New substituted heterocyclic compound as gspts / MYC signal flux regulator

Abstract

Disclosed in the present invention is a new substituted heterocyclic compound having GSPT1 degradation activity, and particularly disclosed is a compound having the structure as shown in formula (I) as a GSPT1 degradation agent, or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotope substitute or an isomer thereof. The compound can be used for preventing or treating diseases related to GSPTs / MYC targets or signaling pathways.

Description

Novel substituted heterocyclic compounds as regulators of GSPTs / MYC signaling flux

[0001] This application requires the applicant to:

[0002] Priority benefit of a prior application, patent application number 202310888792.X, filed with the State Intellectual Property Office of China on July 19, 2023, entitled “Novel Substituted Heterocyclic Compounds as Regulators of GSPTs / MYC Signaling Flux”;

[0003] Priority benefit of the prior application, patent application number 202311838678.2, filed with the State Intellectual Property Office of China on December 28, 2023, entitled “Novel substituted heterocyclic compounds as regulators of GSPTs / MYC signaling flux”;

[0004] Priority benefit of the prior application, patent application number 202410538295.1, filed with the State Intellectual Property Office of China on April 30, 2024, entitled “Novel Substituted Heterocyclic Compounds as Regulators of GSPTs / MYC Signaling Flux”;

[0005] The entirety of the prior application is incorporated into the present disclosure by reference. Technical Field

[0006] The present invention belongs to the field of medicinal chemistry and specifically includes novel substituted heterocyclic compounds with GSPTs degradation activity, compositions containing such compounds, and methods for using such compounds to prepare drugs for treating or preventing diseases related to GSPTs / MYC. Background Art

[0007] The transcription factor family, consisting of c-MYC, L-MYC, and N-MYC, is a major regulator of cellular processes such as cell proliferation, cell differentiation, cell cycle, and metabolism. However, when these proteins become overactive, they accelerate these processes, leading to tumorigenesis. Therefore, MYC is one of the most commonly dysregulated proteins in cancer. In many cancers, MYC is overexpressed or amplified, leading to tumor initiation and progression: for example, MYC overexpression is found in approximately 70% of small cell lung cancers and approximately 15% of non-small cell lung cancers. MYC overexpression is also widely found in other neuroendocrine tumors, such as ovarian cancer, triple-negative breast cancer, bladder cancer, and prostate cancer.

[0008] However, MYC has long been considered resistant to drug development. This is because it lacks a clear binding pocket structurally and functions through protein-protein interactions, providing fewer opportunities for active drugs. Furthermore, MYC also functions in the cell nucleus, regulating a range of signaling pathways, and blocking it could lead to numerous toxicity issues.

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

[0010] Although some GSPT1 degraders are under development, such as MRT-2359, an oral GSPT1 molecular glue degrader that has just entered clinical trials and binds to Cereblon (CRBN) E3 ligase to induce GSPT1 ubiquitination and degradation, selectivity and safety issues are common. There is still a need to develop GSPT1 degraders with higher potency, better drugability, and improved safety.

[0011] Technical Effects

[0012] The present inventors unexpectedly discovered that some heterocyclic compounds or fragments with novel structures have efficient CRBN binding ability, and based on the combination of these compounds or fragments, degraders targeting GSPTs targets were obtained. Furthermore, compared with the reference compound MRT-2359, the new substituted heterocyclic compounds having some of the structures of formula (I) of the present invention not only have higher GSPTs degradation activity and anti-tumor cell proliferation activity, but also have better anti-proliferative effects, as well as good pharmacokinetic properties (including longer T1 / 2, higher exposure), bioavailability and safety, and are more suitable as candidate drugs for development for the prevention or treatment of diseases related to GSPTs / MYC targets or signaling pathways.

[0013] Summary of the Invention

[0014] The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product thereof.

[0015] wherein A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0016] It is a fragment structure capable of binding to ubiquitinated proteins or chaperone proteins, and is preferably selected from the following structures: in, represents any single bond 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;

[0017] 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-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group are optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH;

[0018] L1 and L2 are independently selected from the group consisting of absence, a 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, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

[0019] Y is independently selected from O, S or ═NR0;

[0020] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 Rd9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0021] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0022] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0023] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0024] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0025] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0026] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0027] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0028] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0029] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0030] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IA):

[0031] in,

[0032] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0033] It is a fragment structure capable of binding to ubiquitinated proteins or chaperone proteins, and is preferably selected from the following structures: in, represents any single bond 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(Rd4 )-、-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;

[0034] 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-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group are optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH;

[0035] L1 and L2 are independently selected from the group consisting of absence, a single bond, -C(R d1 )(R d2 )-、-OC(Rd1 )(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, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

[0036] Y is independently selected from O, S or ═NR0;

[0037] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0038] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0039] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0040] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH or C 1-10 Alkyl, C 2-10Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, pentafluorinated sulfur, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0041] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, CN, sulfur 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0042] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0043] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0044] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0045] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0046] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0047] p and q are arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0048] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IB),

[0049] in,

[0050] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0051] It is a fragment structure capable of binding to ubiquitinated proteins or chaperone proteins, and is preferably selected from the following structures: in, represents any single bond 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;

[0052] 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-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group are optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH;

[0053] L1 and L2 are independently selected from the group consisting of absence, a 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(Rd6 )-、-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 bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

[0054] Y is independently selected from O, S or ═NR0;

[0055] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0056] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0057] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0058] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0059] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, CN, sulfur 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0060] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0061] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0062] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0063] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0064] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0065] p and q are arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0066] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IC),

[0067] in,

[0068] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0069] L0 is independently selected from the group consisting of absence, a single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR d5 )-, -O-, -S-, -N(R0)C(=O)-;

[0070] Any represents a single bond or a double bond;

[0071] 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;

[0072] L1, L2 and L3 are independently selected from the group consisting of absence, a 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 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 bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

[0073] Y is independently selected from O, S or ═NR0;

[0074] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0075] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0076] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0077] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0078] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, pentafluorosulfur, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0079] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0080] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0081] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0082] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0083] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0084] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (ID),

[0085] in,

[0086] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0087] L0 is independently selected from the group consisting of absence, a single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR d5 )-, -O-, -S-, -N(R0)C(=O)-;

[0088] Any represents 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(Rd4 )-、-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 are independently selected from the group consisting of absence, a 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 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 bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

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

[0092] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0093] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0094] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0095] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0096] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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, C3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, pentafluorosulfur, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0097] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0098] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[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 an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0102] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IE):

[0103] in,

[0104] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0105] L0 is independently selected from the group consisting of absence, a single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NRd5 )-, -O-, -S-, -N(R0)C(=O)-;

[0106] Any represents a single bond or a double bond;

[0107] 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;

[0108] X3 and X4 are arbitrarily and independently selected from C(R d1 ) or N;

[0109] L1, L2 are independently selected from the group consisting of absence, a 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 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 )(Rd2 )C(R d1 )(R d2 )-、-C(R d1 )(R d2 )C(=O)-、(=O)C(R d1 )(R d2 ), olefinic bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl is connected to the A or B ring and the other end is connected to C=O;

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

[0111] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 1-3Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0112] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0113] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, N,N-di(C1-10 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0114] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0115] Every R d1 、R d2 、R d3 、R d4、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0116] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0117] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[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 an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0121] p is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0122] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IF),

[0123] in,

[0124] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0125] It is a fragment structure capable of binding to ubiquitinated proteins or chaperone proteins, and is preferably selected from the following structures: in, represents any single bond 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;

[0126] Z is independently selected from -C(R d1 )(R d2 )-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(Rd6 )-、-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-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group are optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH;

[0127] L1 and L2 are independently selected from the group consisting of absence, a 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, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

[0128] Y is independently selected from O, S or ═NR0;

[0129] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0130] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0131] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0132] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0133] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkynyl or C1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2- 10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0134] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0135] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0136] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0137] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0138] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0139] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (1-IC),

[0140] in,

[0141] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0142] L1 and L2 are independently selected from the group consisting of absence, a 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 )-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is connected to the A or B ring, and the other end is connected to Z;

[0143] X is independently selected from O, S or ═NR0;

[0144] R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0145] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate, most preferably, the carboxyl surrogate is: The hydrogen on R1 is preferably replaced by one or more atoms selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0146] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0147] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0148] R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0149] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0150] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0151] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0152] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0153] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0154] If and only if R d1 and R d2 When both are hydrogen, R2 is not hydrogen, and n is not 0, or R1 is sulfur pentafluoride.

[0155] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (1-ID),

[0156] in,

[0157] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0158] L1 and L2 are independently selected from the group consisting of absence, a 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 )-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is connected to the A or B ring, and the other end is connected to Z;

[0159] X is independently selected from O, S or ═NR0;

[0160] R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 1-3Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0161] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate, most preferably, the carboxyl surrogate is: The hydrogen on R1 is preferably replaced by one or more atoms selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0162] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0163] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0164] R d1、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0165] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0166] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0167] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0168] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0169] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0170] If and only if t is 0, n is not 0 and 1, or R1 is sulfur pentafluoride.

[0171] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (1-IE),

[0172] in,

[0173] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0174] L1 and L2 are independently selected from the group consisting of absence, a 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 )-, an olefinic bond, an acetylenic bond, a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, and a 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is connected to the A or B ring, and the other end is connected to Z;

[0175] X is independently selected from O, S or ═NR0;

[0176] R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0177] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate, most preferably, the carboxyl surrogate is: The hydrogen on R1 is preferably replaced by one or more atoms selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0178] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0179] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0180] Every R d1 may be the same or different and independently selected from deuterium, halogen, CN, sulfur 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0181] R d2 、R d3 、R d4 、R d5 and R d6 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0182] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0183] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0184] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0185] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0186] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0187] p is an integer arbitrarily selected from 1, 2, 3, and 4.

[0188] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (1-IF),

[0189] in,

[0190] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0191] D is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0192] L1 and L2 are independently selected from the group consisting of absence, a 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 )-, olefinic bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group;

[0193] X is independently selected from O, S or ═NR0;

[0194] R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0195] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl surrogate, most preferably, the carboxyl surrogate is: The hydrogen on R1 is preferably replaced by one or more atoms selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0196] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0197] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0198] R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0199] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0200] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0201] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0202] n may be the same or different and is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0203] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0204] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IF),

[0205] in,

[0206] A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spiro ring or a bridged ring structure;

[0207] X1 and X2 are arbitrarily and independently selected from double bonds, C(R d1 ) or N;

[0208] L1, L2 and L3 are independently selected from the group consisting of absence, a 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 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 bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl is connected to the A or B ring and the other end is connected to C=O;

[0209] Y is independently selected from O, S or ═NR0;

[0210] Each R0 can be the same or different and is arbitrarily and independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NRd1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0211] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0212] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0213] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0214] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0215] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0216] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0217] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0218] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0219] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0220] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IG) or (IH),

[0221] in,

[0222] Any independently represents a single bond or a double bond;

[0223] L1 and L2 are independently selected from the group consisting of absence, a 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, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is connected to the A or B ring and the other end is connected to Z;

[0224] Y is independently selected from O, S or ═NR0;

[0225] Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the hydrogen atoms on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic group are optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0226] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0227] Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0228] Every R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R d7 、R d8 and R d9 may be the same or different and independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3- 10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0229] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0230] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0231] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0232] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0233] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0234] p is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0235] According to an embodiment of the present invention, R0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH.

[0236] According to an embodiment of the present invention, the carboxyl substitute is:

[0237] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (II):

[0238] wherein Ring B is selected from a 5-14 membered heterocyclyl group and a 5-14 membered heteroaryl group;

[0239] L2 is selected from unsubstituted or optionally substituted with one, two or more R L Substituted with the following groups: 1-6 Alkyl, 3-8 membered heterocyclic group; each R L The same or different, independently selected from C 1-6 Alkyl, C 1-6 alkoxy;

[0240] L3 is selected from O, NR L31 、C(R L32 )(R L33 );R L31 、R L32 、R L33 The same or different, independently selected from H, C 1-6 Alkyl, halogen, CN, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0241] R1 is selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0242] R2 is selected from H, halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0243] m is selected from 0, 1, 2, 3, 4, 5;

[0244] n is selected from 0, 1, 2, 3, 4, 5.

[0245] According to an embodiment of the present invention, ring B is selected from a 9-12 membered heterocyclic group and a 9-12 membered heteroaryl group; the heterocyclic group may be a condensed ring formed by at least two of a dihydropyrrole ring, a dihydrofuran ring, a tetrahydropyrrole ring, a tetrahydrofuran ring and a benzene ring; the heteroaryl group may be a condensed ring formed by at least two of a benzene ring, a pyrrole ring and a furan ring;

[0246] According to an embodiment of the present invention, ring B is selected from

[0247] According to an embodiment of the present invention, Selected from

[0248] According to an embodiment of the present invention, Selected from

[0249] According to an embodiment of the present invention, L2 is selected from unsubstituted or optionally substituted with one, two or more R L The following groups substituted: methylene, azetidinyl; preferably, R L is methyl;

[0250] According to an embodiment of the present invention, L2 is selected from CH2, (For example ).

[0251] According to an embodiment of the present invention, L3 is selected from O, NH, CH2.

[0252] According to an embodiment of the present invention, R1 is selected from H, halogen, CN, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0253] According to an embodiment of the present invention, R1 is selected from H, halogen, CN, halogenated C 1-3 alkoxy;

[0254] According to an embodiment of the present invention, R1 is selected from H, F, Cl, CN, trifluoromethyl, trifluoromethoxy.

[0255] According to an embodiment of the present invention, R2 is selected from H, halogen, oxo (=O).

[0256] According to an embodiment of the present invention, R2 is selected from H, F, and oxo.

[0257] According to an embodiment of the present invention, Selected from For example

[0258] In one embodiment of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer, isotope substitution, is a new compound selected from the structures disclosed in the examples.

[0259] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions.

[0260] According to an embodiment of the present invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural.

[0261] According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

[0262] The oral dosage form is not particularly limited and may be any oral dosage form known in the art, preferably tablets, capsules, suspensions or oral solutions, etc.

[0263] According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient selected from at least one of the following excipients, including but not limited to a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH adjuster, a solubilizer or cosolvent, and an osmotic pressure regulator. Those skilled in the art can easily determine how to select the corresponding excipients and their corresponding amounts based on the requirements of the specific dosage form.

[0264] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0265] Another object of the present invention is to provide the use of the above-mentioned compound in the preparation of a medicament for preventing and / or treating diseases associated with the MYC / GSPTs signaling pathway, including but not limited to cancer, metabolic diseases, autoimmune diseases, inflammatory diseases, and the like.

[0266] The present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers, and isotopic substitutions, and the use of the pharmaceutical composition in preventing and / or treating diseases associated with the MYC / GSPTs signaling pathway. The diseases associated with the MYC / GSPTs signaling pathway are as defined above.

[0267] The present invention also provides a method for preventing and / or treating diseases associated with the MYC / GSPTs signaling pathway, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the compounds of Formula (I), pharmaceutically acceptable salts, solvates, enantiomers, and isotopically substituted compounds thereof, or administering to a patient a preventively or therapeutically effective amount of the aforementioned pharmaceutical composition. The diseases associated with the MYC / GSPTs signaling pathway are as defined above.

[0268] In some embodiments, the patient is a mammal, preferably a human.

[0269] Definition and Explanation:

[0270] C 1-20 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 and C 20 ; C 2-10 Selected from C2, C3, C4, C5, C6, C7, C8, C9 and C 10 ; C 3-10 Selected from C3, C4, C5, C6, C7, C8, C9 and C 10 ;

[0271] As used herein, the term "alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms, also referred to as "C 1-20 Alkyl". For example, "C 1-10 "Alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups 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 the like or isomers thereof.

[0272] As used herein, the term "alkylene" refers to a group of the formula -(CH2) n -a linear or branched divalent hydrocarbon group. Non-limiting examples include ethylene and propylene.

[0273] As used herein, the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.

[0274] The term "aliphatic ring", "carbocycle" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The carbocycle may be monocyclic or polycyclic, and may be a saturated cycloalkyl or may optionally contain one, two or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group. In the case of a carbocycle having multiple rings, these rings may form spirocyclic, fused ring and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; and non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.

[0275] The term "aryl" or "aromatic ring" means: It should be understood that it preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0276] The term "spirocyclic" refers to a ring system in which two rings share one ring atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0277] The term "paracyclic" refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0278] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0279] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom or atomic group 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, it contains 3 to 12 ring atoms, 1-4 of which are heteroatoms (e.g., 1, 2, 3, and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present) or an oxygen or sulfur atom (particularly in the case of forming an onium salt). The heterocyclic group can include fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, and can also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group can be bicyclic, and its non-limiting examples include hexahydrocyclopenta [c] pyrrole -2 (1H) - base, hexahydro pyrrolo [1,2-a] pyrazine -2 (1H) - base. The heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

[0280] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0281] As used herein, the term "heteroaryl / heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, , isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or acinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and / or phenoxazinyl, etc.

[0282] The heteroaryl group / heteroaromatic ring may 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, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0283] Unless otherwise specified, heterocyclic groups, heteroaryls, or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include substituted or bonded to other groups at one, two, or more positions thereof, including pyridin-2-yl, pyridin-2-ene, pyridin-3-yl, pyridin-3-ene, pyridin-4-ene, and pyridin-4-ene; thienyl or thienylene includes thien-2-yl, thien-2-ene, thien-3-ene, and thien-3-ene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, etc.

[0284] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0285] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in 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, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids such as arginine, and 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 both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0286] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0287] As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention, wherein the parent compound is modified by salification with an acid or alkali. 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 acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, and the like. Conventional non-toxic salts include, but are not limited to, those 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, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene The inorganic base and organic base described in the following examples are selected from sodium, potassium, magnesium, calcium, etc. or amines, diethylamine, triethylamine, ethanolamine, etc.

[0288] 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 the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0289] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0290] Some compounds of the present invention may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, solvated forms are comparable to unsolvated forms and are included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms.

[0291] As used herein, the term "solvate" refers to an association formed between one or more solvent molecules and a compound 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. Thus, the term "hydrate" refers to an association formed when the solvent molecule is water.

[0292] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0293] The diagrammatic representations of racemic, ambiscalemic, scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration at a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be encompassed within the scope of this invention.

[0294] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0295] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, 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 pure desired enantiomer. 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0296] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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, whether radioactive or not, are encompassed within the scope of the present invention.

[0297] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0298] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0299] When a substituent's bond crosses two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which it is bonded to a compound included in the general chemical formula but not specifically mentioned, such substituent may be bonded to any atom therein. Combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0300] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0301] The present invention will now be 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 art of organic synthesis. The examples of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or by methods modified therefrom. Preferred methods include, but are not limited to, the methods described below.

[0302] Unless otherwise specified, all solvents used in the present invention are commercially available and do not require further purification when used. The reaction is usually carried out using anhydrous solvents under an inert atmosphere of nitrogen. Nuclear magnetic resonance spectra are measured on a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts are reported in the form of δ (ppm). Mass spectrometry is performed using an Agilent 1200 series (plus 6110 / and 1956A) LC / MS or Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in positive and negative modes.

[0303] The abbreviations used are as follows: aq is aqueous solution; TLC is thin layer chromatography; RT is room temperature; MeOH is methanol; EtOH is ethanol; EtOAc is ethyl acetate; THF is tetrahydrofuran; equivalent is eq; CDI is carbonyldiimidazole; DCM is dichloromethane; PE is petroleum ether; DIAD is diisopropyl azodicarboxylate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; CBz is benzyloxycarbonyl; BOC is tert-butyl benzoate. Butylcarbonyl; 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.

[0304] Compounds can be named manually or using The product is named after the manufacturer. If purchased commercially, the supplier's catalog name can also be used. TLC or LC-MS is usually used to determine whether the reaction is complete. DETAILED DESCRIPTION

[0305] In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

[0306] Example 1. Synthesis of N-(3-chloro-4-methylphenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxamide (Compound 1):

[0307] 1) Synthesis of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindol-2-yl)piperidine-2,6-dione

[0308] To a microwave vial containing 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, 3.09 mmol) in N,N-dimethylformamide (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (0.94 g, 3.71 mmol), potassium acetate (0.91 g, 9.28 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.25 g, 0.309 mmol). The atmosphere was replaced with nitrogen for 5 minutes, the mixture was sealed, and the mixture was heated at 100°C with stirring for 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction solution to precipitate a solid, which was filtered. The filter cake was washed with water and diethyl ether, and the solid was collected and dried to give 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindol-2-yl)piperidine-2,6-dione (1.06 g, yield: 93%), LCMS m / z: 371 [M+H] + .

[0309] 2) Synthesis of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate

[0310] To a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindol-2-yl)piperidine-2,6-dione (532 mg, 1.44 mmol) in water (2 mL) and 1,4-dioxane (6 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (488 mg, 1.72 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (114 mg, 0.14 mmol), and potassium phosphate (915 mg, 4.31 mmol). The mixture was heated at 90°C with stirring for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate:petroleum ether = 0-33% elution) to give tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate (264 mg, yield: 46%), LCMS m / z: 400 [M+H] + .

[0311] 3) Synthesis of 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0312] At room temperature, 2,2,2-trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate (264 mg, 0.66 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next reaction without further purification. LCMS m / z: 300 [M+H] + .

[0313] 4) Synthesis of N-(3-chloro-4-methylphenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxamide

[0314] To a solution of 3-chloro-4-methylaniline (62 mg, 0.044 mmol) and triethylamine (333 mg, 3.3 mmol) in dichloromethane (4 mL) was added bis(trichloromethyl) carbonate (65 mg, 0.22 mmol) at 0°C and stirred at room temperature for 1 hour. A solution of 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.66 mmol) in dichloromethane (5 mL) was then added dropwise to the reaction mixture and stirred at room temperature for another 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give N-(3-chloro-4-methylphenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxamide (78 mg, yield: 38%), LCMS m / z: 467 [M+H] + .

[0315] Example 2, Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (Compound 2):

[0316] 1) Synthesis of methyl 4-bromoindoline-6-formate:

[0317] At 0 ° C, triethylsilane (13.73 g, 118.05 mmol) was slowly added to a solution of 4-bromo-1H-indole-6-carboxylic acid methyl ester (20 g, 78.7 mmol) in 2,2,2-trifluoroacetic acid (200 mL), and the mixture was heated at 60 ° C and stirred for 2 hours. The mixed reaction solution 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 solution was washed with saturated brine (300 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 = 15 / 1) to give 4-bromoindoline-6-carboxylic acid methyl ester (15.0 g, 58.6 mmol, yield: 74.5%), LCMS m / z: 256 [M+H] + .

[0318] 2) Synthesis of methyl 4-bromo-7-iodoindoline-6-formate:

[0319] 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 heated to 80 ° C with stirring for 0.5 hours. The mixed reaction solution 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] + .

[0320] 3) Synthesis of 6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylic acid 1-(tert-butyl) ester:

[0321] 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 dichloromethane (20 mL). The mixture was heated at 60°C and stirred for 16 hours. The mixed reactants were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 1-(tert-butyl) 6-methyl 4-bromo-7-iodoindoline-1,6-dicarboxylate (750 mg, 1.56 mmol, yield: 85%) as a yellow solid. LCMS: m / z: 382 [M+H-100] + .

[0322] 4) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylate:

[0323] To a mixed solution of 1-(tert-butyl)-6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylate (750 mg, 1.56 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) at room temperature were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (480 mg, 3.12 mmol), potassium carbonate (646 mg, 4.68 mmol), and Pd(dppf)Cl2.CH2Cl2 (600 mg, 0.82 mmol). The mixture was heated to 70°C under nitrogen in a sealed tube and stirred for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylate (360 mg, 0.942 mmol, yield: 60.4%), LCMS m / z: 326 [M+H-56] + .

[0324] 5) Synthesis of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester):

[0325] To a solution of 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylate (360 mg, 0.942 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added NaIO4 (1.0 g, 4.71 mmol) and K2OsO4 (17 mg, 0.047 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixed reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 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 6-methyl 4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) (100 mg, 0.26 mmol, yield: 27.7%), LCMS m / z: 328 [M+H-56] + .

[0326] 6) Synthesis of tert-butyl 4-bromo-7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate:

[0327] To a solution of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) (100 mg, 0.26 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (128 mg, 0.78 mmol) in dichloromethane (10 mL) were added triethylamine (0.5 mL), sodium triacetoxyborohydride (110 mg, 0.52 mmol), and acetic acid (1 mL). 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 tert-butyl 4-bromo-7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate (80 mg, 0.172 mmol, yield: 66.3%). LCMS m / z: 464 [M+H] + .

[0328] 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:

[0329] 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)-carboxylate (80 mg, 0.172 mmol) in 1,4-dioxane (8 mL) was added (tributylstannyl)methanol (1.1 g, 3.45 mmol) and Pd(PPh3)4 (88 mg, 0.086 mmol). Under nitrogen, the mixture was heated at 100°C in a sealed tube with stirring for 16 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated 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)-carboxylate (60 mg, 0.144 mmol, yield: 84.0%), LCMS m / z: 416

[0330] [M+H] +

[0331] 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)-carboxylate:

[0332] To a solution 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 (60 mg, 0.144 mmol) in 1,4-dioxane (3.0 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (46 mg, 0.144 mmol) and 4-dimethylaminopyridine (20 mg, 0.158 mmol) at room temperature, and the mixture was heated at 90°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 100% B in 15 min; detector: 254 nm). When the mobile phase B content reached 75%, the fractions containing the product were collected and concentrated under reduced pressure to give compound 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, yield: 54.5%), LCMS m / z: 637 [M+H] +

[0333] 9) Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate:

[0334] To a solution 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)-carboxylate (50 mg, 0.078 mmol) in dichloromethane (3.0 mL) was added 2,2,2-trifluoroacetic acid (1.0 mL) and stirred at room temperature for 1 hour. The mixed reaction solution 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 x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 100% B in 15 min; detector: 254 nm). When the mobile phase B content reached 60%, the fractions containing the product were collected and concentrated under reduced pressure. Compound (7-(2,6-dioxopiperidin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (19.09 mg, 0.0356 mmol, yield: 45.6%), LCMS m / z: 578 [M+41+H]. +

[0335] 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).

[0336] 19 F NMR(377MHz,DMSO-d6)δ-57.197,-125.995.

[0337] Example 3, Synthesis of (2-(2,6-oxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (Compound 3):

[0338] 1) Preparation of methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate:

[0339] Methyl 2,3-dihydrobenzofuran-5-carboxylate (25 g, 0.14 mol) 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 mixed reaction solution was poured into ice water (100 mL), and the precipitated solid was filtered. The filter cake was washed with ethyl acetate (100 mL). The solid was collected and dried to obtain methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate (15 g, 0.067 mol, 47.8% yield).

[0340] 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).

[0341] 2) Synthesis of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate:

[0342] Methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate (13 g, 0.058 mol) was dissolved in ethanol (130 mL) and water (26 mL). 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 mixed reaction solution was filtered, concentrated under reduced pressure, and diluted with ethyl acetate (300 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (11 g, 0.057 mol, yield: 97.7%).

[0343] 1 H 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 7-amino-4-bromo-2,3-dihydrobenzofuran-5-methyl carboxylate:

[0345] To a solution of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (12.4 g, 64.24 mmol) in N,N-dimethylformamide (240 mL) was slowly added NBS (11.44 g, 64.24 mmol) over 2 hours. 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 x 3). The combined organic phases were washed with saturated brine (500 mL x 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 afford methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate (14.13 g, 0.052 mol, 80.8% yield).

[0346] 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).

[0347] 4) Preparation of 7-amino-4-vinyl-2,3-dihydrobenzofuran-5-methyl carboxylate:

[0348] To a solution 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-dioxaborolane (19.2 g, 143.38 mmol) in 1,4-dioxane (200 mL) and water (20 mL) was added Pd(dppf)Cl2 (6.98 g, 9.56 mmol) and K2CO3 (19.78 g, 143.35 mmol). The mixture was heated at 80°C with stirring under nitrogen for 16 hours. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 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% to 10%, 254 nm) to give methyl 7-amino-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (8 g, 36.52 mmol, yield: 76.3%), LCMS m / z: 220 [M+H] + .

[0349] 5) Synthesis of methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate:

[0350] To H2O (5 mL) containing 7-amino-4-vinyl-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester (2 g, 9.13 mmol) was added NaNO2 (661 mg, 9.59 mmol) and HBr (4 mL), stirred at 0°C for 1 hour, and cuprous bromide (2.6 g, 18.26 mmol) was added to the mixed reaction solution and stirred at 0°C for 3 hours. The mixed reaction was 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 decompressed. The residue was purified by column silica gel chromatography (ethyl acetate / EA = 0-10%, 254 nm) to give 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester (890 mg, 3.14 mmol, yield: 34.4%).

[0351] 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).

[0352] 6) Synthesis of methyl 7-bromo-4-formyl-2,3-dihydrobenzofuran-5-carboxylate:

[0353] To a solution of methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (890 mg, 4.06 mmol) in tetrahydrofuran (10 mL) and H₂O (2 mL) was added K₂OsO₄ (269 mg, 0.81 mmol), stirred at room temperature for 0.5 h, then NaIO₄ (3.5 g, 16.26 mmol) was added, and stirred at room temperature for 3 h. The mixed reaction solution 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% to 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] + .

[0354] 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:

[0355] To a solution of 3-aminopiperidine-2,6-dione hydrochloride (538 mg, 3.26 mmol) in dichloromethane (5 mL) was added triethylamine (659 mg, 6.53 mmol), methyl 7-bromo-4-formyl-2,3-dihydrobenzofuran-5-carboxylate (310 mg, 1.09 mmol), STAB (691 mg, 3.26 mmol), and HOAc (0.2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. H2O (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 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% to 10%, 254 nm) to give 3-(5-bromo-3-oxo-1,3,7,8-tetrahydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (330 mg, 0.90 mmol, yield: 83.1%), LCMS m / z: 367 [M+H] + .

[0356] 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:

[0357] To a solution of 3-(5-bromo-3-oxo-1,3,7,8-tetrahydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (300 mg, 0.82 mmol) in 1,4-dioxane (10 mL) were added (tributyltinyl)methanol (5.27 g, 16.44 mmol) and Pd(PPh3)4 (474 ​​mg, 0.41 mmol). The mixture was heated at 100°C and stirred for 16 hours under nitrogen. Potassium fluoride solution (10 mL) was added to the reaction mixture, stirred for 30 minutes, and then extracted with dichloromethane (30 mL x 3). The combined organic fractions were washed with saturated brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0% to 10%, 254 nm) to give 3-(5-(hydroxymethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (60 mg, 0.19 mmol, yield: 23.0%), LCMS m / z: 317 [M+H]+ .

[0358] 9) Synthesis of (2-(2,6-oxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate:

[0359] To a solution of 3-(5-(hydroxymethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (40 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was added phenyl 2-fluoro-5-(trifluoromethoxyphenyl)carbamate (47 mg, 0.15 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol), and the mixture was heated at 90°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by preparative HPLC (Waters 3767 / QDA, column: SunFire C18 19*250 mm, 10 μm; mobile phase A: 10 mmol / L A:H2O, mobile phase B: ACN, flow rate: 20 mL / min; gradient: 53% to 63%; retention time: 7.4-8.2 minutes, 17 minutes) to give (2-(2,6-oxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (8.89 mg, 0.016 mmol, yield: 13.0%), LCMS m / z: 579 [M+H] + .

[0360] 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).

[0361] 19F NMR(377MHz,DMSO-d6)δ-57.21(s),-125.94(s).

[0362] Example 4. Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxo-1,2,3,6,7,8-hexahydrocyclopentadienyl[e]isoindol-5-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (Compound 4):

[0363] 1) Synthesis of (E)-N-(2,3-dihydro-1H-inden-4-yl)-2-(hydroxyimino)acetamide:

[0364] To a solution of 2,2,2-trichloroethane-1,1-diol (13.92 g, 84.08 mmol) and anhydrous sodium sulfate (56.80 g) in water (200 mL) was added hydroxylamine hydrochloride (21.68 g, 312 mmol) and 2,3-dihydro-1H-inden-4-amine (8.00 g, 60.08 mmol) in water (64 mL). The mixture was heated to 75°C and stirred for 16 hours. The mixed reaction solution was added to water (500 mL) and extracted with ethyl acetate (600 mL x 2). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with dichloromethane (200 mL) and ethyl acetate (20 mL) and filtered to give (E)-N-(2,3-dihydro-1H-inden-4-yl)-2-(hydroxyimino)acetamide (7.70 g, 37.70 mmol, yield: 62.7%), LCMS m / z: 205 [M+H] + .

[0365] 2) Synthesis of 1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione:

[0366] At 70°C, (E)-N-(2,3-dihydro-1H-inden-4-yl)-2-(hydroxyimino)acetamide (7.70 g, 37.7 mmol) was added portionwise to stirred methanesulfonic acid (30 mL) and heated at 70°C for 2 hours. The reaction mixture was poured into water (1500 mL) and extracted with ethyl acetate (2000 mL x 2). The combined organic phases were washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (5.34 g, 28.53 mmol, yield: 75.7%), LCMS m / z: 188 [M+H]. + .

[0367] 3) Synthesis of 4-amino-2,3-dihydro-1H-indene-5-carboxylic acid:

[0368] 1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (5.30 g, 28.31 mmol) was added to a vigorously stirred aqueous solution containing potassium hydroxide (10.64 g, 189.69 mmol) and potassium chloride (10.55 g, 141.56 mmol). The mixture was stirred vigorously and 27% hydrogen peroxide solution (6 mL) was added dropwise at 8-10°C. The resulting mixed reaction solution was stirred at 20°C for 1 hour. Acetic acid was added to the reaction solution to precipitate a solid, which was collected and dried under vacuum to give 4-amino-2,3-dihydro-1H-indene-5-carboxylic acid (4.09 g, crude product). LCMS m / z: 178 [M+H] +

[0369] 4) Synthesis of methyl 4-amino-2,3-dihydro-1H-indene-5-carboxylate:

[0370] At 0 ° C, thionyl chloride (82.37 g, 692.43 mmol) was added to a solution of 4-amino-2,3-dihydro-1H-indene-5-carboxylic acid (4.09 g, 23.08 mmol) in methanol (40 mL). The mixed reaction solution was heated at 80 ° C and stirred for 16 hours. The mixed reaction solution was poured into water (400 mL) and extracted with ethyl acetate (400 mL × 2). The combined organic phases were washed with saturated brine (400 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 = 10 / 1) to give 4-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (2.70 g, 14.12 mmol, yield: 61.2%), LCMS m / z: 192 [M+H] + .

[0371] 5) Synthesis of methyl 4-amino-7-bromo-2,3-dihydro-1H-indene-5-carboxylate:

[0372] To a solution of methyl 4-amino-2,3-dihydro-1H-indene-5-carboxylate (1.50 g, 7.84 mmol) in N,N-dimethylformamide (15 mL) was added N-bromosuccinimide (1.53 g, 8.62 mmol) and stirred at room temperature for 2 hours. The mixed reaction solution was poured into water (400 mL) and extracted with ethyl acetate (400 mL × 2). The combined organic phases were washed with saturated brine (80 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-amino-7-bromo-2,3-dihydro-1H-indene-5-carboxylate (1.77 g, 6.55 mmol, yield: 83.5%), LCMS m / z: 272 [M+H] + .

[0373] 6) Synthesis of methyl 7-bromo-4-iodo-2,3-dihydro-1H-indene-5-carboxylate:

[0374] To a solution of methyl 4-amino-7-bromo-2,3-dihydro-1H-indene-5-carboxylate (1.77 g, 6.55 mmol) in concentrated hydrochloric acid (16 mL) was added a solution of sodium nitrite (994 mg, 14.41 mmol) in water (12 mL) at 0°C. The mixed reaction solution was stirred at 0°C for 15 min. Potassium iodide (4.78 g, 28.82 mmol) in water (21 mL) was added dropwise to the mixed reaction solution at 0°C. The mixed reaction solution was stirred at room temperature for 2.5 hours. The mixed reaction solution was poured into water (300 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed with saturated brine (400 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=20 / 1) to give methyl 7-bromo-4-iodo-2,3-dihydro-1H-indene-5-carboxylate (1.90 g, 4.99 mmol, yield: 76.1%).

[0375] 1 H NMR (400MHz, DMSO-d6) δ7.64(s,1H),3.84(s,3H),3.07(t,J=7.6,2H),3.01(t,J=7.6,2H),2.10-2.02(m,2H)

[0376] 7) Synthesis of methyl 7-bromo-4-vinyl-2,3-dihydro-1H-indene-5-carboxylate:

[0377] At room temperature and under nitrogen protection, 7-bromo-4-iodo-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (3.13 g, 8.21 mmol) and

[0378] To a solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.26 g, 8.21 mmol) and anhydrous potassium carbonate (5.66 g, 41.05 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was added Pd(dppf)Cl2 (600 mg, 0.82 mmol), heated at 80°C, and stirred for 16 hours. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed with saturated brine (400 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 = 10 / 1) to afford methyl 7-bromo-4-vinyl-2,3-dihydro-1H-indene-5-carboxylate (1.24 g, 4.41 mmol, yield: 53.7%).

[0379] 1 H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.04-6.97(m,1H),5.53-5.49(m,1H),5.42-5 .38(m,1H),3.77(s,3H),3.08(t,J=7.6,2H),2.94(t,J=7.6,2H),2.10-2.01(m,2H)

[0380] 8) Synthesis of methyl 7-bromo-4-formyl-2,3-dihydro-1H-indene-5-carboxylate:

[0381] To a solution of methyl 7-bromo-4-vinyl-2,3-dihydro-1H-indene-5-carboxylate (1.24 g, 4.41 mmol) in tetrahydrofuran (12 mL) and water (12 mL) at room temperature were added sodium periodate (4.71 g, 22.05 mmol) and potassium osmate (73 mg, 0.22 mmol). The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (200 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 = 10 / 1) to afford methyl 7-bromo-4-formyl-2,3-dihydro-1H-indene-5-carboxylate (646 mg, 2.28 mmol, yield: 51.7%).

[0382] 1H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.88(s,1H),3.88(s,3H),3.22(t,J=7.6Hz,2H),2.94(t,J=7.6Hz 2H),2.13-2.06(m,2H)

[0383] 9) Synthesis of 3-(5-bromo-3-oxo-3,6,7,8-tetrahydrocyclopenta[e]isoindol-2(1H)-yl)piperidine-2,6-dione:

[0384] To a solution of methyl 7-bromo-4-formyl-2,3-dihydro-1H-indene-5-carboxylate (466 mg, 1.64 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (540 mg, 3.29 mmol) in dichloromethane (20 mL) were added triethylamine (1 mL), sodium acetate borohydride (697 mg, 3.29 mmol), and acetic acid (2 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (Chromatographic conditions: Column: Spherical C18, 20-40 μm, 80 g; Mobile phase A: Water; Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 5% B to 100% B over 15 minutes; Detector: 254 nm). At 50% B, fractions containing the desired product were collected and concentrated under reduced pressure to give 3-(5-bromo-3-oxo-3,6,7,8-tetrahydrocyclopenta[e]isoindol-2(1H)-yl)piperidine-2,6-dione (250 mg, 0.69 mmol, yield: 41.8%), LCMS m / z: 363 [M+H] +

[0385] 10) Synthesis of 3-(5-(hydroxymethyl)-3-oxo-3,6,7,8-tetrahydrocyclopenta[e]isoindol-2(1H)-yl)piperidine-2,6-dione:

[0386] To a solution of 3-(5-bromo-3-oxo-3,6,7,8-tetrahydrocyclopenta[e]isoindol-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.28 mmol) in 1,4-dioxane (8 mL) was added (tributyltin)methanol (1.8 g, 5.5 mmol) and Pd(PPh3)4 (142 mg, 0.14 mmol) at room temperature, and the mixture was heated at 100°C with stirring for 16 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give 3-(5-(hydroxymethyl)-3-oxo-3,6,7,8-tetrahydrocyclopenta[e]isoindol-2(1H)-yl)piperidine-2,6-dione (80 mg, 0.26 mmol, yield: 92.48%), LCMS m / z: 315 [M+H] +

[0387] 11) Synthesis of (2-(2,6-dioxopiperidin-3-yl)-3-oxo-1,2,3,6,7,8-hexahydrocyclopentadienyl[e]isoindol-5-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate:

[0388] To a solution of 3-(5-(hydroxymethyl)-3-oxo-3,6,7,8-tetrahydrocyclopenta[e]isoindol-2(1H)-yl)piperidine-2,6-dione (80 mg, 0.25 mmol) in 1,4-dioxane (3 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (80 mg, 0.25 mmol) and 4-dimethylaminopyridine (34 mg, 0.28 mmol) at room temperature. The mixture was heated at 90°C with stirring for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 100% B over 15 minutes; detector: 254 nm). When the mobile phase B content reached 60.5%, fractions containing the product were collected and concentrated under reduced pressure to give (2-(2,6-dioxapiperidin-3-yl)-3-oxo-1,2,3,6,7,8-hexahydrocyclopenta[e]isoindol-5-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (61.93 mg, 0.16 mmol, yield: 45.5%). LCMS m / z: 558 [M+Na+H] + .

[0389] 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.93(s,1H),7.84(d,J=2.4Hz,1H),7 .64(s,1H),7.38(t,J=9.2Hz,1H),7.14-7.11(m,1H),5.26(s,2H),5.15-5.1 1(m,1H),4.43(d,J=17.2Hz,1H),4.28(d,J=17.2Hz,1H),3.02-2.92(m,5H), 2.62-2.58(m,1H),2.42-2.39(m,1H),2.18-2.11(m,2H),1.99-1.98(m,1H).

[0390] 19 F NMR(377MHz,DMSO-d6)δ-57.201,-126.068.

[0391] Example 5. Synthesis of (7-(2,6-dioxohesperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (Compound 5):

[0392] 1) Preparation of methyl 5-bromo-3-hydroxy-2-methylbenzoate:

[0393] At 0 ° C, to a solution of methyl 3-amino-5-bromo-2-methylbenzoate (4.00g 16.4mmol) and sulfuric acid (40mL, 10% H2O), water (1mL) containing sodium nitrite (1.40g 16.4mmol) was added dropwise. Then, sulfuric acid (50% aqueous solution) was added at room temperature and heated to 100 ° C with stirring for 1 hour. The mixed reaction solution was diluted with water (250mL×2) and extracted with dichloromethane (250mL×3), 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 (2.20g, 8.98mmol, yield: 54.7%).

[0394] 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).

[0395] 2) Synthesis of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate:

[0396] 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) were added potassium carbonate (2.48 g, 17.9 mmol) and sodium iodide (135 mg, 0.9 mmol), and the mixture was heated at 100°C with stirring for 24 hours under nitrogen protection. The mixed reaction solution 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%).

[0397] 1 H 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)3.36(s,6H),2.27(s,3H).

[0398] 3) Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylate:

[0399] To a flask containing methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (2.40 g, 7.2 mmol) and PPA (2.40 g) was added xylene (48 mL) and heated at 130°C with stirring for 16 hours. The mixed reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3), 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%).

[0400] 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).

[0401] 4) Preparation of methyl 4-bromo-7-(bromomethyl)benzofuran-6-carboxylate:

[0402] To a solution of methyl 4-bromo-7-methylbenzofuran-6-carboxylate (1.20 g, 4.46 mmol) in carbon tetrachloride (12 mL) at 0°C were added azobisisobutyronitrile (73 mg, 0.45 mmol) and N-bromosuccinimide (873.5 mg, 4.9 mmol), and the mixture was heated to 110°C with stirring for 16 hours. The mixed reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3), 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%).

[0403] 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).

[0404] 5) Synthesis of 3-(4-bromo-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione:

[0405] At room temperature, N,N-diisopropylethylamine (2.23 g, 17.25 mmol) was added to a solution of 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) in 1,4-dioxane (1 mL). The mixture was heated at 100°C and stirred for 4 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (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-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (600 mg, 1.65 mmol, yield: 48.0%), LCMS m / z: 395 [M+Na] +

[0406] 6) Synthesis of compound 3-(4-(hydroxymethyl)-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione:

[0407] To a solution of 3-(4-bromo-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (530 mg, 1.46 mmol) and (tributyltinyl)methanol (4.69 g, 14.60 mmol) in 1,4-dioxane (15 mL) was added Pd(PPh3)4 (335 mg, 0.29 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 100°C for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 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 a 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-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (50 mg, 0.16 mmol, yield: 11.0%), LCMS m / z: 315 [M+H] +

[0408] 7) Synthesis of (7-(2,6-dioxohesperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate:

[0409] To a solution of 3-(4-(hydroxymethyl)-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (50 mg, 0.16 mmol) and phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (76 mg, 0.24 mmol) in 1,4-dioxane (2 mL) was added 4-dimethylaminopyridine (23 mg, 0.19 mmol) at room temperature. The mixture was heated at 90°C with stirring 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 (7-(2,6-dioxohesperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)methyl 2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (30.02 mg, 0.06 mmol, yield: 35.2%), LCMS m / z: 577 [M+MeCN] + .

[0410] 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).

[0411] 19 F NMR(377MHz,DMSO-d6)δ-57.21,-125.94.

[0412] Example 6, Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea (Compound 6):

[0413] 1) Synthesis of 5-fluoro-7-nitro-2,3-dihydrobenzofuran:

[0414] 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. Water (125 mL) was then added dropwise at -10°C to quench the mixture, followed by extraction with ethyl acetate (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 5-fluoro-7-nitro-2,3-dihydrobenzofuran (11.9 g, 65.03 mmol, yield: 99.8%).

[0415] 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).

[0416] 2) Synthesis of 5-fluoro-2,3-dihydrobenzofuran-7-amine:

[0417] Pd and C (15.3 g, 10% content) were added to a solution of 5-fluoro-2,3-dihydrobenzofuran (11.9 g, 65.03 mmol) in ethyl acetate (100 mL). 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 purified by silica gel column chromatography (eluent PE: EA = 0% to 50%, R f =0.5) and purified to give 5-fluoro-2,3-dihydrobenzofuran-7-amine (7.5 g, 49.02 mmol, yield: 75.4%).

[0418] 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).

[0419] 3) Synthesis of 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine:

[0420] To 5-fluoro-2,3-dihydrobenzofuran-7-amine (0.3 g, 1.959 mmol) in DMF (30 mL) at 0°C under nitrogen was added NBS (0.27 g, 1.567 mmol). The mixture was stirred at 0°C for 1 hour under nitrogen. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent PE:EA = 0% to 50%) to afford 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (347 mg, 1.496 mmol, yield: 76.3%).

[0421] 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).

[0422] 4) Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine

[0423] Under nitrogen, to a solution 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) were added 2,6-bisbenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 with stirring for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water (130 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were dried, filtered, and concentrated to dryness. The crude compound was purified by normal phase column chromatography (eluent PE:EA = 0% to 50%) to give 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol, yield: 84.8%) as a yellow solid. LCMS m / z: 443 [M+H] +

[0424] 5) Synthesis of 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine

[0425] To a mixed solution of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-amine (4.04 g, 9.14 mmol) in MeCN (10 mL), HCl (12 M, 2 M), and water (10 mL) was added a solution of NaNO2 (820 mg, 11.88 mmol) in water (2 mL) at 0°C. The mixture was stirred at 0°C for 1 hour under nitrogen. A solution of potassium iodide (3.03 g, 18.28 mmol) in water (5 mL) was then added dropwise to the mixed solution, and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 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% to 30%) to give 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] + .

[0426] 6) Synthesis of tert-butyl (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate

[0427] To a solution of 2,6-bisbenzyloxy-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (500 mg, 0.904 mmol) in toluene (28 mL) was added tert-butyl azetidin-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). The mixture was heated at 120°C with stirring for 18 hours. The reaction system 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% to 10%) to give tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate (238 mg, 0.398 mmol, yield: 44.0%).

[0428] 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).

[0429] 7) Synthesis of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate

[0430] To a solution of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate (200 mg, 0.335 mmol) in ethyl acetate (50 mL) were added Pd / C (356 mg) and Pd(OH)2 (470.4 mg). The mixture was heated at 40°C and stirred for 8 hours under a hydrogen atmosphere. The mixed reaction liquid was filtered and concentrated under reduced pressure to yield tert-butyl 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate (133 mg, 0.317 mmol, yield: 94.7%). LCMS m / z: 420 [M+H].

[0431] 8) Preparation of 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione:

[0432] To a solution of tert-butyl 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate (133 mg, 0.317 mmol) in dichloromethane (16 mL) was added 2,2,2-trifluoroacetic acid (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction mixture was concentrated to give 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (101 mg, 0.317 mmol, yield: 100%) as a yellow solid. LCMS m / z: 320 [M+H] + .

[0433] 9) Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea:

[0434] To a solution of 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (101 mg, 0.317 mmol) in 1,4-dioxane (20 mL) was added phenyl (4-chloro-2-fluorophenyl)carbamate (84.32 mg, 0.317 mmol) and DMAP (46.4 mg, 0.380 mmol). The mixture was heated at 90°C with stirring for 2 hours. The mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (system: Waters 3767 / Qda; column: Sunfire C18, 19*250 mm, 10 um; mobile phase A: H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 46-56%, retention time: 9.6-10.5 min of 16 min) to give 1-(4-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea (70 mg, 0.143 mmol, 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).

[0435] Example 7, Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (4-chloro-2-fluorophenyl)carbamate (Compounds 7A and 7B):

[0436] 1) Synthesis of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-ol

[0437] 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) was added azetidin-3-ol (264 mg, 3.614 mmol), K3PO4 (1.074 g, 5.061 mmol), and Brettphos Pd G3 (66 mg, 0.0723 mmol). The mixture was heated at 110°C and stirred for 16 hours under nitrogen. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 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 give 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-ol (215 mg, 0.431 mmol, yield: 59.6%), LCMS m / z: 499 [M+H] + .

[0438] 2) Synthesis of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0439] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidine-3-ol (230 mg, 0.461 mmol) in ethyl acetate (60 mL) were added Pd / C (491 mg) and Pd(OH)2 (647 mg, 0.461 mmol) and stirred at 25 ° C for 1.5 hours under a hydrogen atmosphere. The mixed reaction solution was filtered and the filtrate was collected and concentrated under reduced pressure to obtain

[0440] The reaction mixture was concentrated to give 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (103 mg, 0.322 mmol, yield: 69.8%), LCMS m / z: 321 [M+H] + .

[0441] 3) Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (4-chloro-2-fluorophenyl)carbamate (Compounds 7A and 7B)

[0442] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (104 mg, 0.325 mmol) in 1,4-dioxane (20 mL) was added phenyl (4-chloro-2-fluorophenyl)carbamate (86.45 mg, 0.325 mmol) and DMAP (48 mg, 0.39 mmol). The mixture was heated at 90°C with stirring for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 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 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (4-chloro-2-fluorophenyl)carbamate (80 mg, 0.163 mmol, yield: 50.0%), LCMS m / z: 492 [M+H] + .

[0443] 4) Separation of enantiomers (compounds 7A and 7B):

[0444] 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-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*25 mm 10 μm; 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; cycle temperature: 9.0 min) to obtain two isomers: C101-N309A and C101-N309B:

[0445] Compound 7A: Peak 1 chiral-HPLC: 3.048 min, (4.19 mg, 0.008 mmol, yield: 5.22%); LCMS m / z: 492 [M+H] + .

[0446] 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).

[0447] Compound 7B: Peak 2 chiral-HPLC: 5.211 min, (3.08 mg, 0.006 mmol, yield: 3.85%), LCMS: m / z: 492 [M+H] + .

[0448] 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).

[0449] Example 8, Synthesis of N-(4-chloro-2-fluorophenyl)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)acetamide (Compound 8):

[0450] 1) Synthesis of tert-butyl 3-(2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)azetidine-1-carboxylate:

[0451] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (215 mg, 1.00 mmol) and 4-chloro-2-fluoroaniline (146 mg, 1.00 mmol) in DMF (2 mL) was added DIEA (258 mg, 2.00 mmol) and HATU (570 mg, 1.50 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS showed 37% of the product. The mixed reaction solution was quenched with saturated NH4Cl (50 mL) and extracted with EA (30 mL×2). The combined organic phase was 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)azetidine-1-carboxylate (200 mg, 0.58 mmol, yield: 58.3%), LCMS m / z: 343 [M+H] + .

[0452] 2) Synthesis of 2-(azetidin-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide:

[0453] To a solution of tert-butyl 3-(2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)azetidine-1-carboxylate (200 mg, 0.58 mmol) in DCM (6 mL) was added TFA (2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS showed 76% of the product. The mixture was diluted with DCM (20 mL) and concentrated under reduced pressure. The residue was purified by flash reverse 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 over 25 min; detector: 254 nm). At 42% B, the fractions containing the product were collected and concentrated under reduced pressure to give 2-(azetidin-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)azetidin-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide:

[0455] At room temperature and under a nitrogen atmosphere, to a solution of 2,6-bis(benzyloxy)-3-(5-fluoro-7-iodo-2,3-dihydrobenzofuran-4-yl)pyridine (300 mg, 0.54 mmol) and 2-(azetidin-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide (131 mg, 0.54 mmol) in 1,4-dioxane (5 mL) were added Cs2CO3 (880 mg, 2.70 mmol) and Xantphos Pd G3 (1.02 g, 1.08 mmol). The mixture was heated to 110 ° C and stirred for 16 hours. LCMS showed 37% of the product. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with EA (30 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=10 / 1) to give 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide (180 mg, 0.27 mmol, yield: 49.9%), LCMS m / z: 668 [M+H] + .

[0456] 4) Synthesis of N-(4-chloro-2-fluorophenyl)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)acetamide:

[0457] Under nitrogen at room temperature, 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(4-chloro-2-fluorophenyl)acetamide (70 mg, 0.105 mmol) was dissolved in ethyl acetate (20 mL) and PtO2 (14 mg) was added. Under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hours. LCMS showed 23% of the product. The mixture reaction solution was filtered and the filter cake was washed with ethyl acetate (50 mL). The collected filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: XBridge C18, 19*250 mm, 10 um; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50% to 60%; retention time: 9.2-9.9 min, 16 min) to obtain N-(4-chloro-2-fluorophenyl)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)acetamide) (6.60 mg, 0.013 mmol, yield: 12.8%), LCMS m / z: 490 [M+H] + .

[0458] 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).

[0459] 19 F NMR(377MHz,DMSO-d6)δ-121.36,132.11.

[0460] Example 9, Synthesis of 1-(4-cyano-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea (Compound 9):

[0461] To a solution of 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (40 mg, 0.12 mmol) and DMAP (18 mg, 0.15 mmol) in 1,4-dioxane (2.0 mL) was added phenyl (4-cyano-2-fluorophenyl)carbamate (38 mg, 0.15 mmol). The mixture was heated at 90°C with stirring for 3 hours. LCMS indicated the reaction was complete, and the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 3767 / oda, column: XBridge C18, 19*250mm, 10um; mobile phase A: 10mmol / L% NaHCO3 / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 35% to 43%; retention time: 6.5-7.4 minutes, 17min) to give 1-(4-cyano-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea (14.53mg, 0.03mmol, yield: 25.0%), LCMS m / z: 482[M+H] + .

[0462] 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.

[0463] Example 10, Synthesis of 1-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)urea (Compound 10):

[0464] To a solution of 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (40 mg, 0.12 mmol) and DMAP (18 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (47 mg, 0.15 mmol). The mixture was heated at 90°C with stirring for 3 hours. LCMS indicated the reaction was complete, and the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography under the following conditions (Waters 3767 / oda, column: XBridge C18, 19*250mm, 10um; mobile phase A: 10mmol / L% NaHCO3 / H2O, B: ACN; flow rate: 20mL / min; gradient: 35% to 43%; retention time: 6.8-7.4min, 17min) to give 1-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)urea (18.86mg, 0.035mmol, yield: 28%), LCMS m / z: 541[M+H] + .

[0465] 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 F NMR(377MHz,DMSO-d6)δ-57.102,-126.256,-131.483.

[0466] Example 11. Synthesis of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate and its enantiomers (MRANK-023-001-1 and MRANK-023-001-2):

[0467] 1) Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0468] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (100 mg, 0.31 mmol) in 1,4-dioxane (5 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (98.4 mg, 0.31 mmol) and DMAP (45.7 mg, 0.37 mmol). Heat and stir at 90°C for 8 hours. The mixed reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (100 mg, 0.18 mmol, yield: 58.1%), LCMS m / z: 542 [M+H] + .

[0469] 2) Preparation of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate and its enantiomers

[0470] A solution of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (100 mg, 0.18 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: Waters SFC 150, chromatographic column: (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: 5.0mL; cycle time: 7.0min) to obtain two isomers: MRANK-023-001-1 and MRANK-023-001-2:

[0471] MRANK-023-001-1: Peak 1 Chiral-HPLC: 1.803 min, (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate or enantiomer (17.9 mg, 0.033 mmol, yield: 17.9%), LCMS m / z: 542 [M+H] + .

[0472] 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

[0473] MRANK-023-001-2: Peak 2 Chiral HPLC: 2.556 min, (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate or enantiomer (13.4 mg, 0.025 mmol, yield: 13.4%), LCMS m / z: 542 [M+H] + .

[0474] 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.

[0475] Example 12, Synthesis of (R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenylacetamide and its enantiomers (MRANK-023-002-1 and MRANK-023-002-2):

[0476] 1) Synthesis of tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)amino)-2-oxoethyl)azetidine-1-carboxylate

[0477] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (1.00 g, 4.65 mmol) and 2-fluoro-5-(trifluoromethoxy)aniline (907 mg, 4.65 mmol) in DMF (10 mL) was added DIEA (1.20 g, 9.30 mmol) and HATU (2.65 g, 6.98 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. The mixed reaction solution 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=1 / 1) to give tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)amino)-2-oxoethyl)azetidine-1-carboxylate (1.80 g, 4.59 mmol, yield: 98.9%), LCMS m / z: 337 [M+H-56] + .

[0478] 2) Synthesis of (2-(azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0479] To a solution of tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)amino)-2-oxoethyl)azetidine-1-carboxylate (900 mg, 2.30 mmol) in DCM (30 mL) was added TFA (9 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with DCM (20 mL) and concentrated under reduced pressure to give a crude yellow oily compound (720 mg). The residue was purified by reverse phase flash 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 over 25 min; detector: 254 nm). At 42% B, the fractions containing the product were collected and concentrated under reduced pressure to give (2-(azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (600 mg, 2.05 mmol, yield: 89.4%), LCMS m / z: 293 [M+H] +

[0480] 3) Synthesis of 2-(1-(4-bromo-5-fluorobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0481] To a solution of (2-(azetidin-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) in 1,4-dioxane (10 mL) was added Cs2CO3 (2.45 g, 7.52 mmol), Pd2(dba)3 (174 mg, 0.19 mmol) and BINAP (118 mg, 0.19 mmol) at room temperature under a nitrogen atmosphere. Heat at 100 ° C and stir for 16 hours. The mixed reaction solution was diluted with water (100 mL) 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)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (500 mg, 0.99 mmol, yield: 52.5%), LCMS m / z: 505 [M+H] + .

[0482] 4) Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0483] To a solution of 2-(1-(4-bromo-5-fluorobenzofuran-7-yl)azetidin-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-dioxaborolan-2-yl)pyridine) (621 mg, 1.49 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was added Pd(dppf)Cl2 (146 mg, 0.20 mmol) and Na2CO3 (315 mg, 2.97 mmol), and the mixture was heated at 90°C with stirring for 16 hours. The mixed reaction solution 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)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (500 mg, 0.70 mmol, yield: 70.5%), LCMS m / z: 716 [M+H] + .

[0484] 5) Synthesis of 2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide

[0485] To a solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (370 mg, 0.52 mmol) in EA (50 mL) was added Pd / C (370 mg) and Pd(OH)2 (370 mg) at room temperature and nitrogen, and the mixture was stirred for 16 hours under H2 atmosphere. The mixed reaction solution was filtered through a celite pad, and the filter cake was washed with EA (50 mL). The filtrate was collected and concentrated under reduced pressure to give a crude product. The crude product was purified by column silica gel chromatography (PE / EA=1 / 1) to give 2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (90 mg, 0.17 mmol, yield: 32.3%), LCMS m / z: 540 [M+H] + .

[0486] 6) Preparation of (R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenylacetamide and its enantiomers (MRANK-023-002-1 and MRANK-023-002-2):

[0487] Compound 2-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (90 mg, 0.17 mmol) was purified by SFC (chromatographic adjustment: Waters SFC 150, column: Two isomers, MRANK-023-002-1 and MRANK-023-002-2, were prepared using a column column (1250 x 30 mm, 10 μm diameter); A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0 mol / L methanolamine solution); A:B = 50:50; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection: 2.0 mL; cycle time: 7.8 min; sample solution preparation: dissolve the sample in approximately 20 mL of methanol).

[0488] 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)azetidin-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] + .

[0489] 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).

[0490] 19 F NMR(377MHz,DMSO-d6)δ-57.20,-126.23.

[0491] 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)azetidin-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] + .

[0492] 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).

[0493] 19 F NMR(377MHz,DMSO-d6)δ-57.20,-126.23.

[0494] Example 13. Synthesis of (2S,3R)-1-(4-(((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate and its enantiomers (MRANK-023-003SR-1 and MRANK-023-003SR-2):

[0495] 1) Synthesis of (2S, 3R)-2-methylazetidine-3-ol

[0496] A solution of tert-butyl (2S,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (1.00 g, 5.35 mmol) in hydrochloric acid / ethyl acetate (10 mL, 4 M) was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with EA (20 mL) and concentrated under reduced pressure to give (2S,3R)-2-methylazetidine-3-ol (720 mg, crude product).

[0497] 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).

[0498] 2) Synthesis of (2S, 3R)-1-(4-bromo-5-fluorobenzofuran-7-yl)-2-methylazetidin-3-ol

[0499] To a solution of (2S,3R)-2-methylazetidin-3-ol (483 mg, 5.56 mmol) and 4-bromo-5-fluoro-7-iodobenzofuran (1.90 g, 5.56 mmol) in 1,4-dioxane (20 mL) were added Cs2CO3 (7.25 g, 22.24 mmol), Pd2(dba)3 (513 mg, 0.56 mmol), and BINAP (349 mg, 0.56 mmol) at room temperature, and the mixture was stirred at 100°C for 16 hours. The mixed reaction solution was diluted with water (100 mL) and 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 give (2S,3R)-1-(4-bromo-5-fluorobenzofuran-7-yl)-2-methylazetidin-3-ol (500 mg, 1.67 mmol, yield: 29.9%), LCMS m / z: 300 [M+H] +

[0500] 3) Synthesis of (2S,3R)-1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)-2-methylazetidin-3-ol

[0501] To a solution of (2S,3R)-1-(4-bromo-5-fluorobenzofuran-7-yl)-2-methylazetidin-3-ol (500 mg, 1.67 mmol) and (2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine) (1.05 g, 2.51 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was added Pd(dppf)Cl2 (241 mg, 0.33 mmol) and Na2CO3 (531 mg, 5.01 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80°C 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 (2S,3R)-1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)-2-methylazetidin-3-ol (600 mg, 1.17 mmol, yield: 70.4%), LCMS m / z: 511 [M+H] + .

[0502] 4) Synthesis of 3-(5-fluoro-7-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0503] At room temperature and 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-methylazetidine-3-ol (580 mg, 1.14 mmol) in EA (50 mL), and the mixture was stirred at room temperature for 4 hours under H2 atmosphere. The mixed reaction solution was filtered through celite, and the filter cake was washed with EA (100 mL). The filtrate was collected and concentrated under reduced pressure to give 3-(5-fluoro-7-((2S, 3R)-3-hydroxy-2-methylazetidine-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (450 mg, crude product), LCMS m / z: 335 [M+H] + .

[0504] 5) Synthesis of (2S,3R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0505] To a solution of 3-(5-fluoro-7-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (100 mg, 0.30 mmol) in 1,4-dioxane (5 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (95 mg, 0.30 mmol) and DMAP (44, 0.36 mmol), and the mixture was heated at 90°C with stirring for 16 hours. The mixed reaction solution 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 give (2S,3R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (60 mg, 0.11 mmol, yield: 36.1%), LCMS m / z: 556 [M+H] + .

[0506] 6) Preparation of (2S,3R)-1-(4-(((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate and its enantiomers (MRANK-023-003SR-1 and MRANK-023-003SR-2)

[0507] The compound (2S,3R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (60 mg, 0.11 mmol) was purified by SFC (conditions as follows: Waters SFC 150, column: REGIS (S, S) WHELK-O-1, 1250*30 mm Two isomers, MRANK-023-003SR-1 and MRANK-023-003SR-2, were prepared using a column chromatography column (10 μm; A: supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / L methanolic ammonia solution); A:B = 60:40; wavelength: 214 nm; flow rate: 120 mL / min; column temperature: RT; back pressure: 100 bar; injection: 7.0 mL; cycle time: 13.44 min; sample solution preparation: dissolve the sample in approximately 35 mL of methanol).

[0508] MRANK-023-003SR-1: Peak 1: Chiral HPLC: 1.062 min; (2S,3R)-1-(4-(((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate or enantiomer (25.39 mg, 0.05 mmol, yield: 42.3% yield), LCMS m / z: 555.9 [M+H] + .

[0509] 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).

[0510] 19 F NMR(377MHz,DMSO-d6)δ-57.23,-125.79.

[0511] MRANK-023-003SR-2: Peak 2: Chiral HPLC: 2.967 min; (2S,3R)-1-(4-(((S)-2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-methylazetidin-3-yl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate or enantiomer (27.85 mg, 0.05 mmol, 46.4% yield), LCMS m / z: 555.9 [M+H] + .

[0512] 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).

[0513] 19 F NMR(377MHz,DMSO-d6)δ-57.23,-125.79.

[0514] Example 14. Synthesis of N-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)4-chloro-2-fluoroaniline-1-sulfonamide and its isomers (MRANK-103-003-1 and MRANK-103.003-2):

[0515] 1) Synthesis of 2-oxooxazolidine-3-sulfonyl chloride

[0516] At 0°C, chlorosulfonic acid isocyanate (6.0 g, 42.25% mmol) was added to a solution of 2-bromoethane-1-ol (5.3 g, 42.25 mmol) in DCM (30 mL) and stirred at room temperature for 3 hours. The mixed reaction solution was directly used for the next reaction.

[0517] 2) Synthesis of N-(4-chloro-2-fluorophenyl)-2-oxoxazolidine-3-sulfonamide

[0518] To a solution of 4-chloro-2-fluoroaniline (2 g, 13.7 mmol) in DCM (40 mL) was added TEA (2.76 g, 27.4 mmol) and 2-oxooxazolidine-3-sulfonyl chloride (7.6 g, 41.1 mmol) at 0°C, and the mixture was stirred at room temperature for 3 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (PE / EA = 3:1) to give a crude product. The crude product was purified by reverse phase flash 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 to 32% B in 25 min; detector: 254 nm) to give N-(4-chloro-2-fluorophenyl)-2-oxoxazolidine-3-sulfonamide (300 mg, 1.01 mmol, yield: 7.42%), LCMS m / z: 295 [M+H] + .

[0519] 3) Synthesis of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate

[0520] To a solution of tert-butyl (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzofuran-7-yl)azetidin-3-yl)carbamate (1 g, 1677 mmol) in EA (100 mL) were added Pd / C (300 mg) and Pd(OH)2 (300 mg). The mixed reaction solution was concentrated under reduced pressure to give tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate (650 mg, crude product). LCMS m / z: 420 [M+H] + .

[0521] 4) Synthesis of 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione

[0522] To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)carbamate (650 mg, 1.55 mmol) in DCM (20 mL) was added TFA (4 mL), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by reverse 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 to 11% B, retention time: 6.5 min of 25 min; detector: 254 nm) to give 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (460 mg, 1.44 mmol, yield: 93.03%), LCMS m / z: 320 [M+H] + .

[0523] 5) Synthesis of N-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)4-chloro-2-fluoroaniline-1-sulfonamide

[0524] To a solution of 3-(7-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (250 mg, 0.78 mmol) in 1.4-dioxane (5 mL) was added N-(4-chloro-2-fluorophenyl)-2-oxooxazolidine-3-sulfonamide (345 mg, 1.17 mmol) and DMAP (380 mg, 3.12 mmol) at room temperature. The mixture was heated at 100°C with stirring for 2 hours. The mixed reaction solution was diluted with water (50 mL) 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% to 20%) to give compound MRANK-103-003 (50 mg, 0.09 mmol, yield: 12.16%), LCMS m / z: 527 [M+H] + .

[0525] 6) Preparation of N-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)4-chloro-2-fluoroaniline-1-sulfonamide and its isomers (MRANK-103-003-1 and MRANK-103.003-2):

[0526] Compound MRANK-103-003 (50 mg, 0.09 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Two isomers, MRANK-103-003-1 and MRANK-103.003-2, were prepared by column size: 250*30 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0 mol / l ammonia in MeOH), A:B = 55:45; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; column pressure: 100 bar; injection volume: 6.5 mL; cycle time: 8.5 min.

[0527] 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] + .

[0528] 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.

[0529] 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] + .

[0530] 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.

[0531] Example 15. Synthesis of (R)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea or its S-enantiomer (MRANK-103-004-1 and MRANK-103-004-2):

[0532] 1) Synthesis of 1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea

[0533] To a solution of 3-(7-(3-(3-aminoazetidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (80 mg, 0.25 mmol) in 1,4-dioxane (5 mL) was added phenyl (5-chloro-2-fluorophenyl)carbamate (80 mg, 0.3 mmol) and DMAP (40 mg, 0.3 mmol). The mixed reaction solution was quenched by adding water (50 mL) and extracted with EA (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by 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% to 52%; retention time: 7.7-8.6 min over 17 min) to afford 1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea (50 mg, 0.10 mmol, yield: 40.0%), LCMS m / z: 491 [M+H] + .

[0534] 2) Synthesis of (R)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea or the S-enantiomer

[0535] Compound 1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea (50 mg, 0.101 mmol) was purified by supercritical fluid chromatography (SFC): (Conditions: System: SHIMADZU SHIMADDU LC-20AP; column name: REGIS (S, S) WHELK-O1 column dimensions: 250*25 mm, 10 μm; mobile phase A: EtOH (+0.1% 7.0 mol / l ammonia in MeOH); mobile phase B: ACN; A:B = 70:30; detection wavelength: 214 nm; flow rate: 40 mL / min; column temperature: RT; back pressure: 100 bar, injection: 4.0 mL; cycle time: 5 minutes) was used to obtain two isomers: MRANK-103-004-1 and MRANK-103-004-2:

[0536] MRANK-103-004-1: Peak 1, Chiral HPLC: 3.062 min; (R)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea or enantiomer (0.95 mg, 0.0019 mmol, yield: 1.91%), LCMS m / z: 491 [M+H] + .

[0537] 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.

[0538] MRANK-103-004-2: Peak 2, Chiral HPLC: 4.868 min; (S)-1-(5-chloro-2-fluorophenyl)-3-(1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl)urea or enantiomer (1.30 mg, 0.0026 mmol, yield: 2.62%), LCMS m / z: 491 [M+H] + .

[0539] 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.

[0540] Example 16. Synthesis of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate and its enantiomers (MRANK-103-005-1 and MRANK-103-005-2):

[0541] 1) Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate

[0542] To a solution of 3-(5-fluoro-7-(3-hydroxyazetidin-1-yl)-2,3-dihydrobenzofuran-4-yl)piperidine-2,6-dione (100 mg, 0.31 mmol) in 1,4-dioxane (5.0 mL) was added phenyl (5-chloro-2-fluorophenyl)carbamate (122 mg, 0.46 mmol) and DMAP (60 mg, 0.46 mmol) at room temperature. The mixture was heated at 90°C and stirred for 16 hours. LCMS showed 12.8% of the desired product. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (Waters 3767 / Oda, column: XBridge C18, 19*250 mm, 10 um; mobile phase A: 30 mmol / L% TFA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 36% to 42%; retention time: 6.8-7.4 min, 17 min) to give 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate

[0543] (75 mg, 0.15 mmol, yield: 48.8%), LCMS m / z: 492 [M+H] + .

[0544] 2) Synthesis of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate and its enantiomers (MRANK-103-005-1 and MRANK-103-005-2)

[0545] The compound 1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate (75 mg, 0.15 mmol) was purified by SFC (conditions: system: SHIMADZU LC-20AP; column name: Chromatographic column size: 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) to obtain two isomers: MRANK-103-005-1 and MRANK-103-005-2:

[0546] MRANK-103-005-1: Peak 1: Chiral HPLC: 2.997 min; Compound (R)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate or enantiomer (8.45 mg, 0.017 mmol, yield: 11.27%), LCMS m / z: 492 [M+H] + .

[0547] 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).

[0548] 19 F NMR(377MHz,DMSO-d6)δ-126.082,-126.436.

[0549] MRANK-103-005-2: Peak 2: Chiral HPLC: 3.210 min: (S)-1-(4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)azetidin-3-yl (5-chloro-2-fluorophenyl)carbamate or enantiomer (7.63 mg, 0.016 mmol, yield: 10.17%), LCMS m / z: 492 [M+H] + .

[0550] 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).

[0551] 19 F NMR(377MHz,DMSO-d6)δ-126.072,-126.401.

[0552] Example 17. Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydro-2H-furo[2,3-e]isoindol-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0553] 1) Synthesis of methyl 2,3-dihydrobenzofuran-6-carboxylate

[0554] To a solution of methyl benzofuran-6-carboxylate (10.00 g, 56.82 mmol) in methanol (100 mL) was added palladium on carbon (5.90 g) at room temperature. The mixture was stirred at room temperature for 16 hours under hydrogen protection. The mixed reaction solution 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] + .

[0555] 2) Synthesis of methyl 7-nitro-2,3-dihydrobenzofuran-6-carboxylate

[0556] At 0 ° C, to a solution of methyl 2,3-dihydrobenzofuran-6-carboxylate (6.90 g, 38.76 mmol) in dichloromethane (69 mL), fuming nitric acid (3.45 mL) and acetic anhydride (34.5 mL) were slowly added dropwise, and stirred at 0 ° C for 0.5 hours under a nitrogen atmosphere. The mixture was slowly poured into ice water and extracted with ethyl acetate (100 mL × 2). The combined organic phase was 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%).

[0557] 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).

[0558] 3) Synthesis of methyl 7-amino-2,3-dihydrobenzofuran-6-carboxylate

[0559] At room temperature, palladium carbon (3.73 g) was added to a solution of methyl 7-nitro-2,3-dihydrobenzofuran-6-carboxylate (6.33 g, 28.38 mmol) in methanol (100 mL). The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The mixed reaction solution 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] + .

[0560] 4) Synthesis of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-6-carboxylate

[0561] To a solution of methyl 7-amino-2,3-dihydrobenzofuran-6-carboxylate (4.87 g, 25.23 mmol) in carbon tetrachloride (100 mL) at 0°C was added N-bromosuccinimide (6.74 g, 37.85 mmol) and stirred at room temperature under nitrogen for 3 hours. The mixed reaction solution 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] + .

[0562] 5) Synthesis of methyl 4-bromo-7-iodo-2,3-dihydrobenzofuran-6-carboxylate

[0563] 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) at 0°C was added a solution of sodium nitrite (355 mg, 5.15 mmol) in water (3 mL). The mixture was stirred at 0°C for 1 hour. Then, a solution of potassium iodide (3.05 g, 18.40 mmol) in water (12 mL) was added at 0°C and stirred 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 give methyl 4-bromo-7-iodo-2,3-dihydrobenzofuran-6-carboxylate (594 mg, 1.55 mmol, yield: 42.1%).

[0564] 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).

[0565] 6) Synthesis of methyl 4-bromo-7-vinyl-2,3-dihydrobenzofuran-6-carboxylate

[0566] 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) at room temperature were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (638 mg, 4.14 mmol), potassium carbonate (857 mg, 4.62 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (171 mg, 0.15 mmol). The mixed reaction solution was sealed in a tube and heated at 70°C under nitrogen with stirring for 16 hours. The mixed reaction solution was 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 give methyl 4-bromo-7-vinyl-2,3-dihydrobenzofuran-6-carboxylate (580 mg, 2.05 mmol, yield: 99%), LCMS m / z: 283 [M+H] + .

[0567] 7) Synthesis of methyl 4-bromo-7-formyl-2,3-dihydrobenzofuran-6-carboxylate

[0568] At room temperature, sodium periodate (2.21 g, 10.25 mmol) and potassium osmate dihydrate (33 mg, 0.10 mmol) were added to a solution of 4-bromo-7-vinyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (580 mg, 2.05 mmol) in tetrahydrofuran (10 mL) / water (10 mL), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution 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 4-bromo-7-formyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (150 mg, 0.53 mmol, yield: 25.68%), LCMS m / z: 285 [M+H] + .

[0569] 8) Synthesis of 3-(4-bromo-6-oxo-2,3,6,8-tetrahydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0570] To a solution of 3-amino-2,6-piperidinedione hydrochloride (228 mg, 1.38 mmol) in dichloromethane (10 mL) at room temperature were added triethylamine (600 μL), methyl 4-bromo-7-formyl-2,3-dihydrobenzofuran-6-carboxylate (130 mg, 0.46 mmol), sodium acetate borohydride (195 mg, 0.92 mmol), and glacial acetic acid (1.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reverse 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 to 50% B in 12 min; detector: 254 nm). When the mobile phase B content reached 45%, the fraction containing the product was collected and concentrated under reduced pressure to obtain the compound 3-(4-bromo-6-oxo-2,3,6,8-tetrahydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (70 mg, 0.19 mmol, yield: 42.16%). LCMS m / z: 365.0 [M+H] + .

[0571] 9) Synthesis of 3-(4-(hydroxymethyl)-6-oxo-2,3,6,8-tetrahydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0572] To a solution of 3-(4-bromo-6-oxo-2,3,6,8-tetrahydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (70 mg, 0.19 mmol) in 1,4-dioxane (5 mL) at room temperature was added (tributylstannyl)methanol (1.22 g, 3.80 mmol) and tetrakistriphenylphosphine palladium (102 mg, 0.10 mmol). The mixture was heated at 100°C with stirring for 16 hours under nitrogen. The reaction mixture was 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-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (50 mg, 0.16 mmol, yield: 82.5%), LCMS m / z: 317 [M+H] +

[0573] 10) Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydro-2H-furo[2,3-e]isoindol-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0574] To a solution of 3-(4-(hydroxymethyl)-6-oxo-2,3,6,8-tetrahydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (50 mg, 0.16 mmol) in 1,4-dioxane (5 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (60 mg, 0.192 mmol) and 4-dimethylaminopyridine (23 mg, 0.192 mmol) at room temperature. The mixture was heated at 90°C with stirring for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by reverse 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 to 60% B in 12 min; detector: 254 nm). When the mobile phase B content reached 50%, the fractions containing the product were collected and concentrated under reduced pressure to give the compound (7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydro-2H-furo[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] + .

[0575] 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).

[0576] 19 F NMR(377MHz,DMSO-d6)δ-57.23,-126.07.

[0577] Example 18. Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (C101-N110):

[0578] 1) Synthesis of methyl 4-bromoindoline-6-carboxylate

[0579] At 0 ° C, triethylsilane (13.73 g, 118.05 mmol) was slowly added to a solution of 4-bromo-1H-indole-6-carboxylic acid methyl ester (20 g, 78.7 mmol) in 2,2,2-trifluoroacetic acid (200 mL), and the mixture was heated at 60 ° C and stirred for 2 hours. The mixed reaction solution 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 solution was washed with saturated brine (300 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 = 15 / 1) to give 4-bromoindoline-6-carboxylic acid methyl ester (15.0 g, 58.6 mmol, yield: 74.5%), LCMS m / z: 256 [M+H] + .

[0580] 2) Synthesis of methyl 4-bromo-7-iodoindoline-6-carboxylate.

[0581] 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 heated to 80 ° C with stirring for 0.5 hours. The mixed reaction solution 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] + .

[0582] 3) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylate

[0583] 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 dichloromethane (20 mL). The mixture was heated at 60°C and stirred for 16 hours. The mixed reactants were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 1-(tert-butyl) 6-methyl 4-bromo-7-iodoindoline-1,6-dicarboxylate (750 mg, 1.56 mmol, yield: 85%) as a yellow solid. LCMS: m / z: 382 [M+H-100] + .

[0584] 4) Synthesis of 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylate

[0585] To a mixed solution of 1-(tert-butyl)-6-methyl-4-bromo-7-iodoindoline-1,6-dicarboxylate (750 mg, 1.56 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) at room temperature were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (480 mg, 3.12 mmol), potassium carbonate (646 mg, 4.68 mmol), and Pd(dppf)Cl2.CH2Cl2 (600 mg, 0.82 mmol). The mixture was heated to 70°C under nitrogen in a sealed tube and stirred for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylate (360 mg, 0.942 mmol, yield: 60.4%), LCMS m / z: 326 [M+H-56] + .

[0586] 5) Synthesis of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester)

[0587] To a solution of 1-(tert-butyl) 6-methyl-4-bromo-7-vinylindoline-1,6-dicarboxylate (360 mg, 0.942 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added NaIO4 (1.0 g, 4.71 mmol) and K2OsO4 (17 mg, 0.047 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixed reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 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 6-methyl 4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) (100 mg, 0.26 mmol, yield: 27.7%), LCMS m / z: 328 [M+H-56] + .

[0588] 6) Synthesis of tert-butyl 4-bromo-7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate

[0589] To a solution of 6-methyl-4-bromo-7-formylindoline-1,6-dicarboxylic acid (1-tert-butyl ester) (100 mg, 0.26 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (128 mg, 0.78 mmol) in dichloromethane (10 mL) were added triethylamine (0.5 mL), sodium triacetoxyborohydride (110 mg, 0.52 mmol), and acetic acid (1 mL). 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 tert-butyl 4-bromo-7-(2,6-dioxopiperidin-3-yl)-6-oxo-3,6,7,8-tetrahydropyrrolo[3,4-g]indole-1(2H)-carboxylate (80 mg, 0.172 mmol, yield: 66.3%). LCMS m / z: 464 [M+H] + .

[0590] 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

[0591] 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)-carboxylate (80 mg, 0.172 mmol) in 1,4-dioxane (8 mL) was added (tributylstannyl)methanol (1.1 g, 3.45 mmol) and Pd(PPh3)4 (88 mg, 0.086 mmol). Under nitrogen, the mixture was heated at 100°C in a sealed tube with stirring for 16 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol=10 / 1) to give tert-butyl 7-(2,6-dioxopiperidin-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 [M+H] +

[0592] 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)-carboxylate

[0593] To a solution 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 (60 mg, 0.144 mmol) in 1,4-dioxane (3.0 mL) was added phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (46 mg, 0.144 mmol) and 4-dimethylaminopyridine (20 mg, 0.158 mmol) at room temperature, and the mixture was heated at 90°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 100% B in 15 min; detector: 254 nm). When the mobile phase B content reached 75%, the fractions containing the product were collected and concentrated under reduced pressure to give compound 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, yield: 54.5%), LCMS m / z: 637 [M+H] +

[0594] 9) Synthesis of (7-(2,6-dioxopiperidin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (C101-N110)

[0595] To a solution 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)-carboxylate (50 mg, 0.078 mmol) in dichloromethane (3.0 mL) was added 2,2,2-trifluoroacetic acid (1.0 mL) and stirred at room temperature for 1 hour. The mixed reaction solution 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 x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 100% B in 15 min; detector: 254 nm). When the mobile phase B content reached 60%, the fractions containing the product were collected and concentrated under reduced pressure. Compound (7-(2,6-dioxopiperidin-3-yl)-6-oxo-1,2,3,6,7,8-hexahydropyrrolo[3,4-g]indol-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (19.09 mg, 0.0356 mmol, yield: 45.6%), LCMS m / z: 578 [M+41+H]. +

[0596] 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).

[0597] 19F NMR(377MHz,DMSO-d6)δ-57.197,-125.995.

[0598] Example 19. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-furo[3,2-e]isoindol-5-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (C101-N200):

[0599] 1) Synthesis of methyl 5-bromo-4-hydroxy-2-methylbenzoate

[0600] 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). 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 phase was 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] + .

[0601] 2) Synthesis of methyl 5-bromo-4-(2,2-dimethoxyethoxy)-2-methylbenzoate

[0602] To a solution of methyl 5-bromo-4-hydroxy-2-methylbenzoate (6.20 g, 25.31 mmol) in N,N-dimethylformamide (70 mL) was added 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) at room temperature. The mixture was heated at 100°C with stirring for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 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%).

[0603] 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).

[0604] 3) Synthesis of methyl 7-bromo-4-methylbenzofuran-5-carboxylate

[0605] To a solution of methyl 5-bromo-4-(2,2-dimethoxyethoxy)-2-methylbenzoate (3.60 g, 10.81 mmol) in chlorobenzene (50 mL) at room temperature was added PPA (3.60 g), and the mixture was heated at 130°C with stirring for 3 hours. The mixed reaction solution 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%).

[0606] 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).

[0607] 4) Synthesis of methyl 7-bromo-4-(bromomethyl)benzofuran-5-carboxylate

[0608] To a solution of methyl 7-bromo-4-methylbenzofuran-5-carboxylate (1.30 g, 4.83 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.04 g, 5.80 mmol) and azobisisobutyronitrile (159 mg, 0.97 mmol) at room temperature, and the mixture was stirred at 80°C for 16 hours. The mixed reaction solution was collected, 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%).

[0609] 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).

[0610] 5) Synthesis of 3-(5-bromo-3-oxo-1,3-dihydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione

[0611] To a solution of methyl 7-bromo-4-(bromomethyl)benzofuran-5-carboxylate (1.50 g, 4.31 mmol) in acetonitrile (30 mL) was added 3-aminopiperidine-2,6-dione (1.41 g, 8.62 mmol) and N,N-diisopropylethylamine (1.00 g, 7.76 mmol) at room temperature. The mixture was heated at 80°C with stirring for 36 hours. The mixed reaction solution was quenched with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (300 mL x 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-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (1.50 g, 4.13 mmol, yield: 96.2%), LCMS m / z: 365 [M+2+H] + .

[0612] 6) Synthesis of 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione

[0613] At room temperature, to a solution of 3-(5-bromo-3-oxo-1,3-dihydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (200 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was added (tributyltin)methanol (3.51 g, 11.00 mmol) and Pd(PPh3)4 (285 mg, 0.28 mmol). Under nitrogen protection, the mixture was heated at 100°C with stirring for 16 hours. 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-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (80 mg, 0.25 mmol, yield: 45.5%), LCMS m / z: 315 [M+H] + .

[0614] 7) Synthesis of 2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-furo[3,2-e]isoindol-5-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0615] To a solution of 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (70 mg, 0.22 mmol) in 1,4-dihydroquinone (2 mL) at room temperature, 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 at 110°C with stirring for 3 hours. The mixed reaction solution was filtered and purified by reverse phase flash column chromatography (conditions as follows: chromatographic 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 to 95% B, 20 minutes; detector: 214 nm). Fractions containing the product at a concentration of 55% B were collected and concentrated under reduced pressure to give 3-(5-(hydroxymethyl)-3-oxo-1,3-dihydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (21.48 g, 0.04 mmol, yield: 18.2%), LCMS m / z: 558 [M+23]. + .

[0616] 1 H 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).

[0617] 19 F NMR(377MHz,DMSO-d6)δ-57.21,-125.88.

[0618] Example 20, Synthesis of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)methyl)-2,2-difluoroacetamide (C101-N201):

[0619] 1) Synthesis of methyl 7-(((tert-butyloxycarbonyl)amino)methyl)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate

[0620] At room temperature and under nitrogen atmosphere, Pd(dppf)Cl2 (519 mg, 0.71 mmol) and K2CO3 (1.46 g, 10.59 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL) containing methyl 7-bromo-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (1.00 g, 3.53 mmol) and potassium (((tert-butyloxycarbonyl)amino)methyl)trifluoroborate (2.51 g, 10.59 mmol). The mixture was heated at 100°C and stirred for 16 hours. LCMS showed 35% product formation. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 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 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] + .

[0621] 2) Synthesis of methyl 7-(((tert-butoxycarbonyl)amino)methyl)-4-formyl-2,3-dihydrobenzofuran-5-carboxylate

[0622] To a solution of methyl 7-(((tert-butoxycarbonyl)amino)methyl)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (670 mg, 2.01 mmol) in tetrahydrofuran (7 mL) and water (7 mL) at room temperature were added NaIO (2.17 mg, 10.05 mmol) and KOsO·2H O (74 mg, 0.20 mmol). The reaction 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 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] + .

[0623] 3) Synthesis of 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

[0624] To a solution of 3-aminopiperidine-2,6-dione hydrochloride (515 mg, 3.12 mmol) in dichloromethane (10 mL) at room temperature were added 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). The mixture was stirred at 30°C for 16 hours. LCMS showed 48% product formation. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (20 mL x 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-furo[3,2-e]isoindol-5-yl)methyl)carbamate (300 mg, 0.72 mmol, yield: 60.5%), LCMS m / z: 360 [M+H-56] + .

[0625] 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

[0626] At room temperature, 2,2,2-trifluoroacetic acid (6 mL) was added to a solution of 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 (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 mixed reaction solution was diluted with dichloromethane (20 mL) and concentrated under reduced pressure to give 3-(5-(aminomethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furan[3,2-e]isoindol-2-yl)piperidine-2,6-dione (250 mg, crude product), LCMS m / z: 357 [M+MeCN+H] + .

[0627] 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)

[0628] To a solution of 3-(5-(aminomethyl)-3-oxo-1,3,7,8-tetrahydro-2H-furo[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) in N,N-dimethylformamide (3 mL) was added DIEA (248 mg, 1.92 mmol) and HATU (547 mg, 1.44 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH 3 .H 2 O); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B-70% B over 20 minutes; detector: 254 nm). At 35% B, fractions containing the product were collected and concentrated under reduced pressure to give 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[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] + .

[0629] 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).

[0630] 19 F NMR(377MHz,DMSO-d6)δ-101.32.

[0631] Example 21, Synthesis of 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopyrimidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)methyl)urea (C101-N202):

[0632] To a solution of 3-(5-(aminomethyl)-3-oxo-1,3,3,7,8-tetrahydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (100 mg, 0.32 mmol) and 2-chloro-4-isocyanato-1-methylbenzene (54 mg, 0.32 mmol) in tetrahydrofuran (3 mL) was added triethylamine (129 mg, 1.28 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH 3 .H 2 O); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B to 70% B over 20 minutes; detector: 254 nm). At 30% B, fractions containing the product were collected and concentrated under reduced pressure to obtain 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopyrimidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)methyl)urea (33.98 mg, 0.07 mmol, yield: 22.1%). LCMS m / z: 483 [M+H] + .

[0633] 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).

[0634] Example 22, Synthesis of 2-(4-chlorophenyl)-N-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)methyl)-2,2-difluoroacetamide (C101-N203):

[0635] 1) Preparation of 5-bromo-3-hydroxy-2-methylbenzoic acid methyl ester

[0636] To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (18.40 g, 75.41 mmol) in 10% sulfuric acid (200 mL) at 0°C was added 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 at 100°C and stirred for 1 hour. The mixed reaction solution was quenched with water (300 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 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]+.

[0637] 2) Synthesis of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate

[0638] To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (10.00 g, 40.82 mmol) in N,N-dimethylformamide (100 mL) was added 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) at room temperature. The mixture was heated at 100°C and stirred for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 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%).

[0639] 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).

[0640] 3) Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylate

[0641] At room temperature, polyphosphoric acid (10.10 g) was added to a solution of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (10.10 g, 30.33 mmol) in xylene (100 mL), and the mixture was heated at 130 ° C and stirred for 16 hours. The mixed reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layer was 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%).

[0642] 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).

[0643] 4) Synthesis of methyl 4-cyano-7-methylbenzofuran-6-carboxylate

[0644] At room temperature, zinc cyanide (1.74 g, 14.88 mmol) and tetrakistriphenylphosphine palladium (428 mg, 0.37 mmol) were added to a solution of methyl 4-bromo-7-methylbenzofuran-6-carboxylate (2.00 g, 3.72 mmol) in NMP (10 mL). The mixture was heated at 140 ° C and stirred for 2 hours under a nitrogen atmosphere. The mixed reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layer was 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] + .

[0645] 5) Preparation of methyl 7-(bromomethyl)-4-cyanobenzofuran-6-carboxylate

[0646] At room temperature, NBS (1.29 g, 7.26 mmol) and AIBN (100 mg, 0.61 mmol) were added to a solution of methyl 4-cyano-7-methylbenzofuran-6-carboxylate (1.30 g, 6.05 mmol) in carbon tetrachloride (20 mL). The mixture was heated at 80°C and stirred for 16 hours. The mixed reaction solution 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] + .

[0647] 6) Synthesis of 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindole-4-carbonitrile

[0648] To a solution of methyl 7-(bromomethyl)-4-cyanobenzofuran-6-carboxylate (600 mg, 2.04 mmol) in DMA (10 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (1.01 g, 6.12 mmol) and sodium bicarbonate (514 mg, 6.12 mmol) at room temperature. The mixture was stirred at 80° C. under nitrogen for 16 hours. 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-furo[2,3-e]isoindole-4-carbonitrile (256 mg, 0.83 mmol, yield: 40.5%), LCMS m / z: 310 [M+H]. + .

[0649] 7) Synthesis of 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0650] To a solution of 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindole-4-carbonitrile (200 mg, 0.65 mmol) in DMA (15 mL) was added Pd / C (50 mg, 55% water content) and HCOOH (1.5 mL) at room temperature. The mixture was heated at 50°C with stirring for 30 min under a hydrogen atmosphere. The mixed reaction solution was filtered. The filtrate was collected, concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic conditions: system: Waters 2767 / QDA; column: Sunfire C18 19*250mm*10μm, flow rate: 20mL / min;: A-0.1% FA / H2O; mobile phase B: ACN: gradient 5-5%; retention time: 10.0-12.0-12.0=18min) to give 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (15 mg, 0.048mmol, yield: 7.35%), LCMS m / z: 297 [M-NH2] + .

[0651] 8) Synthesis of 2-(4-chlorophenyl)-N-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)methyl)-2,2-difluoroacetamide (C101-N203)

[0652] To a solution of 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (5 mg, 0.016 mmol) in DMF (1.0 mL) at room temperature were added 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), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was purified by preparative HPLC (chromatographic conditions: Waters 2767 / Qda, column: sunfire C18, 19*250*10 μm, 80 g; mobile phase A: 0.1% FA / H2O; mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 44-44% B; retention time 9.4-10.4 min of 16 min) to purify 2-(4-chlorophenyl)-N-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)methyl)-2,2-difluoroacetamide (1.31 mg, 0.0026 mmol, yield: 16%). LCMS m / z: 502 [M+H] + .

[0653] 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).

[0654] 19F NMR (377MHz, DMSO-d6): δ-101.561.

[0655] Example 23, Synthesis of 1-(3-chloro-4-methylphenyl)-3-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6-furo[2,3-e]isoindol-4-yl)methyl)urea (C101-N204):

[0656] To a solution of 3-(4-(aminomethyl)-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (10.0 mg, 0.032 mmol) in DMF (1.0 mL) at room temperature were added 2-chloro-4-isocyanato-1-toluene (8.0 mg, 0.048 mmol) and triethylamine (10.0 mg, 0.096 mmol), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was purified by preparative 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 16 min) to give 1-(3-chloro-4-methylphenyl)-3-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6-furo[2,3-e]isoindol-4-yl)methyl)urea (3.09 mg, 0.0064 mmol, yield: 19%), LCMS m / z: 481 [M+H] + .

[0657] 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).

[0658] Example 24. Synthesis of N-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)-2-(trifluoromethoxy)benzamide (C101-N205):

[0659] 1) Synthesis of methyl 5-bromo-3-hydroxy-2-methylbenzoate

[0660] At 0 ° C, a solution of methyl 3-amino-5-bromo-2-methylbenzoate (18.40 g, 75.41 mmol) in sulfuric acid (200 mL, 10% content) was added to a solution of sodium nitrite (5.20 g, 75.41 mmol) in water (5 mL), stirred at room temperature for 1 hour, and then sulfuric acid (200 mL, 50% content) was added at room temperature, heated to 100 ° C and stirred for 1 hour. The mixed reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic phase was 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] + .

[0661] 2) Synthesis of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate

[0662] To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (10.00 g, 40.82 mmol) in N,N-dimethylformamide (100 mL) was added 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) at room temperature. The mixture was heated at 100°C and stirred for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 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%).

[0663] 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).

[0664] 3) Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylate

[0665] To a solution of methyl 5-bromo-3-(2,2-dimethoxyethoxy)-2-methylbenzoate (10.10 g, 30.33 mmol) in xylene (100 mL) at room temperature was added polyphosphoric acid (10.10 g), heated at 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%).

[0666] 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).

[0667] 4) Synthesis of methyl 4-((tert-butyloxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate

[0668] To a solution of methyl 4-bromo-7-methylbenzofuran-6-carboxylate (1.00 g, 3.72 mmol) in 1,4-dioxane (10 mL) was added 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) at room temperature. The mixture was stirred at 90°C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 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 give methyl 4-((tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (563 mg, 1.02 mmol, yield: 49.8%), LCMS m / z: 250 [M-56+H] + .

[0669] 5) Synthesis of methyl 4-(bis(tert-butyloxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate

[0670] To a solution of methyl 4-((tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (1.00 g, 3.28 mmol) in tetrahydrofuran (20 mL) was added di-tert-butyl dicarbonate (1.43 g, 6.56 mmol) and 4-dimethylaminopyridine (40 mg, 0.33 mmol) at room temperature. The mixture was heated at 80°C with stirring for 16 hours. The mixed reaction solution 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-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (985 mg, 2.43 mmol, yield: 74.0%).

[0671] 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).

[0672] 6) Synthesis of methyl 4-(bis(tert-butyloxycarbonyl)amino)-7-(bromomethyl)benzofuran-6-carboxylate

[0673] To a solution of methyl 4-(bis(tert-butoxycarbonyl)amino)-7-methylbenzofuran-6-carboxylate (985 mg, 2.43 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (520 mg, 2.92 mmol) and azobisisobutyronitrile (39 mg, 0.24 mmol) at room temperature, and the mixture was heated at 80°C with stirring for 16 hours. The mixed reaction solution 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%).

[0674] 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).

[0675] 7) Synthesis of di-tert-butyl (7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)iminodicarbonate

[0676] To a solution of methyl 4-(bis(tert-butoxycarbonyl)amino)-7-(bromomethyl)benzofuran-6-carboxylate (300 mg, 0.62 mmol) in acetonitrile (10 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (203 mg, 1.24 mmol) and DIEA (160 mg, 1.24 mmol) at room temperature. The mixture was heated at 80°C with stirring for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 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 di-tert-butyl (7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)imidodicarbonate (163 mg, 0.33 mmol, yield: 52.5%), LCMS m / z: 400 [M-100+H] + .

[0677] 8) Synthesis of 3-(4-amino-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione

[0678] To a solution of di-tert-butyl (7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)imidodicarbonate (140 mg, 0.28 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure to afford 3-(4-amino-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (84 mg, 0.28 mmol, yield: >99%), LCMS m / z: 300 [M+H]+.

[0679] 9) Synthesis of N-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)-2-(trifluoromethoxy)benzamide (C101-N205)

[0680] To a solution of 3-(4-amino-6-oxo-6,8-dihydro-7H-furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (84 mg, 0.28 mmol) in N,N-dimethylformamide (2 mL) was added 2-(trifluoromethoxy)benzoic acid (87 mg, 0.0.42 mmol), HATU (106 mg, 0.28 mmol), and DIEA (36 mg, 0.28 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by preparative HPLC (system: Waters 2767 / QDA; column: Sunfire C18 19*250*10 μm; 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 over 16 min) to give N-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-6H-furo[2,3-e]isoindol-4-yl)-2-(trifluoromethoxy)benzamide (27.13 mg, 0.056 mmol, yield: 19.8%), LCMS m / z: 488 [M+H] + .

[0681] 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).

[0682] 19F NMR (377MHz, DMSO-d6): δ-56.51

[0683] Example 25. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)-2-(trifluoromethoxy)benzamide (C101-N206):

[0684] 1) Synthesis of methyl 7-nitro-2,3-dihydrobenzofuran-5-carboxylate

[0685] To a solution of methyl 2,3-dihydrobenzofuran-5-carboxylate (25.0 g, 140.45 mmol) in acetic anhydride (300 mL) was added fuming nitric acid (17.98 g, 280.90 mmol) at 0°C. The mixture was stirred at room temperature under nitrogen for 16 hours. The mixed reaction solution 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]+.

[0686] 2) Synthesis of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate

[0687] To a solution of 7-nitro-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester (21.5 g, 96.41 mmol) in ethanol (400 mL) and water (80 mL) was added iron (53.99 g, 964.1 mmol) and NH4Cl (51.10 g, 964.1 mmol), heated at 100 ° C and stirred for 3 hours. The mixed reaction liquid was filtered and the filtrate was collected. The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1, R f =0.6) to give methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (18.0 g, 93.26 mmol, yield: 96.7%), LCMS m / z: 235 [M+MeCN] + .

[0688] 3) Synthesis of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate

[0689] To a solution of methyl 7-amino-2,3-dihydrobenzofuran-5-carboxylate (5.0 g, 25.91 mmol) in N,N-dimethylformamide (50 mL) at 0°C was added NBS (4.82 g, 27.20 mmol) and stirred at 0°C for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was 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 to 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] + .

[0690] 4) Synthesis of methyl 4-bromo-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate

[0691] To a solution of methyl 7-amino-4-bromo-2,3-dihydrobenzofuran-5-carboxylate (1.0 g, 3.7 mmol) in N,N-dimethylformamide (30 mL) was added 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) at room temperature. The mixture was heated at 30°C and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 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] + .

[0692] 5) Synthesis of methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate

[0693] To a solution of methyl 4-bromo-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate (400 mg, 0.87 mmol) in 1,4-dioxane (10 mL) and HCl (2.0 mL) were added potassium trifluoro(vinyl)borate (233 mg, 1.74 mmol), Pd(dppf)Cl2 (318 mg, 0.435 mmol), and K2CO3 (360 mg, 2.61 mmol). The mixture was heated at 80°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and quenched with saturated sodium bicarbonate (50 mL), followed by extraction with ethyl acetate (50 mL x 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 to 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] + .

[0694] 6) Synthesis of methyl 4-formyl-7-(2-(trifluoromethoxy)benzamido)-2,3-dihydrobenzofuran-5-carboxylate

[0695] To a solution of methyl 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylate (300 mg, 0.74 mmol) in tetrahydrofuran (30 mL) and water (6 mL) was added K₂OsO₄ (63 mg, 0.17 mmol) and stirred at room temperature for 20 min. NaIO₄ (736 mg, 3.44 mmol) was then added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was then extracted with ethyl acetate (10 mL x 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] + .

[0696] 7) Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)-2-(trifluoromethoxy)benzamide (C101-N206)

[0697] At room temperature, 7-(2-(trifluoromethoxy)benzamido)-4-vinyl-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester was dissolved in

[0698] To a solution of 2,6-dione (80 mg, 0.19 mmol) in dichloromethane (2 mL) were added 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), and the mixture was stirred at 25°C for 2 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (system: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 um; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 40% to 45%; retention time: 7.8-8.2 min (17 min)) to give N-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3,7,8-tetrahydro-1H-furo[3,2-e]isoindol-5-yl)-2-(trifluoromethoxy)benzamide (11.14 mg, 0.023 mmol, yield: 11.65%), LCMS m / z: 490 [M+H] + .

[0699] 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).

[0700] 1 F NMR (400 MHz, DMSO-d6) δ 56.45

[0701] Example 26. Synthesis of 6-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)benzofuran-4-yl)methyl ((2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (C101-N300):

[0702] 1) Synthesis of ethyl 4-hydroxybenzofuran-6-carboxylate

[0703] At room temperature and under nitrogen protection, sodium ethoxide (9.45 g, 139.0 mmol) was added to ethanol (150 mL) containing furan-2-carboxaldehyde (6.0 g, 62.5 mmol) and diethyl succinate (13.7 g, 78.9 mmol) and refluxed for 4 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 1-3 with aqueous hydrochloric acid solution (3 M) and extracted with ethyl acetate (3x100 mL). The combined organic phase was washed with water (2×45 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 heated at 160° C. with stirring for 8 hours. After the reaction was complete, the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (25 mL) and H₂O (15 mL) and concentrated under reduced pressure to remove excess acetic anhydride. Ethyl acetate (80 mL) and aqueous Na₂CO₃ (25 mL, 10%) were then added for dilution. The organic phase was collected and the aqueous phase was extracted with ethyl acetate (2 x 40 mL). The combined organic phases were washed with H₂O (2 x 35 mL) and saturated brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (100 mL) was added for dissolution, followed by potassium carbonate (20.34 g, 147.4 mmol) and heated under reflux for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and the solvent was removed by concentration under reduced pressure. The residue was neutralized with aqueous hydrochloric acid (3 M) and extracted with ethyl acetate (2 x 75 mL). The combined organic phases were washed with water (2 x 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] + .

[0704] 2) Synthesis of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-carboxylate

[0705] To a solution of ethyl 4-hydroxybenzofuran-6-carboxylate (1.5 g, 7.28 mmol) dissolved in DMF (20.0 mL) were added triethylamine (1.47 g, 14.56 mmol) and NPTF (3.90 g, 10.92 mmol) and stirred at 25 ° C for 16 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (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] + .

[0706] 3) Synthesis of ethyl 4-hydroxymethylbenzofuran-6-carboxylate

[0707] At room temperature, to a solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-carboxylate (1.4 g, 4.14 mmol) and (tributyltinyl)methanol (6.64 g, 20.7 mmol) in 1,4-dioxane (20.0 mL) was added Pd(PPh3)4 (478 mg, 0.414 mmol) and heated at 100 ° C with stirring for 16 hours. The mixed reaction solution 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 80%) to give ethyl 4-hydroxymethylbenzofuran-6-carboxylate (470 mg, 2.14 mmol, yield: 51.6%), LCMS m / z: 221 [M+H] + .

[0708] 4) Synthesis of ethyl 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylate

[0709] To ethyl 4-hydroxymethylbenzofuran-6-carboxylate (470 mg, 2.14 mmol) dissolved in 1,4-dioxane (10 mL) was added DMAP (314 mg, 2.57 mmol) and phenyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (674 mg, 2.14 mmol) at room temperature, and the mixture was heated at 90°C with stirring for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 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%).

[0710] 5) Synthesis of 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylic acid

[0711] To ethyl 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylate (450 mg, 1.02 mmol) dissolved in tetrahydrofuran (10 mL) and ethanol (2 mL) was added sodium hydroxide (82 mg, 2.04 mmol) at room temperature, and the mixture was heated at 80°C with stirring for 2 hours. The mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 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 HPLC (chromatographic conditions: system: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 um; mobile phase A: 0.1% TFA / H2O, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 62% to 68%; retention time: 20-23 min of 30 min) to give 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylic acid (300 mg, 0.72 mmol, yield: 71.1%).

[0712] 6) Synthesis of 6-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)benzofuran-4-yl)methyl ((2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (C101-N300)

[0713] To a solution of 4-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)benzofuran-6-carboxylic acid (60 mg, 0.15 mmol) and 3-(methylamino)piperidine-2,6-dione (22 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (97 mg, 0.75 mmol) and HATU (86 mg, 0.225 mmol). 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 x 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 HPLC (system: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 um; mobile phase A: 0.1% FA / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 44% to 46%; retention time: 7.1-8.0 min of 17 min) to give 6-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)benzofuran-4-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (22.16 mg, 0.041 mmol, yield: 28.4%).

[0714] LCMS m / z:560[M+Na] + .

[0715] 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).

[0716] 19 F NMR(377MHz,DMSO-d6)δ-57.216,-125.766.

[0717] Example 27. Synthesis of (5-((2,6-dioxopiperidin-3-yl)(methyl)carbamoyl)-2,3-dihydrobenzofuran-7-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate (C101-N301):

[0718] 1) Synthesis of methyl 7-bromo-2,3-dihydrobenzofuran-5-carboxylate

[0719] To 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 a solution of sodium nitrite (2.2 g, 31.0 mmol) in water (20.0 mL) at 0°C and stirred at room temperature for 2 hours. Cuprous bromide (7.4 g, 52.0 mmol) was then added to the reaction mixture, and the mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was 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 to 10: 1) to give methyl 7-bromo-2,3-dihydrobenzofuran-5-carboxylate (2.3 g, 8.98 mmol, yield: 34.6%).

[0720] 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).

[0721] 2) Synthesis of methyl 7-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate

[0722] 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 1,4-dioxane (20.0 mL) was heated at 100°C under nitrogen and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered to reduce pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 to 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] + .

[0723] Synthesis of methyl 7-((((2-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)oxy)methyl)-2,3-dihydrobenzofuran-5-carboxylate

[0724] 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 1,4-dioxane (20.0 mL) was added DMAP (600 mg, 4.9 mmol) at room temperature. The mixture was heated at 90°C under nitrogen and stirred for 16 hours. The mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 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 (petroleu...

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, solvate, enantiomer or isotope-substituted product thereof, in, A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spirocyclic ring or a bridged ring structure; It is a fragment structure capable of binding to ubiquitinated proteins or chaperone proteins, and is preferably selected from the following structures: in, Any represents a single bond or a 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; 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-, olefinic bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH; L1 and L2 are independently selected from the group consisting of absence, a 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 ), olefin bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocyclic alkyl is connected to the A or B ring, and the other end is connected to Z; Y is independently selected from O, S or =NR0; Each R0 may be the same or different and is independently selected from hydrogen, deuterium, C 1-10 Alkoxy, C 1-10 Alkylthio, C 1-10 Alkylamino, -CN, sulfur pentafluoride, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 , C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH; Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by 1 to more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl groups are substituted. Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution; Every R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 and R d9 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, sulfur 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein said 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by 1 to more than one atom selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups; The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; 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 arbitrarily selected from an integer of 0, 1, 2, 3, 4 and 5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (IA) or formula (IB), Wherein, A, B, C, L1, L2, R1, R2, R3, m, n, t independently have the definitions in claim 1; Every R d1 , R d2 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, sulfur 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein said 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by 1 to more than one atom selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups; The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; 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 arbitrarily selected from an integer of 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 or 2, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product thereof, characterized in that: It has the structure of formula (IC), formula (ID) or formula (IE), Wherein, A, R1, R2, R3, L1, L2, m, n, t, and p are independently defined as in claim 1 or 2; L0 is independently selected from the group consisting of absence, a single bond, -C(=O)N(R0)-, -N(R0)-, -C(=NR d5 )-, -O-, -S-, -N(R0)C(=O)-; Any represents 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; L3 is selected from the group consisting of absence, a 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 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 ), olefin bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl and heterocyclic alkyl is connected to the A ring and the other end is connected to C=O.

4. The compound according to any one of claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (IF), Among them, A, B, C, R1, R2, R3, R d1 , R d2 , m, n, t, p, q independently have the definitions as described in any one of claims 1-3.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (1-IC), in, A is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spirocyclic ring or a bridged ring structure; L1 and L2 are independently selected from the group consisting of absence, a 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 )-, olefinic bond, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein one end of the aryl, heteroaryl, cycloalkyl, heterocyclic alkyl is connected to the A or B ring, and the other end is connected to Z; X is independently selected from O, S or =NR0; R0 is independently selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d1 R d2 , C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl group and 5-8 membered heteroaryl group; wherein the hydrogen on R0 is further optionally substituted by 1 to more substituents, and 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 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH; Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate, most preferably, the carboxyl surrogate is: The hydrogen on R1 is preferably replaced by 1 to 1 or more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl groups are substituted. Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2- 10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3- 10 Heterocyclic hydrocarbon substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution; R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 and R d9 may be the same or different and are independently selected from hydrogen, deuterium, halogen, 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein said 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by 1 to more than one atom selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups; The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; 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 arbitrarily selected from an integer of 0, 1, 2, 3, 4 and 5. If and only if R d1 and R d2 When they are both hydrogen, R2 is not hydrogen and n is not 0, or R1 is sulfur pentafluoride.

6. The compound according to any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has a structure of formula (1-ID), formula (1-IE), formula (1-IF) or formula (2-IF), Among them, A, L1, L2, L3, R1, R2, R3, R d1 , X1, X2, m, n, t, p independently have the definitions in any one of claims 1 to 5; D is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spirocyclic ring or a bridged ring structure; Preferably, it has the structure of formula (IG) or (IH), in, Any independently represents a single bond or a double bond; L1 and L2 are independently selected from the group consisting of absence, a 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, acetylenic bond, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein One end of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is connected to the A or B ring, and the other end is connected to Z; Y is independently selected from O, S or =NR0; Each R1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -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, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl 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 or carboxyl surrogate; wherein the hydrogen on R1 is optionally replaced by 1 to more selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1s together with the atoms to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, sulfur pentafluoride, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl groups are substituted. Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; wherein the hydrogen on R2 is optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, -CN, pentafluorinated sulfur, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; Each R3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, CN, sulfur pentafluoride, 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 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon substituted C 1-10 wherein the hydrogen on R3 is optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution; Every R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 and R d9 may be the same or different and are independently selected from hydrogen, deuterium, halogen, CN, sulfur 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein said 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 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by 1 to more than one atom selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups; The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; 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 arbitrarily selected from an integer of 0, 1, 2, 3, 4 and 5. p is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

7. The compound according to claims 1-6, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure shown in formula (II): Wherein, ring B is selected from 5-14 membered heterocyclyl and 5-14 membered heteroaryl; L2 is selected from unsubstituted or optionally substituted with one, two or more R L Substituted with the following groups: 1-6 Alkyl, 3-8 membered heterocyclic group; each R L The same or different, independently selected from C 1-6 Alkyl, C 1-6 Alkoxy; L3 is selected from O, NR L31 , C(R L32 )(R L33 );R L31 , R L32 , R L33 The same or different, independently selected from H, 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, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R2 is selected from H, halogen, oxo (=O), 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, 5; Preferably, ring B is selected from a 9-12 membered heterocyclic group and a 9-12 membered heteroaryl group; the heterocyclic group may be a condensed ring formed by at least two of a dihydropyrrole ring, a dihydrofuran ring, a tetrahydropyrrole ring, a tetrahydrofuran ring and a benzene ring; the heteroaryl group may be a condensed ring formed by at least two of a benzene ring, a pyrrole ring and a furan ring; Preferably, ring B is selected from Preferably, Selected from Preferably, Selected from Preferably, L2 is selected from unsubstituted or optionally substituted with one, two or more R L The following groups substituted: methylene, azetidinyl; preferably, R L is methyl; Preferably, L2 is selected from CH2, (For example )； Preferably, L3 is selected from O, NH, CH2. Preferably, R1 is selected from H, halogen, CN, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Preferably, R1 is selected from H, halogen, CN, halogenated C 1-3 Alkoxy; Preferably, R1 is selected from H, F, Cl, CN, trifluoromethyl, trifluoromethoxy; Preferably, R2 is selected from H, halogen, oxo (=O); Preferably, R2 is selected from H, F, oxo; Preferably, Selected from For example 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: The compound is selected from novel compounds with structures disclosed in the specification of the present invention.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof.

10. Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, in the preparation of a medicament for preventing and / or treating diseases associated with the MYC / GSPTs signaling pathway; preferably, the diseases associated with the MYC / GSPTs signaling pathway include but are not limited to cancers such as lung cancer, gastric cancer, liver cancer and the like.

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