-3-yl)-4-(hydroxymethyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid (60 mg, 0.144 mmol, yield: 84.0%), LCMS m / z: 416 [M+H] +

[0637] 8) Synthesis of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid

[0638]

[0639] At room temperature, a solution of 1,4-dioxane (3.0 mL) containing 7-(2,6-dioxopiridine-3-yl)-4-(hydroxymethyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid tert-butyl ester (60 mg, 0.144 mmol) was added to (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (46 mg, 0.144 mmol) and 4-dimethylaminopyridine (20 mg, 0.158 mmol), and the mixture was heated to 90 °C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-100% B within 15 min; detector: 254 nm). When the content of mobile phase B reached 75%, the fraction containing the product was collected and concentrated under reduced pressure to obtain compound 7-(2,6-dioxopiridine-3-yl)-4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid tert-butyl ester (50 mg, 0.078 mmol, yield: 54.5%), LCMS m / z: 637 [M+H]. +

[0640] 9) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxopiridin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl ester (C101-N110)

[0641]

[0642] To a solution of 7-(2,6-dioxopiperidin-3-yl)-4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylic acid tert-butyl ester (50 mg, 0.078 mmol) in dichloromethane (3.0 mL), 2,2,2-trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) and the pH was adjusted to 6-7 with saturated sodium carbonate solution. The organic phase was collected, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-100% B within 15 min; detector: 254 nm). When the concentration of mobile phase B reached 60%, the fraction containing the product was collected, and the compound (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxopiridine-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl ester (19.09 mg, 0.0356 mmol, yield: 45.6%) was concentrated under reduced pressure. LCMS m / z: 578 [M+41+H] +

[0643] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.89(s,1H),7.84(s,1H),7.38(t,J=9.6H z,1H),7.14-7.12(m,1H),7.05(s,1H),5.95(s,1H),5.17(s,2H),5.11-5.07(m, 1H),4.16(dd,J1=35.2Hz,J2=16.8Hz,2H),3.59(t,J=8.8Hz,2H),3.11-3.06(m, 2H),2.94-2.86(m,1H),2.62-2.51(m,1H),2.40-2.33(m,1H),2.01-1.96(m,1H).

[0644] 19 F NMR(377MHz,DMSO-d6)δ-57.197,-125.995.

[0645] Example 19. Synthesis of methyl 2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-furan[3,2-e]isoindole-5-yl)carbamate (C101-N200):

[0646] 1) Synthesis of methyl 5-bromo-4-hydroxy-2-methylbenzoate

[0647]

[0648] At 0 °C, Br2 (9.64 g, 60.24 mmol) was added to a solution of methyl 4-hydroxy-2-methylbenzoate (10.00 g, 60.24 mmol) in dichloromethane (100 mL) and acetic acid (10 mL), and the mixture was stirred at room temperature for 16 hours under nitrogen protection. The mixture was poured into water (400 mL) and extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated sodium bicarbonate (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give methyl 5-bromo-4-hydroxy-2-methylbenzoate (12.4 g, 50.61 mmol, yield: 84.0%), LCMS m / z: 244 [MH]. + .

[0649] 2) Synthesis of methyl 5-bromo-4-(2,2-dimethoxyethoxy)-2-methylbenzoate

[0650]

[0651] At room temperature, 2-bromo-1,1-dimethoxyethane (8.55 g, 50.62 mmol, 2.0 eq.), K₂CO₃ (6.99 g, 50.62 mmol), and NaI (380 mg, 2.53 mmol) were added to N,N-dimethylformamide (70 mL) containing methyl 5-bromo-4-hydroxy-2-methylbenzoate (6.20 g, 25.31 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give methyl 5-bromo-4-(2,2-dimethoxyethoxy)-2-methylbenzoate (4.00 g, 12.01 mmol, yield: 47.5%).

[0652] 1H NMR (400MHz, CDCl3) δ8.16(s,1H),6.72(s,1H),4.75(t,J=5.2Hz,1H),4.08(d,J=5.2Hz,2H),3.86(s,3H),3.51(s,6H),2.58(s,3H).

[0653] 3) Synthesis of methyl 7-bromo-4-methylbenzofuran-5-carboxylate

[0654]

[0655] PPA (3.60 g) was added to a chlorobenzene (50 mL) solution containing methyl 5-bromo-4-(2,2-dimethoxyethoxy)-2-methylbenzoate (3.60 g, 10.81 mmol), and the mixture was heated to 130 °C and stirred for 3 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give methyl 7-bromo-4-methylbenzofuran-5-carboxylate (1.3 g, 4.83 mmol, yield: 44.7%).

[0656] 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),7.72(d,J=2.0Hz,1H),6.97(d,J=2.0Hz,1H),3.92(s,3H),2.75(s,3H).

[0657] 4) Synthesis of methyl 7-bromo-4-(bromomethyl)benzofuran-5-carboxylate

[0658]

[0659] At room temperature, N-bromosuccinimide (1.04 g, 5.80 mmol) and azobisisobutyronitrile (159 mg, 0.97 mmol) were added to a carbon tetrachloride (20 mL) solution containing methyl 7-bromo-4-methylbenzofuran-5-carboxylate (1.30 g, 4.83 mmol), and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was collected, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give methyl 7-bromo-4-(bromomethyl)benzofuran-5-carboxylate (1.50 g, 4.31 mmol, yield: 89.2%).

[0660] 1H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 7.83 (d, J = 2.0Hz, 1H), 7.08 (d, J = 2.0Hz, 1H), 5.18 (s, 2H), 3.97 (s, 3H).

[0661] 5) Synthesis of 3-(5-bromo-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidine-2,6-dione

[0662]

[0663] At room temperature, 3-aminopiperidine-2,6-dione (1.41 g, 8.62 mmol) and N,N-diisopropylethylamine (1.00 g, 7.76 mmol) were added to a solution of methyl 7-bromo-4-(bromomethyl)benzofuran-5-carboxylate (1.50 g, 4.31 mmol) in acetonitrile (30 mL), and the mixture was heated to 80 °C and stirred for 36 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 3-(5-bromo-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidin-2,6-dione (1.50 g, 4.13 mmol, yield: 96.2%), LCMS m / z: 365 [M+2+H]. + .

[0664] 6) Synthesis of 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidine-2,6-dione

[0665]

[0666] At room temperature, 1,4-dioxane (5 mL) containing 3-(5-bromo-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidine-2,6-dione (200 mg, 0.55 mmol) was added to (tributyltinyl)methanol (3.51 g, 11.00 mmol) and Pd(PPh3)4 (285 mg, 0.28 mmol), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidin-2,6-dione (80 mg, 0.25 mmol, yield: 45.5%), LCMS m / z: 315 [M+H]. + .

[0667] 7) Synthesis of methyl 2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-furan[3,2-e]isoindole-5-yl)carbamate

[0668]

[0669] At room temperature, to a solution of 1,4-dioxane (2 mL) containing 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidin-2,6-dione (70 mg, 0.22 mmol), phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (69 mg, 0.22 mmol) and 4-dimethylaminopyridine (29 mg, 0.24 mmol) were added, and the mixture was heated to 110 °C and stirred for 3 hours. The mixed reaction solution was filtered and purified by reversed-phase rapid column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (containing 0.1% FA); mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 1.5 mL / min: 50 mL / min; gradient: 5% B-95% B, 20 min; detector: 214 nm). The fraction containing the product was collected at a concentration of 55% B and concentrated under reduced pressure to give 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furano[3,2-e]isoindol-2-yl)piperidin-2,6-dione (21.48 g, 0.04 mmol, yield: 18.2%), LCMS m / z: 558 [M+23]. + .

[0670] 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 9.97 (s, 1H), 8.27 (d, J = 2.0Hz, 1H), 7.83(d,J=3.2Hz,1H),7.81(s,1H),7.40-7.36(m,1H),7.20(d,J=2.4Hz,1H ),7.16-7.13(m,1H),5.57(s,2H),5.19-5.15(m,1H),4.70-4.51(m,2H),2 .99-2.90(m,1H),2.65-2.60(m,1H),2.50-2.36(m,1H),2.07-2.03(m,1H).

[0671] 19 F NMR(377MHz,DMSO-d6)δ-57.21,-125.88.

[0672] Example 20: Synthesis of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)-2,2-difluoroacetamide (C101-N201):

[0673] 1) Synthesis of methyl 7-(((tert-Butoxycarbonyl)amino)methyl)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate

[0674]

[0675] Under a nitrogen atmosphere, 1,4-dioxane (10 mL) containing methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (1.00 g, 3.53 mmol) and potassium trifluoroborate (2.51 g, 10.59 mmol) in solution, along with water (2.5 mL), was heated to 100 °C and stirred for 16 hours. LC-MS showed 35% product formation. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were dried over saturated brine (50 mL × 2) with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 7-(((tert-butoxycarbonyl)amino)methyl)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (600 mg, 1.80 mmol, yield: 50.9%), LCMS m / z: 278 [M+H-56]. +.

[0676] 2) Synthesis of methyl 7-(((tert-butoxycarbonyl)amino)methyl)-4-formyl-2,3-dihydrobenzofuran-5-carboxylate

[0677]

[0678] At room temperature, NaIO4 (2.17 mg, 10.05 mmol) and K2OsO4·2H2O (74 mg, 0.20 mmol) were added to a solution of tetrahydrofuran (7 mL) and water (7 mL) containing methyl 7-(((tert-butoxycarbonyl)amino)methyl)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (670 mg, 2.01 mmol) (670 mg, 2.01 mmol). The mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to methyl 7-(((tert-butoxycarbonyl)amino)methyl)-4-formyl-2,3-dihydrobenzofuran-5-carboxylate (420 mg, 1.25 mmol, yield: 62.3%), LCMS m / z: 280 [M+H-56]. + .

[0679] 3) Synthesis of tert-butyl carbamate ((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindole-5-yl)methyl)carbamate

[0680]

[0681] At room temperature, triethylamine (2 mL), methyl 7-((tert-butoxycarbonyl)amino)methyl)-4-formyl-2,3-dihydrobenzofuran-5-carboxylate (400 mg, 1.04 mmol), sodium triacetoxyborohydride (661 mg, 3.12 mol), and acetic acid (3 mL) were added to a solution of 3-aminopiperidine-2,6-dione hydrochloride (515 mg, 3.12 mol) in dichloromethane (10 mL). The mixture was heated to 30 °C and stirred for 16 hours. LC-MS showed 48% product formation. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)carbamate (300 mg, 0.72 mmol, yield: 60.5%), LCMS m / z: 360 [M+H-56] + .

[0682] 4) Synthesis of 3-(5-(aminomethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidine-2,6-dione

[0683]

[0684] At room temperature, 2,2,2-trifluoroacetic acid (6 mL) was added to a solution of ((2-(2,6-dioxopiridin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)carbamate tert-butyl ester (150 mg, 0.36 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with dichloromethane (20 mL) and concentrated under reduced pressure to obtain 3-(5-(aminomethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidin-2,6-dione (250 mg, crude product), LCMS m / z: 357 [M+MeCN+H]. + .

[0685] 5) Synthesis of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)-2,2-difluoroacetamide (C101-N201)

[0686]

[0687] At room temperature, DIEA (248 mg, 1.92 mmol) and HATU (547 mg, 1.44 mmol) were added to a solution of N,N-dimethylformamide (3 mL) containing 3-(5-(aminomethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidine-2,6-dione (150 mg, 0.48 mmol) and 2-(4-chlorophenyl)-2,2-difluoroacetic acid (149 mg, 0.72 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH3·H2O); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B-70% B for 20 min; detector: 254 nm). The fraction containing the product was collected under reduced pressure at 35% B and concentrated to give 2-(4-chlorophenyl)-N-((2-(2,6-dioxoperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)-2,2-difluoroacetamide (15.74 mg, 0.03 mmol, yield: 6.5%) LCMS m / z: 504 [M+H). + .

[0688] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.54(t,J=6.0Hz,1H),7.62(s,4H),7.33(s,1H),5.11-5.06(m,1H),4.71-4.66(m,2H),4.38- 4.33(m,3H),4.21(d,J=17.2Hz,1H),3.27-3.18(m,2H),2.96-2.87(m,1H),2.62-2.57(m,1H),2.42-2.31(m,1H),1.99-1.94(m,1H).

[0689] 19 F NMR(377MHz,DMSO-d6)δ-101.32.

[0690] Example 21: Synthesis of 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxadiazine-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)urea (C101-N202):

[0691]

[0692] At room temperature, triethylamine (129 mg, 1.28 mmol) was added to a tetrahydrofuran (3 mL) solvent containing 3-(5-(aminomethyl)-3-oxo-1,3,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidin-2,6-dione (100 mg, 0.32 mmol) and 2-chloro-4-isocyano-1-methylbenzene (54 mg, 0.32 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to reversed-phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH3·H2O); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B-70% B for 20 min; detector: 254 nm). The fraction containing the product was collected under 30% B and concentrated under reduced pressure to obtain 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxinidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furan[3,2-e]isoindol-5-yl)methyl)urea (33.98 mg, 0.07 mmol, yield: 22.1%). LCMS m / z: 483 [M+H] + .

[0693] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.73(s,1H),7.64(s,J=1.6Hz,1H),7.4 3(s,1H),7.19-7.11(m,2H),6.69(t,J=6.0Hz,1H),5.08(dd,J=13.2Hz,5.2Hz ,1H),4.73(t,J=9.2Hz,2H),4.38-4.20(m,4H),3.29-3.19(m,2H),2.95-2.86 (m,1H),2.61-2.60(m,1H),2.39-2.36(m,1H),2.34(s,3H),2.00-1.94(m,1H).

[0694] Example 22, Synthesis of 2-(4-chlorophenyl)-N-((7-(2,6-dioxopiridin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-yl)methyl)-2,2-difluoroacetamide (C101-N203):

[0695] 1) Preparation of methyl 5-bromo-3-hydroxy-2-methylbenzoate

[0696]

[0697] At 0°C, a solution of methyl 3-amino-5-bromo-2-methylbenzoate (18.40 g, 75.41 mmol) in 10% sulfuric acid (200 mL) was added to a solution of sodium nitrite (5.20 g, 75.41 mmol) in water (5 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of 50% sulfuric acid (200 mL). The mixture was heated to 100°C and stirred for 1 hour. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 50 / 1) to give methyl 5-bromo-3-hydroxy-2-methylbenzoate (9.80 g, 40.00 mmol, yield: 53%). Rt: 1.137 min. LCMS: m / z: 247.0[M+H]+.

[0698] 2) Synthesis of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate

[0699]

[0700] At room temperature, 2-bromo-1,1-dimethoxyethane (13.80 g, 81.64 mmol), anhydrous potassium carbonate (11.27 g, 81.64 mmol), and sodium iodide (612 mg, 4.08 mmol) were added to a solution of N,N-dimethylformamide (100 mL) containing methyl 5-bromo-3-hydroxy-2-methylbenzoate (10.00 g, 40.82 mmol), and the mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 50 / 1) to give methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (10.95 g, 30.33 mmol, yield: 80.5%).

[0701] 1 H NMR (400MHz, DMSO-d6) δ7.47-7.42(m,2H),4.72(t,J=5.2Hz,1H),4.06(d,J=5.2Hz,2H),3.83(s,3H),3.34(d,J=15.6Hz,6H),2.27(s,3H).

[0702] 3) Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylate

[0703]

[0704] Polyphosphoric acid (10.10 g) was added to a xylene (100 mL) solution containing methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (10.10 g, 30.33 mmol), and the mixture was heated to 130 °C and stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give methyl 4-bromo-7-methylbenzofuran-6-carboxylate (7.12 g, 26.47 mmol, yield: 87.2%).

[0705] 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=2.0Hz,1H),7.92(s,1H),7.01(d,J=2.0Hz,1H),3.87(s,3H),2.67(s,3H).

[0706] 4) Synthesis of methyl 4-cyano-7-methylbenzofuran-6-carboxylate

[0707]

[0708] At room temperature, zinc cyanide (1.74 g, 14.88 mmol) and tetraphenylphosphine palladium (428 mg, 0.37 mmol) were added to a 10 mL NMP solution containing methyl 4-bromo-7-methylbenzofuran-6-carboxylate (2.00 g, 3.72 mmol). The mixture was heated to 140 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give methyl 4-cyano-7-methylbenzofuran-6-carboxylate (1.30 g, 6.05 mmol, yield: 81.2%), LCMS m / z: 216 [M+H]. + .

[0709] 5) Preparation of methyl 7-(bromomethyl)-4-cyanobenzofuran-6-carboxylate

[0710]

[0711] At room temperature, NBS (1.29 g, 7.26 mmol) and AIBN (100 mg, 0.61 mmol) were added to a carbon tetrachloride (20 mL) solution containing methyl 4-cyano-7-methylbenzofuran-6-carboxylate (1.30 g, 6.05 mmol), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 10 / 1) to give methyl 7-(bromomethyl)-4-cyanobenzofuran-6-carboxylate (1.12 g, 3.81 mmol, yield: 62.9%), LCMS m / z: 295 [M+H]. + .

[0712] 6) Synthesis of 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-carboxynitrile

[0713]

[0714] At room temperature, 3-aminopiperidine-2,6-dione hydrochloride (1.01 g, 6.12 mmol) and sodium bicarbonate (514 mg, 6.12 mmol) were added to a DMA (10 mL) solution containing methyl 7-(bromomethyl)-4-cyanobenzofuran-6-carboxylate (600 mg, 2.04 mmol). The mixture was heated to 80 °C and stirred for 16 hours under nitrogen protection. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-carboxynitrile (256 mg, 0.83 mmol, yield: 40.5%), LCMS m / z: 310 [M+H]. + .

[0715] 7) Synthesis of 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0716]

[0717] At room temperature, Pd / C (50 mg, 55% water content) and HCOOH (1.5 mL) were added to a DMA (15 mL) solution containing 200 mg (2,6-dioxopiridin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-carboxynitrile (0.65 mmol). The mixture was heated to 50 °C and stirred for 30 min under a hydrogen atmosphere. The reaction mixture was then filtered. The filtrate was collected, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) (chromatographic conditions: system: Waters 2767 / QDA; column: Sunfire C18 19*250mm*10μm; flow rate: 20mL / min; mobile phase: A-0.1% FA / H2O; mobile phase B: ACN: gradient 5-5%; retention time: 10.0-12.0-12.0=18min) to obtain 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione (15mg, 0.048mmol, yield: 7.35%), LCMS m / z: 297 [M-NH2). + .

[0718] 8) Synthesis of 2-(4-chlorophenyl)-N-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindole-4-yl)methyl)-2,2-difluoroacetamide (C101-N203)

[0719]

[0720] At room temperature, 2-(4-chlorophenyl)-2,2-difluoroacetic acid (4.9 mg, 0.024 mmol), HATU (9.0 mg, 0.024 mmol), and DIEA (5.0 mg, 0.048 mmol) were added to a DMF (1.0 mL) solution containing 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione (5 mg, 0.016 mmol), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (chromatographic conditions: Waters 2767 / Qda, column: sunfire C18, 19*250*10um, 80g; mobile phase A: 0.1% FA / H2O; mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 44-44% B; retention time 9.4-10.4 min of 16 min of 16 min) of 2-(4-chlorophenyl)-N-((7-(2,6-dioxopiridin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)methyl)-2,2-difluoroacetamide (1.31 mg, 0.0026 mmol, yield: 16%) LCMS m / z: 502 [M+H) + .

[0721] 1 H NMR (400MHz, DMSO-d6): δ10.99(s,1H),9.75(t,J=6.0Hz,1H),8.21(s,1H),7.60(s,4H),7.49(s,1H),7.20(s,1H),5.16 -5.12(m,1H),4.72(d,J=17.6Hz,1H),4.67(d,J=5.6Hz,2H),4.54(d,J=17.2Hz, 1H),2.97-2.89(m,1H),2.67-2.57(m,1H),2.45-2.41(m,1H),2.04-2.00(m,1H).

[0722] 19F NMR (377MHz, DMSO-d6): δ-101.561.

[0723] Example 23: Synthesis of 1-(3-chloro-4-methylphenyl)-3-((7-(2,6-dioxopiridin-3-yl)-6-oxo-7,8-dihydro-6-furano[2,3-e]isoindol-4-yl)methyl)urea (C101-N204):

[0724]

[0725] At room temperature, 2-chloro-4-isocyano-1-toluene (8.0 mg, 0.048 mmol) and triethylamine (10.0 mg, 0.096 mmol) were added to a DMF (1.0 mL) solution containing 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione (10.0 mg, 0.032 mmol), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (chromatographic conditions: Waters 2767 / QDA; column: Sunfire C18 19*250mm*10um; flow rate: 20mL / min; mobile phase: A-0.1% FA / H2O; mobile phase B: ACN; gradient: 43-43%; retention time: 9.2-10.4 of 16min) to obtain 1-(3-chloro-4-methylphenyl)-3-((7-(2,6-dioxoperidin-3-yl)-6-oxo-7,8-dihydro-6-furano[2,3-e]isoindol-4-yl)methyl)urea (3.09 mg, 0.0064 mmol, yield: 19%), LCMS m / z: 481 [M+H) + .

[0726] 1 H NMR (400MHz, DMSO-d6): δ10.99(s,1H),8.76(s,1H),8.23(d,J=2.4Hz,1H),7.66(d,J=2. 0Hz,1H),7.56(s,1H),7.30(d,J=2.4Hz,1H),7.19-7.13(m,2H),6.87(t,J=6.0Hz,1H),5 .17-5.12(m,1H),4.72(d,J=17.2Hz,1H),4.63(d,J=6.0Hz,2H),4.54(d,J=17.2Hz,1H), 2.97-2.89(m,1H),2.63-2.59(m,1H),2.50-2.48(m,1H),2.23(s,3H),2.05-2.00(m,1H).

[0727] Example 24: Synthesis of N-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)-2-(trifluoromethoxy)benzamide (C101-N205):

[0728] 1) Synthesis of methyl 5-bromo-3-hydroxy-2-methylbenzoate

[0729]

[0730] At 0°C, a solution of methyl 3-amino-5-bromo-2-methylbenzoate (18.40 g, 75.41 mmol) in 200 mL of 10% sulfuric acid was added, followed by a solution of sodium nitrite (5.20 g, 75.41 mmol) in 5 mL of water. The mixture was stirred at room temperature for 1 hour, and then another 200 mL of 50% sulfuric acid was added. The mixture was heated to 100°C and stirred for 1 hour. The mixture was diluted with 300 mL of water and extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give methyl 5-bromo-3-hydroxy-2-methylbenzoate (9.80 g, 40.00 mmol, yield: 53%), LCMS m / z: 247 [M+H]. + .

[0731] 2) Synthesis of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate

[0732]

[0733] At room temperature, 2-bromo-1,1-dimethoxyethane (13.80 g, 81.64 mmol), anhydrous potassium carbonate (11.27 g, 81.64 mmol), and sodium iodide (612 mg, 4.08 mmol) were added to a solution of N,N-dimethylformamide (100 mL) containing methyl 5-bromo-3-hydroxy-2-methylbenzoate (10.00 g, 40.82 mmol), and the mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (10.95 g, 30.33 mmol, yield: 80.5%).

[0734] 1 H NMR (400MHz, DMSO-d6) δ7.47-7.42(m,2H),4.72(t,J=5.2Hz,1H),4.06(d,J=5.2Hz,2H),3.83(s,3H),3.34(d,J=15.6Hz,6H),2.27(s,3H).

[0735] 3) Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylate

[0736]

[0737] Polyphosphoric acid (10.10 g) was added to a xylene (100 mL) solution containing methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (10.10 g, 30.33 mmol), and the mixture was heated to 130 °C and stirred for 16 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 4-bromo-7-methylbenzofuran-6-carboxylate (7.12 g, 26.47 mmol, yield: 87.2%).

[0738] 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=2.0Hz,1H),7.92(s,1H),7.01(d,J=2.0Hz,1H),3.87(s,3H),2.67(s,3H).

[0739] 4) Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate

[0740]

[0741] At room temperature, tert-butyl carbamate (2.18 g, 18.6 mmol), cesium carbonate (2.43 g, 7.44 mmol), and Brettphos Pd G3 (335 mg, 0.37 mmol) were added to a solution of methyl 4-bromo-7-methylbenzofuran-6-carboxylate (1.00 g, 3.72 mmol) in 10 mL. The mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to methyl 4-((tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (563 mg, 1.02 mmol, yield: 49.8%), LCMS m / z: 250 [M-56+H] + .

[0742] 5) Synthesis of methyl 4-(bis(tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate

[0743]

[0744] At room temperature, di-tert-butyl dicarbonate (1.43 g, 6.56 mmol) and 4-dimethylaminopyridine (40 mg, 0.33 mmol) were added to a 20 mL solution of tetrahydrofuran containing methyl 4-((tert-butyloxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (1.00 g, 3.28 mmol). The mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give methyl 4-(bis(tert-butyloxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (985 mg, 2.43 mmol, yield: 74.0%).

[0745] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=2.4Hz,1H),7.56(s,1H),8.87(d,J=2.0Hz,1H),3.86(s,3H),2.73(s,3H),1.40(s,18H).

[0746] 6) Synthesis of methyl 4-(bis(tert-butoxycarbonyl)amino)-7-(bromomethyl)benzofuran-6-carboxylate

[0747]

[0748] At room temperature, N-bromosuccinimide (520 mg, 2.92 mmol) and azobisisobutyronitrile (39 mg, 0.24 mmol) were added to a carbon tetrachloride (20 mL) solution containing methyl 4-(bis(tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (985 mg, 2.43 mmol). The mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 4-(bis(tert-butoxycarbonyl)amino)-7-(bromomethyl)benzofuran-6-carboxylate (607 mg, 1.25 mmol, yield: 51.5%).

[0749] 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=2.0Hz,1H),7.56(s,1H),6.95(d,J=1.6Hz,2H),3.91(s,3H),1.39(s,18H).

[0750] 7) Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)iminodicarbonate ditert-butyl ester

[0751]

[0752] At room temperature, 3-aminopiperidine-2,6-dione hydrochloride (203 mg, 1.24 mmol) and DIEA (160 mg, 1.24 mmol) were added to a 10 mL solution of acetonitrile containing methyl 4-(bis(tert-butoxycarbonyl)amino)-7-(bromomethyl)benzofuran-6-carboxylate (300 mg, 0.62 mmol). The mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give (7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)iminodicarbonate ditert-butyl ester (163 mg, 0.33 mmol, yield: 52.5%), LCMS m / z: 400 [M-100+H] + .

[0753] 8) Synthesis of 3-(4-amino-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0754]

[0755] At room temperature, 2,2,2-trifluoroacetic acid (2 mL) was added to a solution of (7-(2,6-dioxadiazin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)iminodiacetic acid ditert-butyl ester (140 mg, 0.28 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-amino-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidin-2,6-dione (84 mg, 0.28 mmol, yield: >99%), LCMS m / z: 300 [M+H]+.

[0756] 9) Synthesis of N-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)-2-(trifluoromethoxy)benzamide (C101-N205)

[0757]

[0758] At room temperature, 2-(trifluoromethoxy)benzoic acid (87 mg, 0.42 mmol), HATU (106 mg, 0.28 mmol), and DIEA (36 mg, 0.28 mmol) were added to a solution of N,N-dimethylformamide (2 mL) containing 3-(4-amino-6-oxo-6,8-dihydro-7H-furano[2,3-e]isoindol-7-yl)piperidine-2,6-dione (84 mg, 0.28 mmol) and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (HPLC) (system: Waters 2767 / QDA; column: Sunfire C18 19*250*10μm; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 40-40%; retention time: 8.6-9.6 min from 16 min) to obtain N-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furano[2,3-e]isoindol-4-yl)-2-(trifluoromethoxy)benzamide (27.13 mg, 0.056 mmol, yield: 19.8%), LCMS m / z: 488 [M+H). + .

[0759] 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 10.75 (s, 1H), 8.19 (d, J = 2.0Hz, 2H), 7.83(d,J=6.0Hz,1H),7.72-7.68(m,1H),7.60–7.54(m,2H),7.34(d,J=2.4 Hz,1H),5.19-5.14(m,1H),4.74(d,J=17.2Hz,1H),4.56(d,J=17.6Hz,1H), 2.99-2.90(m,1H),2.65-2.60(m,1H),2.54-2.44(m,1H),2.08-2.02(m,1H).

[0760] 19F NMR (377MHz, DMSO-d6): δ-56.51

[0761] Example 25: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furano[3,2-e]isoindol-5-yl)-2-(trifluoromethoxy)benzamide (C101-N206):

[0762] 1) Synthesis of methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate

[0763]

[0764] At 0 °C, fuming nitric acid (17.98 g, 280.90 mmol) was added to a solution of methyl 2,3-dihydrobenzofuran-5-carboxylate (25.0 g, 140.45 mmol) in acetic anhydride (300 mL), and the mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction mixture was poured into ice water, filtered, and the solid was collected and dried under vacuum to give methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate (21.5 g, 96.41 mmol, yield: 68.7%), LCMS m / z: 223 [M+H]+.

[0765] 2) Synthesis of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate

[0766]

[0767] To a solution of methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate (21.5 g, 96.41 mmol) in ethanol (400 mL) and water (80 mL), iron (53.99 g, 964.1 mmol) and NH₄Cl (51.10 g, 964.1 mmol) were added, and the mixture was heated to 100 °C and stirred for 3 hours. The reaction mixture was filtered, and the filtrate was collected. The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was analyzed by gel column chromatography (petroleum ether:ethyl acetate = 5:1, R... f =0.6) Purification yielded methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (18.0 g, 93.26 mmol, yield: 96.7%), LCMS m / z: 235 [M+MeCN] + .

[0768] 3) Synthesis of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate

[0769]

[0770] NBS (4.82 g, 27.20 mmol) was added to N,N-dimethylformamide (50 mL) containing methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (5.0 g, 25.91 mmol), and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0–3:1) to give methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate (4.3 g, 15.80 mmol, yield: 61.0%), LCMS m / z: 274 [M+H+2]. + .

[0771] 4) Synthesis of methyl 4-bromo-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate

[0772]

[0773] At room temperature, 2-(trifluoromethoxy)benzoic acid (1.15 g, 5.6 mmol), DIEA (1.91 g, 4.8 mmol), and HATU (1.91 g, 5.6 mmol) were added to a solution of N,N-dimethylformamide (30 mL) containing methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate (1.0 g, 3.7 mmol). The mixture was heated to 30 °C and stirred for 16 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to give methyl 4-bromo-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate (400 mg, 0.87 mmol, yield: 23.5%), LCMS m / z: 460 [M+H]. + .

[0774] 5) Synthesis of methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate

[0775]

[0776] To a mixture of 1,4-dioxane (10 mL) and (2.0 mL) containing methyl 4-bromo-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate (400 mg, 0.87 mmol), potassium trifluoro(vinyl)borate (233 mg, 1.74 mmol), Pd(dppf)Cl2 (318 mg, 0.435 mmol), and K2CO3 (360 mg, 2.61 mmol) were added, and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and quenched with saturated sodium bicarbonate (50 mL), then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0–4:1, 254 nm) to give methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (300 mg, 0.74 mmol, yield: 84.7%), LCMS m / z: 408 [M+H]. + .

[0777] 6) Synthesis of methyl 4-formyl-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate

[0778]

[0779] To a mixture of tetrahydrofuran (30 mL) and water (6 mL) containing methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (300 mg, 0.74 mmol), K₂O₅O₄ (63 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 20 min. Then, NaIO₄ (736 mg, 3.44 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and quenched with saturated ammonium chloride aqueous solution (10 mL), followed by extraction with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol = 100:0–20:1, 254 nm) to give methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (80 mg, 0.19 mmol, yield: 26.0%), LCMS m / z: 410 [M+H]. + .

[0780] 7) Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furano[3,2-e]isoindol-5-yl)-2-(trifluoromethoxy)benzamide (C101-N206)

[0781]

[0782] At room temperature, methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate was dissolved in...

[0783] To a solution of 80 mg (0.19 mmol) of dichloromethane (2 mL), 3-aminopiperidine-2,6-dione hydrochloride (94 mg, 0.57 mmol), triethylamine (119 mg, 1.14 mmol), sodium triacetoxyborohydride (121 mg, 0.57 mmol), and acetic acid (0.1 mL) were added, and the mixture was stirred at 25 °C for 2 hours. The resulting mixture was then concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (system: Waters 3767 / QDA; column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O; mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 40%–45%; retention time: 7.8–8.2 min (17 min)) to obtain N-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furano[3,2-e]isoindol-5-yl)-2-(trifluoromethoxy)benzamide (11.14 mg, 0.023 mmol, yield: 11.65%), LCMS m / z: 490 [M+H). + .

[0784] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.09(s,1H),7.94(s,1H),7.73(d,J=7.6Hz,1H),7.6 5(t,J=7.6Hz,1H),7.51(dd,J=18.2,8.4Hz,2H),5.11(dd,J=13.3,4.8Hz,1H),4.75(t,J=8. 8Hz,2H),4.39(d,J=16.8Hz,1H),4.25(d,J=17.2Hz,1H),3.28(d,J=8.8Hz,2H),2.91(dd,J= 21.8,9.2Hz,1H),2.63(t,J=17.6Hz,1H),2.39(dd,J=26.5,13.2Hz,1H),2.04-1.92(m,1H).

[0785] 1 F NMR (400MHz, DMSO-d6) δ 56.45

[0786] Example 26: Synthesis of 6-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)benzofuran-4-yl)methyl ester (C101-N300) of 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate:

[0787] 1) Synthesis of ethyl 4-hydroxybenzofuran-6-carboxylate

[0788]

[0789] Under nitrogen protection, sodium ethoxide (9.45 g, 139.0 mmol) was added to 150 mL of ethanol containing furan-2-carboxaldehyde (6.0 g, 62.5 mmol) and diethyl succinate (13.7 g, 78.9 mmol), and the mixture was refluxed for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 1–3 with aqueous hydrochloric acid (3 M) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water (2 x 45 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue and sodium acetate (8.34 g, 101.7 mmol) were dissolved in acetic anhydride (100 mL), and the mixture was heated to 160 °C and stirred for 8 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (25 mL) and H₂O (15 mL), and concentrated under reduced pressure to remove excess acetic anhydride. Then, ethyl acetate (80 mL) and Na₂CO₃ aqueous solution (25 mL, 10% concentration) were added for further dilution. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (2 × 40 mL). The combined organic phases were washed with H₂O (2 × 35 mL) and saturated brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (100 mL) was added to dissolve the mixture, followed by the addition of potassium carbonate (20.34 g, 147.4 mmol), and the mixture was heated under reflux for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was neutralized with hydrochloric acid aqueous solution (3 M) and extracted with ethyl acetate (2 × 75 mL). The combined organic phases were washed with water (2 × 35 mL) and saturated brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 to 4:1) to give ethyl 4-hydroxybenzofuran-6-carboxylate (1.7 g, 8.25 mmol, yield: 13.2%), LCMS m / z: 207 [M+H] + .

[0790] 2) Synthesis of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-carboxylate

[0791]

[0792] To a solution containing ethyl 4-hydroxybenzofuran-6-carboxylate (1.5 g, 7.28 mmol) and DMF (20.0 mL), triethylamine (1.47 g, 14.56 mmol) and NPTF (3.90 g, 10.92 mmol) were added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 100:0 to 6:1) to give ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-carboxylate (1.4 g, 4.14 mmol, yield: 56.9%), LCMS m / z: 339 [M+H]. + .

[0793] 3) Synthesis of ethyl 4-hydroxymethylbenzofuran-6-carboxylate

[0794]

[0795] At room temperature, Pd(PPh3)4 (478 mg, 0.414 mmol) was added to a solution of 1,4-dioxane (20.0 mL) containing ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-carboxylate (1.4 g, 4.14 mmol) and (tributyltinyl)methanol (6.64 g, 20.7 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over saturated brine (30 mL) and anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100% to 80%) to give ethyl 4-hydroxymethylbenzofuran-6-carboxylate (470 mg, 2.14 mmol, yield: 51.6%), LCMS m / z: 221 [M+H]. + .

[0796] 4) Synthesis of ethyl 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylate

[0797]

[0798] At room temperature, DMAP (314 mg, 2.57 mmol) and (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (674 mg, 2.14 mmol) were added to 10 mL of 1,4-dioxane containing ethyl 4-hydroxymethylbenzofuran-6-carboxylate (470 mg, 2.14 mmol), and the mixture was heated to 90 °C and stirred for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100% to 80%) to give ethyl 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylate (450 mg, 1.02 mmol, yield: 47.8%).

[0799] 5) Synthesis of 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylic acid

[0800]

[0801] At room temperature, 10 mL of tetrahydrofuran and 2 mL of sodium hydroxide (82 mg, 2.04 mmol) containing ethyl 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylate (450 mg, 1.02 mmol) were added, and the mixture was heated to 80 °C and stirred for 2 hours. The mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (chromatographic conditions: system: Waters 3767 / QDA, column: SunFire C18, 19*250mm, 10um; mobile phase A: 0.1% TFA / H2O, mobile phase B: ACN; flow rate: 60mL / min; gradient: 62%–68%; retention time: 20–23 min of 30 min) to obtain 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylic acid (300 mg, 0.72 mmol, yield: 71.1%).

[0802] 6) Synthesis of 6-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)benzofuran-4-yl)methyl ester (C101-N300) of ((2-fluoro-5-(trifluoromethoxy)phenyl)carbamate)

[0803]

[0804] To a solution of N,N-dimethylformamide (3 mL) containing 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylic acid (60 mg, 0.15 mmol) and 3-(methylamino)piperidin-2,6-dione (22 mg, 0.15 mmol), N,N-diisopropylethylamine (97 mg, 0.75 mmol) and HATU (86 mg, 0.225 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (system: Waters 3767 / QDA, column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 44%–46%; retention time: 7.1–8.0 min of 17 min) to obtain 6-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)benzofuran-4-yl)methyl ester (22.16 mg, 0.041 mmol, yield: 28.4%).

[0805] LCMS m / z: 560 [M+Na] + .

[0806] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.92(s,1H),8.17(d,J=7.6Hz,1H),7.82(s,1 H),7.64(d,J=49.2Hz,1H),7.42(d,J=16.4Hz,1H),7.39-7.34(m,1H),7.21(d,J=5. 6Hz,1H),7.17-7.10(m,1H),5.48(d,J=11.6Hz,2H),5.18-4.59(m,1H),2.85(d,J=1 3.6Hz,3H),2.58(d,J=16.0Hz,1H),2.47-2.32(m,2H),2.01(dd,J=10.8,5.2Hz,1H).

[0807] 19 F NMR(377MHz,DMSO-d6)δ-57.216,-125.766.

[0808] Example 27: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)-2,3-dihydrobenzofuran-7-yl)methyl ester (C101-N301):

[0809] 1) Synthesis of methyl 7-bromo-2,3-dihydrobenzofuran-5-carboxylate

[0810]

[0811] At 0°C, a solution of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (5.0 g, 26.0 mmol) and hydrobromic acid (50 mL) in acetonitrile (50 mL) was added to a solution of sodium nitrite (2.2 g, 31.0 mmol) in water (20.0 mL), and the mixture was stirred at room temperature for 2 hours. Then, cuprous bromide (7.4 g, 52.0 mmol) was added to the mixture, and the mixture was stirred at 25°C for 16 hours under nitrogen protection. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic residues were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0–10:1) to give methyl 7-bromo-2,3-dihydrobenzofuran-5-carboxylate (2.3 g, 8.98 mmol, yield: 34.6%).

[0812] 1 H NMR (400MHz, DMSO-d6) δ7.99-7.84 (m, 1H), 7.79 (d, J = 1.6Hz, 1H), 4.73 (t, J = 8.8Hz, 2H), 3.82 (s, 3H), 3.35 (t, J = 8.8Hz, 2H).

[0813] 2) Synthesis of methyl 7-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate

[0814]

[0815] A solution of methyl 7-bromo-2,3-dihydrobenzofuran-5-carboxylate (2.0 g, 7.8 mmol), (tributyltinyl)methanol (12.56 g, 39.0 mmol), and Pd(PPh3)4 (901 mg, 0.78 mmol) in 20.0 mL was heated to 100 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0–10:1) to give methyl 7-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate (900 mg, 4.33 mmol, yield: 55.6%), LCMS m / z: 209 [M+H] + .

[0816] Synthesis of methyl 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylate

[0817]

[0818] At room temperature, DMAP (600 mg, 4.9 mmol) was added to a solution of methyl 7-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate (850 mg, 4.1 mmol) and phenyl 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (1.30 g, 4.1 mmol) in 20.0 mL of 1,4-dioxane. The mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100% to 50%) to give methyl 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylate (900 mg, 2.09 mmol, yield: 51.4%), LCMS m / z: 447 [M+NH3+H] + .

[0819] 3) Synthesis of 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid

[0820]

[0821] At room temperature, a solution of methyl 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylate (900 mg, 2.09 mmol) in 10 mL of tetrahydrofuran and 2 mL of water was heated to 80 °C with stirring for 8 hours. The mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (system: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1%). TFA / H2O, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 50%–55%; retention time: 17–18 min of 30 min) purification yielded 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid (350 mg, 0.84 mmol, yield: 40.2%), LCMS m / z: 438 [M+Na] + .

[0822] 4) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)-2,3-dihydrobenzofuran-7-yl)methyl ester (C101-N301)

[0823]

[0824] To a solution of N,N-dimethylformamide (3 mL) containing 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid (70 mg, 0.17 mmol) and (3-(methylamino)piperidin-2,6-dione (24 mg, 0.17 mmol), DIEA (110 mg, 0.85 mmol) and HATU (97 mg, 0.255 mmol) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (system: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 μm; A: 0.1%). FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 43%–47%; retention time: 7.3–8.1 min (17 min)) purification yielded 2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)-2,3-dihydrobenzofuran-7-yl)methyl ester (51.47 mg, 0.095 mmol, yield: 56.6%), LCMS m / z: 540 [M+H) + .

[0825] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.86(s,1H),7.80(s,1H),7.55-7.24(m,3H),7.13(d,J=9.2Hz,1H),5.13(s,2H),5.0 8-4.94(m,1H),4.65(s,2H),3.25(s,2H),2.87(s,3H),2.78(s,1H),2.62(d,J=36.0Hz,1H),2.42-2.31(m,1H),1.99(s,1H). 19 F NMR(377MHz,DMSO-d6)δ-57.212,-125.719.

[0826] Example 28: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (4-(2,6-dioxadiazin-3-yl)-2,3-dihydrobenzofuran-7-yl)methyl ester (C101-N303):

[0827] 1) Synthesis of 7-bromo-2,3-dihydrobenzofuran-4-amine

[0828]

[0829] At 0°C, NBS (2.63 g, 14.8 mmol) was added to a solution of N,N-dimethylformamide (15 mL) containing 2,3-dihydrobenzofuran-4-amine (2.0 g, 14.8 mmol), and the mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. H₂O (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18 spherical 20-35 μm, 100A, 220 g; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 40%–50%; retention time: 19–20 minutes of 30 minutes; detection wavelength: 254 nm) to give 7-bromo-2,3-dihydrobenzofuran-4-amine (1.24 g, 5.79 mmol, yield: 39.15%), LCMS m / z: 214 [M+H]. + .

[0830] 2) Synthesis of 7-bromo-4-iodo-2,3-dihydrobenzofuran

[0831]

[0832] At 0 °C, sodium nitrite (161 mg, 2.33 mmol) was added to a flask containing 10 mL of hydrochloric acid and 10 mL of acetonitrile (500 mg, 2.33 mmol) of 7-bromo-2,3-dihydrobenzofuran-4-amine (500 mg, 2.33 mmol), and the mixture was stirred for 0.5 h. Then potassium iodide (774 mg, 4.66 mmol) was added. The mixture was stirred at 0 °C for 2 h. LC-MS showed that the reaction was complete. H₂O (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 20:1, 254 nm) to give 7-bromo-4-iodo-2,3-dihydrobenzofuran (690 mg, 2.12 mmol, yield: 91%). 1 H NMR (400MHz, CDCl3) δ7.07 (d, J = 8.4Hz, 1H), 6.99 (d, J = 8.4Hz, 1H), 4.68 (t, J = 8.8Hz, 2H), 3.31-3.18 (t, J = 8.8Hz, 2H).

[0833] 3) Synthesis of 2,6-bisbenzyloxy-3-(7-bromo-2,3-dihydrobenzofuran-4-yl)pyridine

[0834]

[0835] To a solution of 1,4-dioxane (20 mL) and aqueous solution containing 7-bromo-4-iodo-2,3-dihydrobenzofuran (690 mg, 2.1 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (960 mg, 2.3 mmol), Pd(dppf)Cl2 (154 mg, 0.21 mmol), and K2CO3 (870 mg, 6.3 mmol) were added, and the mixture was heated to 100 °C and stirred for 2 hours. LC-MS showed that the reaction was complete. H2O (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1254 nm) to give (2,6-bis(benzyloxy)-3-(7-bromo-2,3-dihydrobenzofuran-4-yl)pyridine (810 mg, 1.65 mmol, yield: 79.04%), LCMS m / z: 490 [M+2+H]. + .

[0836] 4) Synthesis of (4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,3-dihydrobenzofuran-7-yl)methanol

[0837]

[0838] To a solution of 1,4-dioxane (30 mL) containing 2,6-bis(benzyloxy)-3-(7-bromo-2,3-dihydrobenzofuran-4-yl)pyridine (810 mg, 1.66 mmol), (tributyltinyl)methanol (5.36 g, 16.7 mmol) and CataCXium Pd G3 (124 mg, 0.166 mmol) were added, and the mixture was heated to 100 °C and stirred for 2 hours. LC-MS showed the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 4:1, 254 nm) to obtain...

[0839] (4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,3-dihydrobenzofuran-7-yl)methanol (550 mg, 1.25 mmol, yield: 75.30%), LCMS m / z: 422 [M+H-18] + ,

[0840] 5) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,3-dihydrobenzofuran-7-yl)methyl ester

[0841]

[0842] To a solution of 1,4-dioxane (15 mL) containing (4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,3-dihydrobenzofuran-7-yl)methanol (450 mg, 1.02 mmol), phenyl 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (321 mg, 1.02 mmol) and 4-dimethylaminopyridine (150 mg, 1.22 mmol) were added, and the mixture was heated to 90 °C and stirred for 2 hours. LC-MS showed that the reaction was complete. 50 mL of H₂O was added to the reaction mixture, and the mixture was extracted with EA (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1, 254 nm) to give (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,3-dihydrobenzofuran-7-yl)methyl ester (500 mg, 0.756 mmol, yield: 74%), LCMS m / z: 683 [M+Na]. +

[0843] 6) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (4-(2,6-dioxadiazin-3-yl)-2,3-dihydrobenzofuran-7-yl)methyl ester (C101-N303)

[0844]

[0845] Pd / C (10 mg) was added to a 3 mL solution of ethyl acetate containing 50 mg (0.075 mmol) of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,3-dihydrobenzofuran-7-yl)methyl ester (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate, and the mixture was stirred at room temperature for 24 hours. LC-MS showed that the reaction was complete. The mixture was filtered and concentrated. The residue was purified by preparative high-performance liquid chromatography (Waters 3767 / Qda column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 55-65%; retention time: 9-9.9min, total 16min) to obtain (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (4-(2,6-dioxadiazin-3-yl)-2,3-dihydrobenzofuran-7-yl)methyl ester (2.35mg, 0.0048mmol, yield: 6.5%), LCMS m / z: 500 [M+18]. + .

[0846] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.80(s,1H),7.85-7.79(m,1H),7.3 6(dd,J=10.0,8.8Hz,1H),7.24-7.04(m,2H),6.69(d,J=7.6Hz,1H),5.09(s ,2H),4.58(t,J=8.4Hz,2H),3.89(dd,J=12.4,4.58Hz,1H),3.21-3.02(m, 2H),2.77-2.65(m,1H),2.58-2.52(m,1H),2.20(m,1H),2.06-1.92(m,1H). 19 F NMR(377MHz,DMSO-d6)δ-57.20,-125.86.

[0847] Example 29: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxopiperidin-3-yl)carbamoyl)benzofuran-7-yl)methyl ester (C101-N304):

[0848]

[0849] To a DMF (3 mL) solution containing 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-5-carboxylic acid (60 mg, 0.15 mmol) and 3-aminopiperidin-2,6-dione (19 mg, 0.15 mmol), DIEA (97 mg, 0.75 mmol) and HATU (86 mg, 0.225 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (chromatographic conditions: system: Waters 3767 / QDA, column: SunFire C18, 19*250mm, 10um; mobile phase: A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 42%–48%; retention time: 7.0–7.9 min of 17 min) to purify (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxopiperidin-3-yl)carbamoyl)benzofuran-7-yl)methyl ester (27.16 mg, 0.052 mmol, yield: 35.7%), LCMS m / z: 524 [M+H). + .

[0850] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.91(s,1H),8.86(d,J=8.4Hz,1H),8.22(d, J=2.4Hz,1H),8.13(s,1H),7.91(s,1H),7.82(d,J=3.6Hz,1H),7.38(dd,J=10.4,9 .2Hz,1H),7.23(t,J=8.8Hz,1H),7.16-7.03(m,1H),5.49(s,2H),4.92-4.74(m,1H ),2.90-2.77(m,1H),2.56(d,J=17.2Hz,1H),2.28-2.12(m,1H),2.06-1.98(m,1H).

[0851] 19 F NMR(377MHz,DMSO-d6)δ-57.216,-125.736.

[0852] Example 30: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxopiperidin-3-yl)carbamoyl)-2,3-dihydrobenzofuran-7-yl)methyl ester (C101-N305):

[0853]

[0854] In a solution of N,N-dimethylformamide (3 mL) containing 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylic acid (70 mg, 0.17 mmol) and 3-aminopiperidine-2,6-dione (22 mg, 0.17 mmol), N,N-diisopropylethylamine (110 mg, 0.85 mmol) and HATU (97 mg, 0.255 mmol) were added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (system: Waters 3767 / QDA; column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O; mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 45%–49%; retention time: 7.1–7.9 min (17 min)) to obtain (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (5-((2,6-dioxadiazin-3-yl)carbamoyl)-2,3-dihydrobenzofuran-7-yl)methyl ester (21.3 mg, 0.04 mmol, yield: 24.1%), LCMS m / z: 526 [M+H). + .

[0855] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),9.85(s,1H),8.59(d,J=8.4Hz,1H),7.80(d,J=4.4Hz,3H),7.37(t,J=9.6Hz,1H),7.15(dd,J=18.8,15.2Hz,1H) ,5.14(s,2H),4.85-4.73(m,1H),4.68(t,J=8.8Hz,2H),3.27(t,J=8.8Hz, 2H),2.90-2.70(m,1H),2.56(s,1H),2.17-2.09(m,1H),2.02-1.95(m,1H). 19 F NMR(377MHz,DMSO-d6)δ-57.212,-125.649.

[0856] Example 31: Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxin-3-yl)benzofuran-4-yl)methyl ester (C101-N307):

[0857] 1) Synthesis of 1-bromo-2-(2,2-dimethoxyethoxy)-4-iodobenzene

[0858]

[0859] At room temperature, K₂CO₃ (7.39 g, 53.52 mmol) and NaI (295 mg, 2.68 mmol) were added to an N,N-dimethylformamide (80 mL) solution containing 2-bromo-5-iodobenzene (8.00 g, 26.76 mmol) and 2-bromo-1,1-dimethoxyethane (5.43 g, 32.11 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. LC-MS showed 97% product. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (50 mL). The combined organic phases were washed twice with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 1-bromo-2-(2,2-dimethoxyethoxy)-4-iodobenzene (8.50 g, 21.96 mmol, yield: 82.1%).

[0860] 1 H NMR (400MHz, DMSO-d6) δ7.46(d,J=1.6Hz,1H),7.34(d,J=8.4Hz,1H),7.25(dd, J=8.4Hz, 2.0Hz, 1H), 4.69 (t, J=4.8Hz, 1H), 4.08 (d, J=5.2Hz, 2H), 3.37 (s, 6H).

[0861] 2) Synthesis of 7-bromo-4-iodobenzofuran

[0862]

[0863] PPA (2.00 g) was added to a 20 mL solution of chlorobenzene containing 1-bromo-2-(2,2-dimethoxyethoxy)-4-iodobenzene (2.00 g, 5.17 mmol) at room temperature, and the mixture was heated to 130 °C and stirred for 16 hours. TLC showed the formation of new spots. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 7-bromo-4-iodobenzofuran (1.00 g, 3.10 mmol, yield: 60.0%). 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=2.4Hz,1H),7.60(d,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),6.92(d,J=8.0Hz,1H).

[0864] 3) Synthesis of (7-bromobenzofuran-4-yl)methanol

[0865]

[0866] Under a nitrogen atmosphere, Pd(PPh3)4 (358 mg, 0.31 mmol) was added to a solution of 1,4-dioxane (5 mL) containing 7-bromo-4-iodobenzofuran (500 mg, 1.55 mmol) and (tributyltin)methanol (983 mg, 3.10 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. TLC showed the formation of new spots. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give (7-bromobenzofuran-4-yl)methanol (220 mg, 0.97 mmol, yield: 62.6%). 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=2.0Hz,1H),7.51(d,J=8.0Hz,1H),7.20-7.18(m,2H),5.35(t,J=5.6Hz,1H),4.72(d,J=5.6Hz,2H).

[0867] 4) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (7-bromobenzofuran-4-yl)methyl ester

[0868]

[0869] At room temperature, DMAP (142 mg, 1.16 mmol) was added to a solution of 1,4-dioxane (5 mL) containing 7-bromobenzofuran-4-yl)methanol (220 mg, 0.97 mmol) and (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (306 mg, 0.97 mmol), and the mixture was heated to 90 °C and stirred for 16 hours. TLC showed the formation of a new spot. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (60 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 8 / 1) to give 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (7-bromobenzofuran-4-yl)methyl ester (300 mg, 0.67 mmol, yield: 69.1%).

[0870] 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 8.18 (d, J = 2.4Hz, 1H), 7.81 (d, J = 4.0Hz, 1H), 7.59 (d,J=8.0Hz,1H),7.40-7.35(m,1H),7.31-7.29(m,2H),7.15-7.12(m,1H),5.43(s,2H).

[0871] 5) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-bis(benzyloxy)pyridin-3-yl)benzofuran-4-yl)methyl ester

[0872]

[0873] At room temperature and under a nitrogen atmosphere, potassium phosphate (267 mg, 1.26 mmol) and Pd(dppf)Cl2 (95 mg, 0.13 mmol) were added to a solution of 1,4-dioxane (4 mL) and H2O (1 mL) containing 7-bromobenzofuran-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (280 mg, 0.63 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (396 mg, 0.95 mmol), and the mixture was heated to 90 °C and stirred for 2 hours. LC-MS showed a 20% product formation. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5; 1) to give (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-bis(benzyloxy)pyridin-3-yl)benzofuran-4-yl)methyl ester (120 mg, 0.18 mmol, yield: 29.1%), LCMS m / z: 659 [M+H] + .

[0874] 6) Synthesis of (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxin-3-yl)benzofuran-4-yl)methyl ester (C101-N307)

[0875]

[0876] Pd / C (14 mg, 10% purity) was added to a 20 mL solution of EA containing 70 mg (0.11 mmol) of 7-(2,6-bis(benzyloxy)pyridin-3-yl)benzofuran-4-yl)methyl ester (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid, and the mixture was stirred at room temperature for 16 hours. LC-MS showed 39% product. The reaction mixture was filtered through a diatomaceous earth mat, the filter cake was washed with EA (50 mL), and the filtrate was collected and concentrated under reduced pressure. The residue was purified by preparative-grade HPLC (under the following conditions: Waters 3767 / Qda, column: XBridge C18, 19*250mm, 10µm; mobile phase A: 10mmol / L% NH3H2O / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 55%–65%; retention time: 7.3–7.9 min, 17 min) to obtain (2-fluoro-5-(trifluoromethoxy)phenyl)carbamic acid (7-(2,6-dioxin-3-yl)benzofuran-4-yl)methyl ester (2.35 mg, 0.005 mmol, yield: 4.6%), LCMS m / z: 498 [M+18). + .

[0877] 1 H NMR (400MHz, CD3CN) δ8.81(s,1H),8.03(s,1H),7.91(s,1H),7.82(d,J=2.4Hz,1H),7.34(d,J=7.6Hz,1H),7.26 -7.21(m,2H),7.09(d,J=2.4Hz,1H),7.03 -7.00(m,2H),4.22(dd,J=12.4Hz,4.8Hz,1H),4.21(d,J=17.2Hz,1H),2.82-2.66(m,2H),2.58-2.47(m,1H),2.25-2.19(m,1H).

[0878] 19 F NMR(377MHz,CD3CN)δ-59.03,131.27.

[0879] Example 32, Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxoperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)urea (C101-N308):

[0880] 1) Synthesis of 5-fluoro-7-nitro-2,3-dihydrobenzofuran

[0881]

[0882] 5-Fluoro-2,3-dihydrobenzofuran (9 g, 65.15 mmol) was dissolved in nitric acid (80 mL) and stirred at -10 °C for 0.5 h. The mixture was then quenched dropwise with water (125 mL) at -10 °C and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 5-fluoro-7-nitro-2,3-dihydrobenzofuran (11.9 g, 65.03 mmol, yield: 99.8%).

[0883] 1 H NMR (400MHz, DMSO-d6) δ7.71-7.68(m,1H),7.63-7.61(m,1H),4.81(t,J=8.0Hz,2H),3.32-3.30(m,2H).

[0884] 2) Synthesis of 5-fluoro-2,3-dihydrobenzofuran-7-amine

[0885]

[0886] To a solution of ethyl acetate (100 mL) containing 11.9 g (65.03 mmol) of 5-fluoro-2,3-dihydrobenzofuran, Pd and C (15.3 g, 10% content) were added, and the mixture was stirred at 25 °C under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent PE: EA = 0%–50%, R...). f =0.5) Purification yielded 5-fluoro-2,3-dihydrobenzofuran-7-amine (7.5 g, 49.02 mmol, yield: 75.4%).

[0887] 1 H NMR (400MHz, DMSO-d6) δ6.24-6.20(m,2H),4.90(s,2H),4.47(t,J=8.0Hz,2H),3.09(t,J=8.0Hz,2H).

[0888] 3) Synthesis of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine

[0889]

[0890] Under nitrogen protection, NBS (0.27 g, 1.567 mmol) was added to 30 mL of DMF containing 0.3 g (1.959 mmol) of 5-fluoro-2,3-dihydrobenzofuran-7-amine. The mixture was stirred at 0 °C for 1 hour under nitrogen protection. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic residues were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent PE: EA = 0%–50%) to give 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (347 mg, 1.496 mmol, yield: 76.3%).

[0891] 1 H NMR (400MHz, DMSO-d6) δ6.40(d,J=8.0Hz,1H),5.10(s,2H),4.55(t,J=8.0Hz,2H),3.13(t,J=8.0Hz,2H).

[0892] 4) Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine

[0893]

[0894] Under nitrogen protection, a mixture of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (2.5 g, 10.78 mmol) dissolved in 1,4-dioxane (102 mL) and water (17 mL) was added, followed by the addition of 2,6-bisbenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (5.4 g, 12.93 mmol), Pd(dppf)Cl2 (0.78 g, 1.078 mmol), and Na2CO3 (3.43 g, 32.33 mmol). The mixture was heated to 80 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water (130 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried, filtered, and concentrated to dryness. The crude compound was subjected to normal-phase column chromatography (eluent PE: EA = 0%–50%) to give a yellow solid 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol, yield: 84.8%). LCMS m / z: 443 [M+H] + .

[0895] 5) Synthesis of 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine

[0896]

[0897] At 0°C, a mixed solution of MeCN (10 mL), HCl (12 M, 2 M), and water (10 mL) containing 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol) was added to a solution of water (2 mL) containing NaNO2 (820 mg, 11.88 mmol). The mixture was stirred at 0°C for 1 hour under nitrogen protection. Then, an aqueous solution of potassium iodide (3.03 g, 18.28 mmol) (5 mL) was added dropwise to the above mixed solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting PE: EA = 0%–30%) to 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (3.4 g, 6.15 mmol, yield: 67.3%), LCMS m / z: 554 [M+H]. + .

[0898] 6) Synthesis of tert-butyl carbamate (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate

[0899]

[0900] To a toluene (28 mL) solution containing 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (500 mg, 0.904 mmol), tert-butyl aziridine-3-ylcarbamate (778 mg, 4.518 mmol), BINAP (56.3 mg, 0.09 mmol), Pd2(dba)3 (82.8 mg, 0.09 mmol), and t-BuONa (174 mg, 1.808 mmol) were added, and the mixture was heated to 120 °C and stirred for 18 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL c×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent PE: EA = 0%–10%) to give tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate (238 mg, 0.398 mmol, yield: 44.0%).

[0901] 1H NMR (400MHz, DMSO-d6) δ7.59-7.57(m,1H),7.55-7.47(m,3H),7.43-7.40(m,2H),7.38-7.28(m,5H),6.50(d,J=8.0Hz,1H),6.1 4(d,J=12Hz,1H),5.36-5.34(m,4H),4.44-4.28(m,3H),4.09-4.02(m,2H),3.66-3.56(m,2H),3.01-2.75(m,2H),1.39(s,9H).

[0902] 7) Synthesis of tert-butyl carbamate (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate

[0903]

[0904] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate (200 mg, 0.335 mmol) in ethyl acetate (50 mL), Pd / C (356 mg) and Pd(OH)₂ (470.4 mg) were added. The mixture was heated at 40 °C and stirred for 8 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azacyclobutane-3-yl)carbamate (133 mg, 0.317 mmol, yield: 94.7%), LCMS m / z: 420 [M+H].

[0905] 8) Preparation of 3-(7-(3-aminoazacyclobutane-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0906]

[0907] To a solution of 133 mg (0.317 mmol) of tert-butyl carbamate in dichloromethane (16 mL), 2,2,2-trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give a yellow solid 3,7-(3-aminoazacyclobutane-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidin-2,6-dione (101 mg, 0.317 mmol, yield: 100%). LCMS m / z: 320 [M+H] + .

[0908] 9) Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(...

Claims

1. The compound represented by formula (I), its pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof, in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures: in, "Any" represents a single or double bond, and when When it is a single bond, X, X1, and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X, X1, and X2 are arbitrarily and independently selected from C(R) d1 ) or N; X3 is arbitrarily and independently selected from C(R) d1 ) or N; Z is independently selected from -C(R) d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、- N(R d6 )S(=O)2-、-N(R d7 )-、-O-、-S-、-C(=O)O-、-OC(=O)-、-OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-、-C(=O)-、- C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 P(=Y)–, -OS(=Y)-, -S(=O)2-, alkene bond, alkyne bond, 6-10 The aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group and 3-8 saturated or partially saturated heterocyclic group; wherein the aryl group, heteroaryl group, cycloalkyl group and heterocyclic group are optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3 and OH. L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-OC(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、-N(R d7 )C(R d1 (R) d2 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bond, alkyne bond, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group and 3-8 saturated or partially saturated heterocyclic group; wherein the aryl group, heteroaryl group, cycloalkyl group and heterocyclic group are connected to ring A or B at one end and connected to Z at the other end; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4 and 5.

2. The compound according to claim 1, its pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof, characterized in that, The compound has the structure of formula (IA). in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures: in, "Any" represents a single or double bond, and when When it is a single bond, X, X1, and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X, X1, and X2 are arbitrarily and independently selected from C(R) d1 ) or N; X3 is arbitrarily and independently selected from C(R) d1 ) or N; L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl groups; wherein the hydrogen on R3 is optionally replaced by one to a plurality of groups selected from hydrogen, deuterium, halogen, oxo, CN, pentafluoride sulfide, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4, and 5; p and q are arbitrarily selected from 0, 1, 2, 3, 4 and 5.

3. The compound according to claim 1, its pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof, characterized in that, The compound has the structure of formula (IB). in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; The fragment structure must be capable of binding to ubiquitinated proteins or chaperone proteins, and preferably selected from the following structures: in, "Any" represents a single or double bond, and when When it is a single bond, X, X1, and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2-; and when When it is a double bond, X, X1, and X2 are arbitrarily and independently selected from C(R) d1 ) or N; X3 is arbitrarily and independently selected from C(R) d1 ) or N; L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -N(R d3 )C(=O)-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4, and 5; p and q are arbitrarily selected from 0, 1, 2, 3, 4 and 5.

4. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof, characterized in that, The compound has the structure of formula (IC). in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; L0 is independently selected from non-existent, single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR)-. d5 )-, -O-, -S-, -N(R0)C(=O)-; "Any" represents either a single bond or a double bond; X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、- O-、-S-、-C(=O)O-、-OC(=O)-、-OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-、-C(=O)-、-C(R d1 )(R d2 )C(=O)-、(=O)C(R d1 )(R d2 )、 -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2, C(R d1 ) or N; L1, L2, and L3 are independently selected from non-existent, single bonds, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、- N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、-O-、-S-、-C(=O)O-、-OC(=O)-、-C(=O)-、- C(=S)-、-S(=O)–、-(R d4 )P(=O)–、-OS(=Y)-、-S(=O)2-、-C(R d1 )(R d2 )C(R d1 )(R d2 )-、-C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, pentafluoride sulfide, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4 and 5.

5. The compound according to any one of claims 1-2, 4, its pharmaceutically acceptable salt, solvate, isotopic substitute or isomer thereof, characterized in that, The compound has the structure of formula (ID). in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; L0 is independently selected from non-existent, single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR)-. d5 )-, -O-, -S-, -N(R0)C(=O)-; "Any" represents either a single bond or a double bond; X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、- O-、-S-、-C(=O)O-、-OC(=O)-、-OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-、-C(=O)-、-C(R d1 )(R d2 )C(=O)-、(=O)C(R d1 )(R d2 )、 -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2, C(R d1 ) or N; L1 and L2 are independently selected from non-existent, single bond, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、- N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、-O-、-S-、-C(=O)O-、-OC(=O)-、-C(=O)-、- C(=S)-、-S(=O)–、-(R d4 )P(=O)–、-OS(=Y)-、-S(=O)2-、-C(R d1 )(R d2 )C(R d1 )(R d2 )-、-C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, pentafluoride sulfide, OH, and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4 and 5.

6. The compound according to any one of claims 1-2, 4-5, its pharmaceutically acceptable salt, solvate, isotopic substitute or isomer thereof, characterized in that, The compound has the structure of formula (IE). in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; L0 is independently selected from non-existent, single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR)-. d5 )-, -O-, -S-, -N(R0)C(=O)-; "Any" represents either a single bond or a double bond; X1 and X2 are arbitrarily and independently selected from -C(R d1 (R) d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、- O-、-S-、-C(=O)O-、-OC(=O)-、-OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-、-C(=O)-、-C(R d1 )(R d2 )C(=O)-、(=O)C(R d1 )(R d2 )、 -C(=S)-, -S(=O)–, -(R d4 )P(=Y)–, -OS(=Y)-, -S(=O)2, C(R d1 ) or N; X3 and X4 are arbitrarily and independently selected from C(R) d1 ) or N; L1 and L2 are independently selected from non-existent, single bond, and -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、- N(R d3 )C(=O)-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-、-O-、-S-、-C(=O)O-、-OC(=O)-、-C(=O)-、- C(=S)-、-S(=O)–、-(R d4 )P(=O)–、-OS(=Y)-、-S(=O)2-、-C(R d1 )(R d2 )C(R d1 )(R d2 )-、-C(R d1 )(R d2 )C(=O)-, (=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R0 can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, and C. 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamine, -CN, sulfide pentafluoride, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4, and 5; p is any integer selected from 0, 1, 2, 3, and 4.

7. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof, characterized in that, The compound has the structure of formula (IF). in, A is any single-ring or polycyclic structure consisting of 3 to 18 carbon atoms, wherein the single-ring or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=X)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-, alkene bond, alkyne bond, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group and 3-8 saturated or partially saturated heterocyclic group; X is independently selected from O, S, or =NR0; R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl, 5-8 heteroaryl, 3-8 saturated or partially saturated cycloalkyl and 3-8 saturated or partially saturated heterocyclic groups, wherein R0 represents C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 The alkoxy group, 6-10 aryl group, 5-8 heteroaryl group, 3-8 saturated or partially saturated cycloalkyl group, and 3-8 saturated or partially saturated heterocyclic group are optionally preferably substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d1 R d2 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic groups, 6-10 aryl groups, and 5-8 heteroaryl groups; wherein the hydrogen on R0 is optionally substituted by one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group may be optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: The hydrogen atom on R1 is preferably selected from one or more groups, including H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 They can be the same or different, and can be arbitrarily and independently selected from deuterium, halogen, CN, sulfonium pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 R d10 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4, and 5; p is any integer selected from 1, 2, 3, and 4.

8. The compound, pharmaceutically acceptable salt thereof, solvate thereof, isotopic substituted derivative thereof, or isomer thereof, according to any one of claims 1-2, 4-6, characterized in that, It has a structure of formula (IG-1) or formula (IG-2). in, Each can independently represent a single bond or a double bond; X1 and X3 are arbitrarily and independently selected from C(R) d1 ) or N; L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4, and 5; p is any integer selected from 0, 1, 2, 3, 4 and 5.

9. The compound according to any one of claims 1-2, 4-6, its pharmaceutically acceptable salt, solvate, isotopic substitute or isomer thereof, characterized in that, The compound has a structure of formula (IH-1), formula (IH-2), or formula (IH-3). in, Each can independently represent a single bond or a double bond; L1 and L2 are independently selected from non-existent, single bond, -C(R) d1 (R) d2 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 -, -O-, -S-, -N(R) d3 )C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -(R d4 )P(=O)–, -OS(=Y)-, -S(=O)2-, -C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 (R) d2 )C(=O)-、(=O)C(R d1 (R) d2 ), olefinic bonds, alkyneic bonds, 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups and 3-8 saturated or partially saturated heterocyclic groups; Y is independently selected from O, S, or =NR0; Each R1 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, pentafluoride sulfide, -OH, -SH, -NH2, -COOH, or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute; wherein the hydrogen on R1 is optionally preferably selected from one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 Substituents may be used to replace the aryl group; or any two adjacent R1 groups together with their attached atoms may form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atom on the aryl group, saturated or partially saturated cycloalkyl group, or heterocyclic alkyl group is optionally selected from hydrogen, deuterium, halogen, -CN, sulfopentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted. Each R2 may be the same or different, and can be independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkylamino, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 Cycloalkylamine, C3-10 heterocyclic alkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl group; wherein the hydrogen on R2 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, -CN, sulfonium pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, hydroxyl groups, and saturated or partially saturated C2 groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; Each R3 may be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, sulfide pentafluoride, OH, SH, NH2, -COOH, or selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon groups, composed of C 3-10 Cyclic hydrocarbon group or C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Alkyl groups, and those composed of C 3-10 Cyclic hydrocarbon group, C 3-10 C-substituted heterocyclic hydrocarbon groups 1-10 Heteroalkyl; wherein the hydrogen on R3 is optionally replaced by one to a plurality of atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Substitution of saturated or partially saturated cycloalkyl or heterocyclic groups; Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 They can be the same or different, and can be arbitrarily and independently selected from hydrogen, deuterium, halogens, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 Heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, via C 3-10 C-substituted cyclic hydrocarbon groups 1-10 Alkyl or C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl-substituted C 3-10 The heterocyclic group is optionally surrounded by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C. 3-10 Saturated or partially substituted groups; saturated cycloalkyl or heterocyclic substituents; The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; t is any integer selected from 0, 1, 2, 3, 4 and 5. p is any integer selected from 0, 1, 2, 3, 4 and 5.

10. The compound according to any one of claims 1-9, its pharmaceutically acceptable salt, solvate, isotopic substitute, or isomer thereof, characterized in that, The compound has the structure of formula (II). Among them, ring B is selected from 5-14-membered heterocyclic groups and 5-14-membered heteroaryl groups; L2 is selected from unsubstituted or optionally by one, two or more R... L The following groups are substituted: C-16 1-6 Alkyl groups, 3-8 membered heterocyclic groups; each R L Same or different, selected independently from C 1-6 Alkyl, C 1-6 Alkoxy; L3 does not exist or is selected from O or NR. L31 C(R) L32 (R) L33 ); R L31 R L32 R L33 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, halogen, CN, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; R1 is selected from H, halogens, CN, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; R2 is selected from H, halogens, oxometalates (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; m is selected from 0, 1, 2, 3, 4, 5; n is selected from 0, 1, 2, 3, 4, and 5; Preferably, ring B is selected from 9-12 membered heterocyclic groups and 9-12 membered heteroaryl groups; the heterocyclic group can be a fused ring formed by at least two of the following: a dihydropyrrole ring, a dihydrofuran ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, and a benzene ring; the heteroaryl group can be a fused ring formed by at least two of the following: a benzene ring, a pyrrole ring, and a furan ring. Preferably, ring B is selected from Preferably, Selected from Preferably, L2 is selected from unsubstituted or optionally substituted by one, two or more R L The following groups are substituted: methylene, azeticyclic butyl; preferably, R L It is methyl; Preferably, L2 is selected from CH2, (For example Preferably, L3 is absent or selected from O, NH, and CH2; Preferably, R1 is selected from H, halogens, CN, NH2, and halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Preferably, R1 is selected from H, halogens, CN, NH2, and halogenated C. 1-3 Alkoxy; Preferably, R1 is selected from H, F, Cl, CN, NH2, trifluoromethyl, and trifluoromethoxy; Preferably, R2 is selected from H, halogens, and oxo (=O); Preferably, R2 is selected from H, F, and oxo (=O); Preferably, Selected from For example 11. The compound, pharmaceutically acceptable salt thereof, solvate thereof, isotopic substituted derivative thereof, or isomer thereof, according to any one of claims 1-10, characterized in that, The compound is selected from novel compounds with structures disclosed in this specification.

12. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, an isotopic substitute thereof, or an isomer thereof.

13. The use of the compound of any one of claims 1-11, its pharmaceutically acceptable salt, solvate, isotopic substitute or isomer thereof, or the pharmaceutical composition of claim 12 in the preparation of the following pharmaceutical products; Use in the preparation of medicaments for the prevention and / or treatment of diseases related to the MYC / GSPTs signaling pathway; and / or Use in the preparation of medicaments for the prevention and / or treatment of diseases associated with or mediated by GSPTs and / or CK1α; and / or Application in the preparation of drugs for the prevention and / or treatment of diseases related to the MYC / GSPTs / CK1a / WNT signaling pathway; Preferably, the diseases include, but are not limited to, cancer, metabolic diseases, autoimmune diseases, and inflammatory diseases; Preferably, the disease is selected from lung cancer, stomach cancer, liver cancer, brain cancer, inflammation, autoimmune diseases, and Alzheimer's disease.

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