Estrogen receptor protein degradation targeting chimera compound and application thereof

Abstract

The invention provides a novel estrogen receptor protein degradation targeting chimera compound and application of the novel estrogen receptor protein degradation targeting chimera compound in medicine. The compound provided by the invention can be used as an estrogen receptor degradation agent for treating estrogen dependent diseases.

Description

An estrogen receptor protein degradation-targeted chimeric compound and its application Technical Field

[0001] The present invention relates to the technical field of chemical pharmaceuticals, and in particular to a compound used as an estrogen receptor degrader and a pharmaceutically acceptable salt thereof, which can be used as a drug for treating or preventing diseases treated by degrading estrogen receptor proteins. Background Art

[0002] The concept of protein degradation targeting chimeras (PROTACs) was proposed in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). Early PROTACs recruited E3 ligases through peptides, but the molecules had poor membrane permeability and limited activity. In 2008, small molecule PROTACs based on the MDM2 E3 ligase appeared, but the activity of these molecules was not good. It was not until 2010 to 2012 that the currently commonly used ligands based on the cereblon (CRBN) and VHL (von Hippel-Lindau) E3 ligases appeared, which enabled the binding level of small molecule ligands to E3 ligases to reach the micromolar level, laying the foundation for the subsequent development of PROTACs. PROTACs molecules are bifunctional molecules, one end of which contains a ligand that binds to the E3 ubiquitin ligase and the other end contains a ligand that binds to the target protein, and the two parts are connected by a linker unit. By bringing the linker unit closer together, PROTACs bring the E3 ligase and target protein into close proximity, leading to polyubiquitination and proteasomal degradation of the target protein. PROTACs employ a completely different mechanism of action from small molecule inhibitors. First, the E3 ubiquitin ligase ligase's ligand recruits the E3 ubiquitin ligase to the vicinity of the target protein, bringing it into close proximity and labeling it for ubiquitination. The labeled target protein is then degraded by the proteasome system in the body, thereby inhibiting the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared to traditional small molecule drugs, due to their altered binding mechanism, PROTACs only require transient binding to the target protein to complete the ubiquitin transfer process before irreversible degradation of the target protein is achieved. Therefore, PROTACs offer the following advantages: 1) stronger degradation and longer-lasting efficacy; 2) higher selectivity for the target protein; and 3) the ability to overcome the resistance to traditional small molecule inhibitors caused by target protein mutations (Cell Chem. Biol. 2018, 25, 67-77).

[0003] Estrogen receptor (ER) is a member of the nuclear hormone receptor family and acts as a ligand-activated transcription factor, involving the upregulation and downregulation of gene expression. The natural hormone of the estrogen receptor is estradiol (E2) and closely related metabolites. The binding of estradiol to the estrogen receptor causes the dimerization of the receptor, and the dimer then binds to the estrogen response element (ERE) on the DNA. The ER-DNA complex recruits other transcription factors responsible for transcribing the DNA downstream of the ERE into mRNA, which is ultimately converted into protein. Alternatively, the interaction of ER with DNA can be indirectly carried out through the intermediacy of other transcription factors, the most obvious of which are fos and jun. Since the expression of a large number of genes is regulated by the estrogen receptor, and since the estrogen receptor is expressed in many cell types, the regulation of the estrogen receptor by combining natural hormones or synthetic ER ligands can have a profound effect on the physiology and pathophysiology of organisms.

[0004] CRBN is a protein encoded by the CRBN gene in humans. Homologs of CRBN are highly conserved from plants to humans. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullin regulator 1 (ROC1). This complex ubiquitinates many other proteins. Through a mechanism that has not yet been fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates many developmental processes, such as limb and auditory bulla formation. Therefore, this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of CRBN, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

[0005] The discovery of CRBN-type E3 ligase ligands was closely related to the study of thalidomide's mechanism of action. In 2010, while investigating thalidomide toxicity, scientists discovered cereblon as a thalidomide-binding protein (Science 2010, 327, 1345). Cerebellum is part of the E3 ubiquitin ligase protein complex, acting as a substrate receptor to selectively target ubiquitinated proteins. This study suggested that thalidomide-cereblon binding in vivo may contribute to thalidomide's teratogenicity. Subsequent studies have shown that this compound and related structures may be useful as anti-inflammatory, anti-angiogenic, and anti-cancer agents. Further structural modifications of thalidomide have resulted in lenalidomide and pomalidomide, which have significantly improved safety and reduced teratogenicity. Lenalidomide was approved by the FDA in 2006. Two groundbreaking papers published in Science in 2014 demonstrated that lenalidomide exerts its effects by degrading two specific B-cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). This further revealed that thalidomide may further degrade target proteins by binding to the E3 ubiquitin ligase complex of cerebellum (Science, 2014, 343, 301; Science, 2014, 343, 305). Based on this, CRBN ligands have been widely used in protein degradation, and a series of CRBN ligand-based PROTACs have been developed. Because CRBN ligands themselves affect their targets and may also degrade zinc finger domain proteins, the design and synthesis of new, highly selective CRBN ligands is particularly important in the synthesis of PROTACs.

[0006] Summary of the Invention

[0007] The present invention provides novel chimeric PROTAC compounds targeting estrogen receptor protein degradation. These molecules exhibit significant activity as estrogen receptor degraders for the treatment of estrogen receptor-mediated or dependent diseases. In one aspect, the present invention provides a compound having the following chemical structure:

[0008] CLM-L-PTM,

[0009] or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates,

[0010] in:

[0011] PTM is the binding portion that targets the estrogen receptor protein and has the following structure:

[0012] R L0is selected from a single bond, -O-, alkylene, and -C(=O)-; preferably, R L0 Selected from single bond, -O-, C 1-3 Alkylene, and -C(=O)-;

[0013] R v Selected from

[0014] R is

[0015] Each time Q appears, each independently selected from CR x and N;

[0016] Q 1 Each occurrence is O, S, or NR x ;

[0017] R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x and R P7 Each occurrence is independently selected from H, carboxyl, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of said alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl;

[0018] Preferably, R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x , and R P7Each occurrence is independently selected from H, carboxyl, a deuterium atom, a halogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 alkoxy, a C1-C6 haloalkyl, a C1-C6 haloalkoxy, a hydroxyl, a C1-C6 hydroxyalkyl, a nitro, a cyano group, an amino group, a C1-C6 alkylamino, a C1-C6 alkylacyl, a C1-C6 alkyloxyacyl, a C1-C6 alkylaminoacyl, a C3-C8 cycloalkyl, a 4-10 membered heterocyclyl, a C5-C6 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl and 5-10 membered heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C5-C 10 Heterocyclic group, 4-10 membered heterocyclic group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkylamino group, C1-C6 alkylacyl group, C1-C6 alkyloxyacyl group, C1-C6 alkylaminoacyl group, C6-C 10 Aryl, C5-C 10 Heteroaryl and 5-10 membered heteroaryl are substituted with one or more substituents; preferably R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x , and R P7 Each occurrence is independently selected from H, carboxyl, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Heterocyclic group, C6-C10 Aryl, C5-C 10 Heteroaryl and 5-10 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C5-C 10 Heterocyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl and 5-10 membered heteroaryl are substituted with one or more substituents; preferably R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x , and R P7 Each occurrence is independently selected from H, carboxyl, hydroxyl, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy;

[0019] m13 is 0, 1, 2, 3, 4, or 5;

[0020] m14 is 0, 1, 2, 3, 4, or 5;

[0021] m15 is 0, 1, 2, 3, 4, or 5;

[0022] m16 is 0, 1, 2, 3, 4, or 5;

[0023] The PTM is preferably:

[0024] L is a bond or chemical linking moiety that covalently links the CLM and the PTM, and

[0025] The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures:

[0026] in:

[0027] W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0028] G and Z are the same or different and are each independently selected from O, S, and Se;

[0029] R 3a 、R3b 、R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl groups, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group,

[0030] R d 、R e 、R f 、R g 、R D 、R E 、R F , and R G Each occurrence is independently C(R m )2、NR m , C(=O), O or S;

[0031] W 3 and W 4 Each time it appears, it is independently CR m or N;

[0032] R t and R T Each occurrence is N or CR independently 2h , and when R D 、R E 、R F , and R G All C(R m )2, R T CR 2h ;

[0033] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6;

[0034] Each occurrence of m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8;

[0035] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7;

[0036] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+m8≤7;

[0037] R m each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0038] R 2h selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an alkenyl group, and an alkynyl group, wherein said alkyl group, heteroalkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0039] R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl;

[0040] R 2 、R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and

[0041] n is 0, 1, 2, or 3;

[0042] Preferably, the compound is not:

[0043] In another embodiment, the compound is a compound having the following chemical structure:

[0044] CLM-L-PTM,

[0045] or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates,

[0046] in:

[0047] PTM is the binding portion that targets the estrogen receptor protein and has the following structure:

[0048] R L0 is selected from a single bond, -O-, alkylene, and -C(=O)-; preferably, R L0 Selected from single bond, -O-, C 1-3 Alkylene, and -C(=O)-;

[0049] R v Selected from

[0050] R is

[0051] Each time Q appears, each independently selected from CR x and N;

[0052] Q 1 O, S or NR x ;

[0053] R P1 、R P2 、R P3 、R P4 、R P5 、R P6 , and R x each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0054] m13 is 0, 1, 2, 3, 4, or 5;

[0055] m14 is 0, 1, 2, 3, 4, or 5;

[0056] m15 is 0, 1, 2, 3, 4, or 5;

[0057] m16 is 0, 1, 2, 3, 4, or 5;

[0058] The PTM is preferably:

[0059] L is a bond or chemical linking moiety that covalently links the CLM and the PTM, and

[0060] The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures:

[0061] in:

[0062] W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0063] G and Z are the same or different and are each independently selected from O, S, and Se;

[0064] R 3a 、R 3b 、R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl groups, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0065] R d 、R e 、R f 、R g 、R D 、R E 、R F , and R G Each occurrence is independently C(R m )2、NR m , C(=O), O or S;

[0066] W 3 and W 4 Each time it appears, it is independently CR m or N;

[0067] R t and R T Each occurrence is N or CR independently 2h , and when R D 、R E 、R F , and R G All C(R m )2, R T CR 2h ;

[0068] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6;

[0069] Each occurrence of m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8;

[0070] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7;

[0071] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+m8≤7;

[0072] R m each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0073] R 2hselected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an alkenyl group, and an alkynyl group, wherein said alkyl group, heteroalkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0074] R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl;

[0075] R 2 、R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and

[0076] n is 0, 1, 2 or 3.

[0077] In one embodiment, the compound is a compound having the following chemical structure:

[0078] CLM-L-PTM,

[0079] or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates,

[0080] in:

[0081] PTM is a binding moiety that targets the estrogen receptor protein and is selected from the following structures:

[0082] L is a bond or chemical linking moiety that covalently links the CLM and the PTM, and

[0083] The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures:

[0084] in:

[0085] Each time Q appears, each independently selected from CR x and N;

[0086] Q 1 O, S or NH;

[0087] R P1 、R P2 、R P3 、R P4 、R P5 、R P6 , and R x each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0088] m13 is 0, 1, 2, 3, 4, or 5;

[0089] m14 is 0, 1, 2, 3, 4, or 5;

[0090] m15 is 0, 1, 2, 3, 4, or 5;

[0091] W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0092] G and Z are the same or different and are each independently selected from O, S, and Se;

[0093] R 3a 、R 3b 、R 3c , and R 3deach independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl groups, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group,

[0094] R d 、R e 、R f 、R g 、R D 、R E 、R F , and R G Each occurrence is independently C(R m )2、NR m , C(=O), O or S;

[0095] W 3 and W 4 Each time it appears, it is independently CR m or N;

[0096] R t and R T Each occurrence is N or CR independently 2h , and when R D 、R E 、R F , and R G All C(R m )2, R T CR 2h ;

[0097] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6;

[0098] Each occurrence of m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8;

[0099] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7;

[0100] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+m8≤7;

[0101] R m each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0102] R 2h selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an alkenyl group, and an alkynyl group, wherein said alkyl group, heteroalkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0103] R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl;

[0104] R 2 、R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and

[0105] n is 0, 1, 2 or 3.

[0106] In one embodiment, W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0107] R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x 、R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x 、R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x 、R 3a 、R 3b 、R 3c , and R 3d Each independently selected from H, hydroxyl, deuterium atom, halogen, C1-C3 alkyl, and C1-C3 alkoxy; preferably R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x 、R 3a 、R 3b 、R 3c , and R 3d are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; preferably R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、R x 、R 3a 、R 3b 、R 3c , and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0108] R d 、R e 、R f and R g Each occurrence is independently C(R m )2 or 0; and / or

[0109] R D 、R E 、R Fand R G Each occurrence is independently C(R m )2 or 0; and / or

[0110] W 3 and W 4 is CH; and / or

[0111] R 2h selected from H, deuterium atoms, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R 2h selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R 2h is selected from H, deuterium atoms, halogen, C1-C3 alkyl, and C1-C3 alkoxy; preferably R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group; and / or

[0112] m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3, preferably m1+m2=1 or m1+m2=2; and / or

[0113] m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0114] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0115] m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4, and m7+m8≤4, preferably m7+m8=2, or m7+m8=3; and / or;

[0116] R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R mEach occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0117] R 1 is selected from H, halogen, C1-C3 alkyl, and hydroxyl; R 1 Preferably selected from H, F, Cl, Br, I, C1-C3 alkyl and hydroxyl; and / or

[0118] R 2 Selected from H, and C1-C3 alkyl; and / or

[0119] n is 0 or 1.

[0120] In one embodiment, wherein the CLM is selected from the following structures:

[0121] W 1 、W 2 、W 3 、W 4 、R 3a 、R 3b 、R 3c 、R 3d 、R d 、R e 、R f 、R t 、R g 、R D 、R E 、RF 、R T 、R G , m3, m4, m5 and m6 are as defined in claim 1, 2, 3 or 4; preferably, R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group;

[0122] m1, m9 and m10 are each independently an integer of 0, 1, 2, 3, 4, or 5, and m1+m9+m10≤5; preferably m1, m9 and m10 are each independently an integer of 0, 1, or 2, and m1+m9+m10≤2, preferably m1+m9+m10=1 or m1+m9+m10=0; and

[0123] m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1.

[0124] In one embodiment, wherein the CLM is selected from the following structures:

[0125] in:

[0126] W1, W2, R3a 、R 3b 、R 3c 、R 3d 、R d 、R e 、R f 、R t 、R g 、R D 、R E 、R F 、R T 、R G , m3, m4, m5 and m6 as defined in claim 1, 23, or 4;

[0127] Preferably:

[0128] R 3a 、R 3b 、R 3c 、R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0129] m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0130] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0131] W1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0132] R d 、R e 、R f 、R g 、R D 、R E 、R F , and R G Each occurrence is independently C(R m )2 or O, R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0133] R t , and R T Each occurrence is N or CR independently 2h , R 2h selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents.

[0134] In one embodiment, wherein the CLM is selected from the following structures:

[0135] in:

[0136] W 1 、W 2 、W 3 、W 4 、R 3a 、R 3b 、R 3c 、R 3d 、R f 、R t 、R g 、R F 、R G , m1, m2, m3, m4, m5, m6, m7, and m8 are as defined in claim 1, 2, 3, or 4, preferably, R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group;

[0137] R 1d 、R 1e 、R 1D and R 1E Each occurrence is independently C(R m )2;

[0138] R T N or CR 2h , when R F and R G All C(R m )2, R T CR 2h ;and

[0139] R 2h , and R m As defined in claim 1, 2, 3 or 4.

[0140] In one embodiment, wherein the CLM is selected from the following structures:

[0141] Among them, W 1 、W 2 、R 3a 、R 3b 、R 3c 、R 3d 、R f 、R t 、R g 、R F 、R G , m3, m4, m5, and m6 as defined in claim 1, 2, 3 or 4; R 1d 、R 1e 、R 1D 、R 1E Each occurrence is independently C(R m )2; R T N or CR 2h And when R F and R G All C(R m )2, R T CR2h ; and, R 2h and R m as defined in claim 1, 2, 3 or 4;

[0142] Preferably:

[0143] R 3a 、R 3b 、R 3c 、R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0144] m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0145] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0146] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0147] R 1d 、R 1e 、R 1D 、R1E 、R f 、R g 、R F , and R G Each occurrence is independently C(R m )2,R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0148] R t Each occurrence is N or CR independently 2h , R T Each time it appears, it is independently CR 2h , R 1h 、R 2h , and R 3h Each is independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents.

[0149] In one embodiment, wherein the CLM is selected from the following structures:

[0150] In one embodiment, wherein L is a bond or is -(B L ) q -:B L Each occurrence is the same or different and is independently selected from: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene, and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 Group substitution; preferably, B L Each occurrence is independently selected from: CR L1 R L2 、O、S、SO、SO2、NR L3, CO, C≡C, 3-16 membered cycloalkylene, 3-16 membered heterocyclylene, 6-10 membered arylene, or 5-10 membered heteroarylene, wherein the 3-16 membered cycloalkylene, 3-16 membered heterocyclylene, 6-10 membered arylene, or 5-10 membered heteroarylene is optionally substituted by 0, 1, 2, 3 or 4 R L1 and / or R L2 group substitution;

[0151] R L1 、R L2 、R L3 , and R L4 Each occurrence is independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclic group, CO-C 3-8 Cycloalkyl, CO-C 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 alkyl), N(C 1-8 Alkylene)(C 3-8 Cycloalkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group) (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2、Si(OH)3、Si(C 1-8Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, COO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 alkyl)2, CONH-C 1-8 Alkyl, CONH-C 3-8 Cycloalkyl, CONH-C 3-11 Heterocyclic group, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2、NHCONH(C 1-8 Alkyl), NHCON(C 1-8 alkyl)2、NHCONH2、N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, and NH SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-8 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently substituted by one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; preferably, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-8 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently selected from F, Cl, Br, I, C 1-6 substituted by one or more substituents selected from alkyl, methoxy, and ethoxy; and

[0152] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0153] Preferably:

[0154] B L Each occurrence is the same or different and is independently selected from: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene, and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 group substitution;

[0155] R L1 、R L2 、R L3 , and R L4 Each occurrence is independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8Cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group) (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2、Si(OH)3、Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 alkyl)2, CONH-C 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2、NHCONH(C 1-8 Alkyl), NHCON(C 1-8 alkyl)2、NHCONH2、N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, and NH SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C5-10 The heteroaryl groups are each independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; and

[0156] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0157] In one embodiment, wherein B L One or more selected from the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3) 2 -、-N(CH3)-、-N(CH2CH3)-、 For the connection point.

[0158] In one embodiment, wherein L is selected from the following structures:

[0159] Covalent bond, -(CH2) j -、-(CH2) p -NH-(CH2) s -、-(CH2) y -NH-(CH2) j -NH-(CH2) s -、-(CH2) p -CO-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -CO-(CH2) j -CO-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -CO-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -、

[0160] Wherein, j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it occurs;

[0161] k, s, p and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0162] It is the connection point of CLM or PTM;

[0163] L is preferably selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -CO-NH-CH2-, -CO-NH-(CH2)2-, -CO-NH-(CH2)3-, -CO-NH-(CH2)4-, -CO-NH-(CH2)5-, -CO-NH-(CH2)6-, -CO-NH-(CH2)7-, -CO-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -CO-NH-(CH2-CH2-O)-CH2-CH2-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-NH--CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-CO-NH-CH2-CH2-(O-CH2-CH2)-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)3-、-CH2-CH2-(O-CH2-C H2)-NH-、-CH2-CH2-(O-CH2-CH2)2-NH-、-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-(O-CH2-CH2)-NH-、-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-NH-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-O-CH2-CH2-CO-、-CO-CH2-CH2-O-CH2-CH2-NH-、-NH-(CH2)4-CO-、-NH-(CH2)5-CO-、-NH-(CH2)6-CO-、-CO-(C H2)4-NH-、-CO-(CH2)5-NH-、-CO-(CH2)6-NH-、-NH-(CH2-CH2-O)-(CH2)3-、-NH-(CH2-CH2-O)-(CH2)4-、-NH-(CH2-CH2-O)-(CH2)5-、-NH-(CH2-CH2-O)-(CH2)6-、-(CH2)3-(O-CH2-CH2)-NH-、-(CH2)4-(O-CH2-CH2)-NH-、-(CH2)5-(O-CH2-CH2)-NH-、-(CH2)6-(O-CH2-CH2)-NH-、-CH2-CH2-O-(CH2)2- CO-、-CH2-CH2-O-(CH2)3-CO-、-CH2-CH2-O-(CH2)4-CO-、-CO-(CH2)2-O-CH2-CH2-、-CO-(CH2)3-O-CH2-CH2-、-CO-(CH2)4-O-CH2-CH2-、-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、-CO-(CH2)5-、-CO-(CH2)6-、-(CH2)2-CO-、-(CH2)3-CO-、-(CH2)4-CO-、-(CH2)5-CO-、-(CH2)6-CO-、-CO-(CH2)2-CO-、-CO-(CH2)3-CO-, -CO-(CH2)4-CO-, -CO-(CH2)5-CO-, -CO-(CH2)6-CO-, -CH2-CO-CH2-, -C H2-CO-(CH2)2-, -CH2-CO-(CH2)3-, -CH2-CO-(CH2)4-, -(CH2)2-CO-CH2-, -(CH2)2-CO-(CH 2)2-, -(CH2)2-CO-(CH2)3-, -(CH2)2-CO-(CH2)4-, -(CH2)3-CO-CH2-, -(CH2)3-CO-(CH2) 2-, -(CH2)3-CO-(CH2)3-, -(CH2)3-CO-(CH2)4-, -(CH2)4-CO-CH2-, -(CH2)4-CO-(CH2)2-, -(CH2)4-CO-(CH2)3-, -(CH2)4-CO-(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH 2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2 )2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)3-O-( CH2)4-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-,

[0164] In one embodiment, the PTM is selected from the following structures:

[0165] R is selected from

[0166] The second aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0167] The third aspect of the present invention provides the use of the above-mentioned compound or its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating or preventing diseases that are treated by degrading estrogen receptor protein.

[0168] Definition and detailed description

[0169] The term "alkyl" as contemplated herein refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0170] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by heteroatoms selected from NH, O and S or one or more -CH- are replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0171] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0172] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0173] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond, wherein alkyl is as defined above. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0174] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0175] Cycloalkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl. The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0176] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0177] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0178] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0179] The term "amino" refers to -NH2.

[0180] The term "cyano" refers to -CN.

[0181] The term "nitro" refers to -NO2.

[0182] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, cerebellin is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation via the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, a third ubiquitin to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation via the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead alter their cellular location or function, for example, through binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by the E3 for chain preparation. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0183] The term "target protein" refers to proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Such proteins include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi, and parasites, among many others, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy, other animals including domestic animals, microorganisms that are targets for testing antibiotics and other antimicrobials, plants, and even viruses, among many others.

[0184] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may but need not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0185] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. It is understood that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) without undue effort which substitutions are possible or impossible. "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are safe and effective for use in mammals and have the desired biological activity. Specific embodiments

[0186] The following examples are directed to the intermediate compounds and final products identified in the specification and synthesis schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed based on their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to each compound within the scope of the present invention as described. Those skilled in the art will readily recognize compounds for which this occurs. In these cases, the reactions can be successfully carried out by conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0187] The starting materials, chemical reagents, and solvents used in the present invention are all commercially available and were purchased from companies such as Anage Chemical, Shanghai Bid Pharmaceutical, Beijing Inocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0188] The structures of the compounds synthesized in this application were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0189] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker AVANCE-400 / 600 NMR spectrometer. Deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. Mass spectrometry (MS) measurements were performed using a Waters Acquity Plus device implementation.

[0190] High performance liquid chromatography (HPLC) was performed using a Waters 2489 instrument.

[0191] The medium-pressure flash preparative chromatograph was COMBIFLASH NEXTGEN 300+.

[0192] As the thin layer chromatography silica gel plate, Silica gel 60 thin layer chromatography silica gel plate (aluminum plate, containing fluorescence) was used.

[0193] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin layer chromatography was purchased from Inokai.

[0194] The reaction progress in the examples was detected by thin layer chromatography (TLC), and the developing solvent used for monitoring the reaction and the eluent used for purifying the compound by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0195] 1. Synthesis of E3 ligase inhibitors

[0196] 1) Synthesis of E3 ligase inhibitor 1

[0197] Step 1: Dimethyl 4-hydroxyphthalate (Compound 1b)

[0198] To a solution of compound 1a (30 g, 164.7 mmol) in methanol (300 mL) was slowly added concentrated sulfuric acid (45 mL). The reaction mixture was stirred at 65°C for 5 hours. The resulting mixture was poured into ice water, filtered, washed with water, and dried in vacuo to afford compound 1b (30.0 g, 87%) as a white solid.

[0199] 1 H NMR (600MHz, DMSO-d6) δ10.66(s,1H),7.70(d,J=8.5Hz,1H),6.96(dd,J=8.5,2.5Hz,1H),6.93(d,J=2.5Hz,1H),3.79(s,3H),3.76(s,3H).LC-MS(ESI):[MH] + =209.22

[0200] Step 2: Dimethyl 4-hydroxy-5-iodophthalate (Compound 1c)

[0201] To a solution of compound 1b (20.0 g, 95.2 mmol) in trifluoroacetic acid (60 mL) was slowly added N-iodosuccinimide (23.6 g, 104.7 mmol). The reaction was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give compound 1c (16.3 g, 51%) as a white solid.

[0202] 1 H NMR(600MHz,DMSO-d6)δ11.59(s,1H),8.11(s,1H),7.02(s,1H),3.79(s,3H),3.77(s,3H).LC-MS(ESI):[MH] + =335.06

[0203] Step 3: Dimethyl 4-acetyl-5-hydroxyphthalate (Compound 1d)

[0204] Under nitrogen, compound 1c (15.0 g, 44.6 mmol), tributyl(1-ethoxyethylene)tin (32.2 g, 89.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3.1 g, 4.5 mmol) were dissolved in tetrahydrofuran (75 mL), heated to 65°C, and stirred for 15 h. After the reaction, 1 M dilute hydrochloric acid solution was added to the system and stirred for 0.5 h, followed by potassium fluoride. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The product was purified by column chromatography (PE:EA = 0-40%) to obtain compound 1d (9.8 g, 87%) as a yellow oil.

[0205] 1 H NMR (400MHz, CDCl3) δ12.65(s,1H),8.37(s,1H),7.12(s,1H),3.96(s,3H),3.92(s,3H),2.73(s,3H).LC-MS(ESI):[M+H] + =253.15

[0206] Step 4: 1'-(tert-butyl) 6,7-dimethyl 4-oxaspiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 1e)

[0207] Compound 1d (5.0 g, 19.8 mmol), N-(tert-butoxycarbonyl)-4-piperidone (1.4 g, 19.8 mmol), and tetrahydropyrrole (4.0 g, 19.8 mmol) were dissolved in methanol (50 mL), and the mixture was stirred at 70°C overnight. The mixture was spin-dried and purified by column chromatography (PE:EA = 0-35%) to give Compound 1e (6.9 g, 80%) as a yellow oil.

[0208] 1 H NMR (600MHz, DMSO-d6) δ8.17(s,1H),7.36(s,1H),3.83(s,3H),3.82(s,3H),3.73(s,2H),3.13(d,J=40 .7Hz,2H),2.96(s,2H),1.95–1.86(m,2H),1.66(dq,J=13.2,5.0Hz,2H),1.40(s,9H).LC-MS(ESI):[MH] + =432.22

[0209] Step 5: 1'-(tert-butyl) 6,7-dimethyl 4-hydroxyspiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 1f)

[0210] To a solution of compound 1e (5.0 g, 11.5 mmol) in methanol (50 mL) was added sodium borohydride (0.7 g, 17.3 mmol) in an ice bath. The reaction was stirred at 70°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to afford compound 1f (3.3 g, 66%) as a white solid.

[0211] 1 H NMR (600MHz, DMSO-d6) δ7.92 (s, 1H), 7.02 (s, 1H), 5.73 (d, J = 6.2Hz, 1H), 4. 74(dt,J=9.3,6.1Hz,1H),3.79(s,6H),3.74–3.64(m,2H),3.06(s,2H),2.1 8(dd,J=13.6,6.1Hz,1H),1.78(ddt,J=23.0,13.5,6.3Hz,2H),1.72–1.64( m,2H),1.57(ddd,J=13.7,11.3,4.7Hz,1H),1.40(s,9H).LC-MS(ESI):[MH] + =464.39

[0212] Step 6: Dimethylspiro[chromene-2,4'-piperidine]-6,7-dicarboxylate (Compound 1g)

[0213] Compound 1f (3.0 g, 6.9 mmol) and triethylsilane (3.2 g, 27.6 mmol) were dissolved in trifluoroacetic acid (30 mL), and the mixture was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give compound 1g (1.8 g, 83%) as a colorless oil.

[0214] 1 H NMR (400MHz, CDCl3) δ7.53(s,1H),7.11(s,1H),6.51(d,J=9.9Hz,1H),5.72(d,J=9.8Hz,1H),4.66(s,2H), 3.93(s,3H),3.89(s,3H),3.42–3.31(m,4H),2.23(d,J=14.6Hz,2H),2.12–2.02(m,2H).LC-MS(ESI):[M+H] + =318.25

[0215] Step 7: Dimethylspiro[chroman-2,4'-piperidine]-6,7-dicarboxylate (Compound 1h)

[0216] Compound 1g (1.6 g, 5.0 mmol) was dissolved in methanol (20 mL) and palladium on carbon (0.2 g) was added. The reaction was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered and dried to give compound 1h (1.3 g, 81%) as a yellow oil.

[0217] 1 H NMR (400MHz, CDCl3) δ7.61(s,1H),7.14(s,1H),3.93(s,3H),3.89(s,3H),3.35(d,J=6. 2Hz,4H),3.30(s,2H),2.87(t,J=6.8Hz,2H),2.05–2.00(m,2H),1.95(t,J=6.7Hz,2H).

[0218] LC-MS(ESI):[M+H] + =320.28

[0219] Step 8: Spiro[chroman-2,4'-piperidine]-6,7-dicarboxylic acid (Compound 1i)

[0220] Compound 1h (1.5 g, 4.7 mmol) was dissolved in a suspension of methanol and water, and lithium hydroxide (1.7 g, 70.5 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. LC-MS (ESI): [M+H] + =292.21

[0221] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]6',8'(7'H)-dione (E3 ligase inhibitor 1)

[0222] Compound 1i (1.3 g, 7.7 mmol) was dissolved in acetic acid (15 mL), and 3-aminopiperidine-2,6-dione hydrochloride (1.52 g, 9.2 mmol) and sodium acetate (2.1 g, 15.5 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse-phase column chromatography to obtain E3 ligase inhibitor 1 (1.6 g, 81%) as a white solid.

[0223] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.74(s,1H),7.38(s,1H),5.10(dd,J=12.9,5.4Hz,1H),3.28–3.14(m,4H),2.95(t,J=6. 8Hz,2H),2.91–2.83(m,1H),2.65–2.53(m,2H),2.07–1.99(m,1H),1.93(q,J=6.2Hz,4H),1.88–1.78(m,2H).LC-MS(ESI):[M+H] + =384.32.

[0224] 2) Synthesis of E3 ligase inhibitor 2

[0225] Step 1: 1'-(tert-Butyl)-6,7-dimethyl-4-oxaspiro[chroman-2,3'-pyrrolidine]-1',6,7-tricarboxylate (Compound 2a) was prepared according to Steps 1 to 3 of Example 1. Compound 1d (5.0 g, 19.8 mmol), 1-tert-butyloxycarbonyl-3-pyrrolidone (1.4 g, 19.8 mmol), and tetrahydropyrrole (4.0 g, 19.8 mmol) were dissolved in methanol (50 mL). The mixture was stirred at 70°C overnight. The product was dried and purified by column chromatography (PE:EA = 0-35%) to afford Compound 2a (5.0 g, 60%) as a yellow oil.

[0226] 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),7.18(s,1H),3.95(s,3H),3.91(s,3H),3.89–3.83(m,1H),3.76–3.64(m,1H),3.62–3.50(m,1H),3. 40(dd,J=17.4,12.4Hz,1H),3.06–2.86(m,2H),2.36–2.25(m,1H),1.97(ddd,J=13.5,10.4,9.0Hz,1H),1.47(d,9H).LC-MS(ESI):[MH] + =418.40

[0227] Step 2: 1'-(tert-butyl) 6,7-dimethyl 4-hydroxyspiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylate (Compound 2b) was added to a solution of Compound 2a (5.0 g, 11.5 mmol) in methanol (50 mL) under ice bath conditions. The reaction was stirred at 70°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to give Compound 2b (5.0 g, 99%) as a white solid. The resulting mixture was used directly in the next reaction. LC-MS (ESI): [M+Na] + =444.33

[0228] Step 3: Methyl spiro[chromene-2,3'-pyrrolidine]-6,7-dicarboxylate (Compound 2c)

[0229] Compound 2b (3.0 g, 7.1 mmol) and triethylsilane (3.3 g, 28.5 mmol) were dissolved in trifluoroacetic acid (30 mL), and the mixture was stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give compound 2c (1.1 g, 51%) as a colorless oil.

[0230] 1 H NMR (600MHz, CDCl3) δ7.53(s,1H),7.09(s,1H),6.61(d,J=9.8Hz,1H),5.79(d,J=9.9Hz,1H),4.53(br s,2H),3.91(s,3H),3.89(s,3H),3.70–3.55(m,3H),3.27(d,J=12.5Hz, 1H),2.54(dd,J=14.2,6.4Hz,1H),2.14(ddd,J=13.8,11.0,6.5Hz,1H).LC-MS(ESI):[M+H] + =304.27

[0231] Step 4: Dimethylspiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylate (Compound 2d)

[0232] Compound 2c (1.0 g, 3.3 mmol) was dissolved in methanol (20 mL) and palladium on carbon (0.1 g) was added. The reaction was stirred under hydrogen at room temperature overnight. The mixture was filtered and dried to give compound 2d (1.0 g, 99%) as a yellow oil.

[0233] 1H NMR (600MHz, CDCl3) δ7.61(s,1H),7.09(s,1H),3.90(s,3H),3.88(s,3H),3.52(dtd,J=17.8,11.4,7.8Hz,2H),3.44(dd,J=12.7, 1.6Hz,1H),3.25(d,J=12.6Hz,1H),2.90(dtd,J=17.3,10.7,6.9Hz,2H),2.28–2.23(m,1H),2.14–2.10(m,2H),2.08–2.02(m,1H).

[0234] LC-MS(ESI):[M+H] + =306.22

[0235] Step 5: Spiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylic acid (Compound 2e)

[0236] Compound 2d (1.0 g, 3.3 mmol) was dissolved in methanol and water, and lithium hydroxide (1.2 g, 49.1 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0237] LC-MS(ESI):[M+H] + =278.22

[0238] Step 6: 7-(2,6-dioxapiperidin-3-yl)-3,4-dihydro-6H-spiro[pyrano[2,3-f]isoindole-2,3'-pyrrolidine]-6,8(7H)-dione (E3 ligase inhibitor 2)

[0239] Compound 2e (801 mg, 4.9 mmol) was dissolved in acetic acid (5 mL), and 3-aminopiperidine-2,6-dione hydrochloride (0.97 g, 6.0 mmol) and sodium acetate (1.3 g, 9.7 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse phase column to obtain E3 ligase inhibitor 2 (312 mg, 26%) as a white solid.

[0240] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.78(s,1H),7.18(s,1H),5.10(dd,J=12.9,5. 4Hz,1H),3.50–3.21(m,4H),3.03–2.84(m,4H),2.66–2.53(m,2H),2.24–2.00(m,4H).

[0241] LC-MS(ESI):[M+H] + =370.34

[0242] 3) Synthesis of E3 ligase inhibitor 3

[0243] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0244] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione was prepared by similar procedures as Step 1 to Step 6 of Example 2.

[0245] 1 H NMR (600MHz, DMSO-d6) δ11.12 (s, 1H), 9.12 (d, J = 49.0Hz, 2H, NH), 7.76 (s, 1H), 7. 30(s,1H),5.10(dd,J=12.9,5.4Hz,1H),4.16(t,J=8.7Hz,4H),2.97(t,J=6.5Hz, 2H),2.88(ddd,J=17.0,13.9,5.5Hz,1H),2.59(dt,J=17.1,3.1Hz,1H),2.54(dd, J=13.1,4.5Hz,1H),2.22(t,J=6.5Hz,2H),2.06–2.00(m,1H).LC-MS(ESI):[M+H] + =356.26.

[0246] 4) Synthesis of E3 ligase inhibitor 4

[0247] Step 1: Dimethyl 4-methylphthalate (Compound 4b)

[0248] Compound 4a (10 g, 55.56 mmol) was dissolved in 100 mL of methanol, followed by the addition of 15 mL of concentrated sulfuric acid. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, and concentrated to afford compound 4b (10.6 g, 91%) as a colorless oil. The product was used directly in the next step without purification.

[0249] 1H NMR (400MHz, CDCl3) δ7.66(d,J=7.9Hz,1H),7.46(d,J=1.7Hz,1H),7.32(dd,J=7.9,1.8,1H),3.89(s,3H),3.88(s,3H),2.40(s,3H)

[0250] Step 2: Dimethyl 4-methyl-5-nitrophthalate (Compound 4c)

[0251] Compound 4b (10 g, 48 mmol) was dissolved in 100 mL of concentrated sulfuric acid, followed by the slow addition of concentrated nitric acid (25 mL, 68%). The reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and concentrated. The crude product was purified by column chromatography to afford compound 4c (5.5 g, 45%) as a white solid.

[0252] 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.64 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 2.69 (s, 3H) Step 3: Dimethyl 4-amino-5-methylphthalate (Compound 4d)

[0253] Compound 4c (5.1 g, 20 mmol) was dissolved in 100 mL of methanol, followed by the addition of 0.51 g of palladium on carbon. The reaction system was purged with nitrogen and hydrogen, and the reaction was allowed to react overnight at room temperature. After completion of the reaction, the mixture was filtered through celite, and the filtrate was collected and concentrated to afford compound 4d (4 g, 91%) as a yellow oil, which was used directly in the next step without purification.

[0254] 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H),6.68(s,1H),5.91(s,2H),3.75(s,3H),3.71(s,3H).LC-MS(ESI):[M+Na] + =246.18

[0255] Step 4: Dimethyl 4-fluoro-5-methylphthalate (Compound 4e)

[0256] Compound 4d (4 g, 17.92 mmol) was added to 10% fluoroboric acid (32 ml) and the solution was suspended. After stirring for 0.5 h, the mixture was cooled to 0-5°C and 4 mL of NaNO2 (1.36 g, 19.71 mmol) aqueous solution was slowly added to carry out diazotization reaction. The mixture was stirred in an ice bath for 0.5 h. The tetrafluoroborate was filtered and the filter cake was collected. The solid was dried under vacuum. The toluene solution of the tetrafluoroborate was then placed in an oil bath at 110°C and stirred. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography to obtain compound 4e (2.31 g, 57%) as a light yellow oil.

[0257] 1 H NMR (400MHz, CDCl3) δ7.61(dd,J=7.2,0.9Hz,1H),7.38(d,J=9.4Hz,1H),3.92(s,3H),3.91(s,3H),2.35(d,J=2.0Hz,3H)

[0258] Step 5: Dimethyl 4-(bromomethyl)-5-fluorophthalate (Compound 4f)

[0259] Compound 4e (2.26 g, 10 mmol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (2.14 g, 12 mmol) and azobisisobutyronitrile (0.16 g, 1 mmol) were added, followed by heating under reflux overnight. After concentration, the mixture was purified by reverse column chromatography to obtain compound 4f (2.14 g, 70%) as a white solid.

[0260] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=7.1Hz,1H),7.40(d,J=9.4Hz,1H),4.51(d,J=1.0Hz,2H),3.94(s,3H),3.93(s,3H)

[0261] Step 6: Dimethyl 4-((1-(tert-butyloxycarbonyl)-4-formylpiperidin-4-yl)methyl)-5-fluorophthalate (Compound 4g)

[0262] Compound 4f (2.14 g, 7 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and potassium tert-butoxide (1.18 g, 10.5 mmol) was slowly added at -30 ° C. After the reaction was allowed to react for 0.5 h, a solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (1.79 g, 8.4 mmol) in tetrahydrofuran (5 mL) was added dropwise at the same temperature. The reaction was brought to room temperature and stirred overnight. The reaction system was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by rapid silica gel column chromatography to obtain compound 4g (1.68 g, 55%) as a colorless oil.

[0263] 1 H NMR (400MHz, CDCl3) δ9.58(d,J=2.3Hz,1H),7.50(d,J=7.1Hz,1H),7.34(d,J=9.5Hz,1H),3.96–3.84(m, 8H),2.91–2.74(m,4H),1.96(d,J=13.0Hz,2H),1.59–1.46(m,2H),1.44(s,9H).LC-MS(ESI):[M-Boc+H] + =338.29

[0264] Step 7: Dimethyl 4-((1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)piperidin-4-yl)methyl)-5-fluorophthalate (Compound 4h)

[0265] Compound 4g (1.66 g, 3.8 mmol) was dissolved in methanol (15 mL), and sodium borohydride (0.215 g, 5.7 mmol) was added under ice-cooling conditions. The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 4h (1.47 g, 88%) as a colorless oil.

[0266] 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=7.0Hz,1H),7.54(d,J=9.7Hz,1H),4.81(t,J=5.0Hz,1H),3.82(s,3H),3.82(s,3H), 3.48–3.39(m,2H),3.21(d,J=5.0Hz,4H),2.74(s,2H),1.42–1.32(m,11H),1.27–1.14(m,2H).LC-MS(ESI):[M-Boc+H] + =340.41

[0267] Step 8: 1'-(tert-Butyloxycarbonyl)spiro[chroman-3,4'-piperidine]-6,7-dicarboxylic acid (Compound 4i)

[0268] Compound 4h (1.45 g, 3.3 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and sodium hydride (0.4 g, 16.5 mmol) was added. The mixture was reacted at 110°C for 2 h. After completion, the reaction was quenched with acetic acid and purified using a reverse-phase column to obtain compound 4i (0.65 g, 51%) as a white solid.

[0269] 1 H NMR(400MHz,DMSO-d6)δ12.93(s,2H),7.50(s,1H),6.92(s,1H),3.99(s,2H),3.53–3.42(m, 2H),3.33–3.23(m,2H),2.75(s,2H),1.40(s,9H),1.39–1.28(m,4H).LC-MS(ESI):[M-Boc+H] + =292.23.

[0270] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-2'H-spiro[piperidin-4,3'-pyrano[2,3-f]isoindole]-6',8'(4'H,7'H)-dione (E3 ligase inhibitor 4)

[0271] Compound 4i (0.63 g, 1.6 mmol) was dissolved in acetic acid (4 mL), and 3-amino-2,6-piperidinedione hydrochloride (0.33 g, 2.0 mmol) and sodium acetate (0.39 g, 4.8 mmol) were added. The mixture was reacted at 110°C overnight. After completion of the reaction, it was purified by reverse-phase column chromatography to obtain E3 ligase inhibitor 4 (0.5 g, 82%) as a white solid.

[0272] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.51(s,2H),7.69(s,1H),7.29(s,1H),5.10(dd,J=12.7,5.4Hz,1H),4.16(s,2H),3.2 5–3.05(m,4H),2.92(s,2H),2.90–2.82(m,1H),2.64–2.52(m,2H),2.05–1.99(m,1H),1.67–1.51(m,4H).LC-MS(ESI):[M+H] + =384.36.5) Synthesis of E3 ligase inhibitor 5

[0273] Step 1: Dimethyl 4-fluorophthalate (Compound 5b)

[0274] To a solution of compound 5a (5.5 g, 30.0 mmol) in methanol (100 mL) was slowly added concentrated sulfuric acid (15 mL). The reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentration under reduced pressure afforded compound 5b (5.7 g, 90%) as a colorless oil. The crude product was used in the next reaction without purification.

[0275] 1 H NMR (400MHz, CDCl3) δ7.82(dd,J=8.6,5.3Hz,1H),7.38(dd,J=8.6,2.6Hz,1H),7.82(ddd,J=8.6,5.3,2.6Hz,1H),3.96(s,3H),3.92(s,3H)

[0276] Step 2: Methyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalate (Compound 5c)

[0277] Diboronic acid pinacol ester (4.5 g, 17.5 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.13 g, 0.47 mmol), and methoxy(cyclooctadiene)iridium dimer (0.16 g, 0.23 mmol) were added to a 10 mL solution of methyl tert-butyl ether. A solution of compound 5b (2.5 g, 11.8 mmol) in methyl tert-butyl ether (10 mL) was then added. The atmosphere was purged with nitrogen and the reaction was stirred at 100°C for 4 h. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain a crude product (3.2 g) which was used in the next step without purification.

[0278] Step 3: Dimethyl 4-fluoro-5-hydroxyphthalate (Compound 5d)

[0279] Potassium peroxymonosulfate (6.15 g) was added to a solution of compound 5c (3.38 g, 10 mmol) in acetonitrile (50 mL), and the reaction was stirred at room temperature overnight. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain compound 5d (1.6 g, 70%) as a white solid.

[0280] 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.50 (d, J = 10.8Hz, 1H), 7.19 (d, J = 8.1Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H). LC-MS (ESI): [M+H]+ =229.18

[0281] Step 4: 1'-((Benzyloxy)carbonyl)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-6,7-dicarboxylic acid (Compound 5e) Compound 5d (23 mg, 0.1 mmol) was dissolved in 1 ml of ultra-dry N,N-dimethylformamide, followed by the addition of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (25 mg, 0.1 mmol) and sodium hydride (6 mg, 0.25 mmol). The reaction was heated to 110°C and stirred for 2 days. The reaction mixture was then reversed to afford Compound 5e (13 mg, 31%) as a white solid.

[0282] 1 H NMR (600MHz, CD3OD) δ7.41–7.35(m,4H),7.33(dd,J=5.9,2.9Hz,1H),7.29(s,1H),7.27(s,1H),5.15(s,2H),4.07(s ,2H),4.01(dt,J=13.6,4.0Hz,2H),3.42–3.32(m,2H),1.82(d,J=13.9Hz,2H),1.76–1.67(m,2H).LC-MS(ESI):[M+H] + =428.36

[0283] Step 5: Benzyl 7'-(2,6-dioxapiperidin-3-yl)-6',8'-dioxa-7',8'-dihydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-1-carboxylate (Compound 5f)

[0284] To a solution of compound 5e (13 mg, 0.03 mmol) in acetic acid (1 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (6 mg, 0.036 mmol) and sodium acetate (7 mg, 0.09 mmol). The reaction was heated to 110°C and stirred for 4 hours. After completion of the reaction, the reaction solution was purified by reverse transpiration to afford compound 5f (12 mg, 77%) as a white solid.

[0285] 1H NMR(600MHz,CD3OD)δ7.42(s,1H),7.40–7.31(m,6H),5.15(s,2H),5.08(dd,J=12.9,5.5Hz,1H),4.14(s,2H),4.01(dt,J=13.8,4.0Hz,2H),3.43–3 .32(m,2H),2.91–2.83(m,1H),2.79–2.69(m,2H),2.14–2.09(m,1H),1.83 (d,J=13.9Hz,2H),1.74(td,J=14.4,12.9,4.8Hz,2H).LC-MS(ESI):[M+H] + =520.29.

[0286] Step 6: 7'-(2,6-dioxapiperidin-3-yl)-7'-hydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-6',8'-dione (E3 ligase inhibitor 5)

[0287] Palladium on carbon (5 mg) was added to a methanol solution of compound 5f (11 mg, 0.02 mmol), the atmosphere was replaced with hydrogen, and the reaction mixture was stirred under hydrogen for 6 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain a white solid E3 ligase inhibitor 5 (7 mg, 90%).

[0288] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.50(s,1H),7.48(s,1H),5.09(dd,J=12.8,5.3Hz,1H),4.27(s,2H),3.25(d,J=12.7Hz,2H),3.18–3. 11(m,2H),2.89(ddd,J=16.7,13.7,5.3Hz,1H),2.64–2.53(m,2H),2.03(ddd,J=13.3,5.7,3.4Hz,1H),1.92–1.86(m,4H).LC-MS(ESI):[M+H] + =386.32

[0289] 6) Synthesis of E3 ligase inhibitor 6

[0290] Step 1: tert-Butyl 4-(dibromomethyl)piperidine-1-carboxylate (Compound 6b)

[0291] Under nitrogen, compound 6a (5 g, 25.1 mmol) and triphenylphosphine (26.3 g, 100.4 mmol) were dissolved in anhydrous acetonitrile (50 mL). Carbon tetrabromide (16.7 g, 50.2 mmol) was added portionwise to the reaction system at 0°C. After 30 minutes of reaction, the reaction system was warmed to room temperature and allowed to react overnight. After completion of the reaction, the reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 6b (5.5 g, 62%) as a white solid.

[0292] 1 H NMR (600MHz, DMSO-d6) δ3.37 (s, 4H), 2.41 (dd, J = 7.2, 4.7Hz, 4H), 1.41 (d, J = 0.9Hz, 9H).

[0293] Step 2: tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (Compound 6c)

[0294] Under nitrogen, compound 6b (5.2 g, 18.9 mmol) was dissolved in tetrahydrofuran (34 mL) and methanol (17 mL). Ammonium chloride (4.04 g, 75.6 mmol) was added to the reaction system at 0°C. After reacting at 0°C for 30 min, zinc powder (4.9 g, 75.6 mmol) was added portionwise and allowed to react overnight at room temperature. After completion of the reaction, the reaction system was filtered, and the filter cake was washed with methanol. The resulting filtrate was spin-dried under reduced pressure, and the concentrated crude product was purified by column chromatography to afford compound 6c (2.6 g, 50%) as a white oil.

[0295] 1 H NMR (600MHz, DMSO-d6) δ6.26(t,J=1.3Hz,1H),3.34(dt,J=16.4,6.3Hz,4H),2.32–2.27(m,2H),2.23(ddd,J=7.2,4.4,1.2Hz,2H),1.41(s,9H).

[0296] Step 3: Under nitrogen protection, compound 6c (2 g, 7.3 mmol), compound 5c (2.64 g, 7.8 mmol) prepared by steps 1 and 2 of Example 5, palladium acetate (163 mg, 0.73 mmol), triphenylphosphine (382 mg, 1.46 mmol), and cesium carbonate (7.14 g, 21.9 mmol) were added sequentially to a reaction flask. 1,4-dioxane (20 mL) and water (2 mL) were also added. After nitrogen substitution, the reaction was continued at 110°C for 4 hours. After completion of the reaction, the reaction system was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography to yield compound 6d (1.4 g, 47%) as a pale yellow oil.

[0297] 1 H NMR (600MHz, DMSO-d6) δ7.65(d,J=7.0Hz,1H),7.60(d,J=9.7Hz,1H),6.32(s,1H),3.83(s,3H),3.82(s,3H),3.43(t,J =5.8Hz,2H),3.35(s,1H),3.33(s,1H),2.37–2.32(m,2H),2.25(t,J=5.9Hz,2H),1.42(s,9H).LC-MS(ESI):[M-Boc+H] + =308.28.

[0298] Step 4: Dimethyl 4-(bromo(1-(tert-butyloxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-5-fluorophthalate (Compound 6e)

[0299] Under nitrogen protection, compound 6d (7 g, 17.2 mmol) was dissolved in tetrahydrofuran (140 mL) and water (140 mL), and N-bromosuccinimide (6.12 g, 34.4 mmol) was added. The mixture was allowed to react at room temperature overnight. After completion of the reaction, the excess tetrahydrofuran was removed by concentration under reduced pressure. After addition of water, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography to yield compound 6e (4.9 g, 56%) as a pale yellow oil. LC-MS (ESI): [M-Boc+H] + =404.30 / 406.30.

[0300] Step 5: Dimethyl 4-(1-(tert-butyloxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-5-fluorophthalate (Compound 6f)

[0301] Under nitrogen, compound 6e (10.9 g, 21.61 mmol) was dissolved in toluene (80 ml), and tris(trimethylsilyl)silane (8.06 g, 32.42 mmol) and azobisisobutyronitrile (357 mg, 2.16 mmol) were added. The mixture was allowed to react overnight at 90°C. After completion of the reaction, the residue was concentrated under reduced pressure to remove excess toluene. The crude product was purified by column chromatography to afford compound 6f (1.5 g, 16%) as a pale yellow oil.

[0302] 1 H NMR (600MHz, DMSO-d6) δ7.77(d,J=6.9Hz,1H),7.52(d,J=9.5Hz,1H),4.62(s,1H),3.82(d, J=2.1Hz,6H),3.66(s,2H),3.34(s,4H),2.79(s,2H),1.38(s,9H).LC-MS(ESI):[M-Boc+H] + =326.37.

[0303] Step 6: 1'-(tert-Butyl)-5,6-dimethyl-3H-spiro[benzofuran-2,4'-piperidine]-1',5,6-tricarboxylate (Compound 6g): Under nitrogen protection, Compound 6f (1.6 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (2 ml), sodium hydride (300 mg, 7.52 mmol) was added, and the mixture was reacted at 110°C overnight. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified by reverse transpiration to yield Compound 6g (660 mg, 43%) as a pale yellow solid.

[0304] 1 H NMR (600MHz, CDCl3) δ7.58(s,1H),7.15(s,1H),3.93(s,3H),3.89(s,3H),3.56(t,J=5.7Hz,2H),3.42(t,J= 5.8Hz,2H),2.42(t,J=5.9Hz,2H),2.24(t,J=5.9Hz,2H),1.61(s,2H),1.50(s,9H).LC-MS(ESI):[M-Boc+H] + =306.23.

[0305] Step 7: 1'-(tert-Butyloxycarbonyl)-3H-spiro[benzofuran-2,4'-piperidine]-5,6-dicarboxylic acid (Compound 6h)

[0306] Under nitrogen, compound 6g (660 mg, 1.63 mmol) was dissolved in methanol (9 ml) and water (1 ml). Lithium hydroxide (389 mg, 16.28 mmol) was added and allowed to react overnight at room temperature. The concentrated crude product was purified by reverse transpiration to afford compound 6h (600 mg, 97%) as a pale yellow solid.

[0307] 1 H NMR (400MHz, DMSO-d6) δ7.39(s,1H),6.37(s,1H),3.17(s,2H),2.29(d,J=51.9Hz,4 H),1.98(dd,J=13.7,6.9Hz,2H),1.64(s,2H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] + =278.26.

[0308] Step 8: 6-(2,6-dioxopiperidin-3-yl)spiro[furan[2,3-f]isoindole-2,4'-piperidine]-5,7(3H,6H)-dione (E3 ligase inhibitor 6)

[0309] Compound 6h (400 mg, 1.06 mmol) was dissolved in acetic acid (5 mL), and 3-aminopiperidine-2,6-dione hydrochloride (169 mg, 1.32 mmol) and sodium acetate (260 mg, 3.18 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse phase column to obtain E3 ligase inhibitor 6 (170 mg, 43%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ7.46(s,1H),7.11(s,1H),5.04(dd,J=12.8,5.4Hz,1H),2.99–2.79(m,5H),2.6 2–2.54(m,1H),2.53(s,1H),2.38(q,J=6.3Hz,4H),2.04–1.96(m,1H),1.90(s,2H).LC-MS(ESI):[M+H] + =370.34.

[0310] 7) Synthesis of E3 ligase inhibitor 7

[0311] Step 1: 2-Benzyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (Compound 7b)

[0312] Compound 7a (5 g, 33 mmol) was dissolved in anhydrous acetonitrile (50 ml). Tetrabutylammonium bromide (1.23 g, 3.3 mmol) and anhydrous potassium carbonate (14 g, 99 mmol) were added to the solution. Benzyl chloride (5.5 g, 43 mmol) was slowly added to the system and allowed to react overnight at 30°C. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 7b (7.5 g, 94%) as a white solid.

[0313] 1 H NMR (400MHz, CDCl3) δ7.37–7.20(m,5H),5.95–5.83(m,2H),4.63(s,2H),3.20–3.01(m,2H),2.61(m,2H),2.31–2.10(m,2H).LC-MS(ESI):[M+H] + =242.22

[0314] Step 2: 2-Benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole (Compound 7c)

[0315] Lithium aluminum tetrahydride (3.2 g, 82 mmol) was added to 40 mL of anhydrous tetrahydrofuran at 0°C, followed by compound 7b (5 g, 20.7 mmol). After an ice bath for 5 minutes, the reaction system was moved to a 70°C oil bath and allowed to react for 3 hours. After the reaction, water was slowly added dropwise to the reaction solution while still in an ice bath until bubbles ceased. The filtrate was collected by filtration and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration afforded compound 7c (3.2 g, 73%) as a yellow oil.

[0316] 1 H NMR (400MHz, CDCl3) δ7.43–7.24(m,5H),5.87(t,J=2.7Hz,2H),3.67(s,2H),3.05–2.90(m,2H),2.44(m,2H),2.29–2.16(m,4H),1.92(m,2H)

[0317] Step 3: 2-Benzyloctahydro-1H-isoindol-5-ol (Compound 7d)

[0318] Compound 7c (5 g, 23.44 mmol) was dissolved in 20 mL of tetrahydrofuran at 0°C. 25 mL of 2M borane-tetrahydrofuran complex was added under ice-cooling. After 12 h of reaction, 13 mL of anhydrous methanol, 10.5 mL of 3M NaOH solution, and 10.5 mL of hydrogen peroxide were added to the reaction solution, which was then reacted at 60°C for 6 h. After completion of the reaction, the solution was cooled to room temperature and extracted with ethyl acetate. The organic phase was saturated with brine and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography to afford compound 7d (1.2 g, 22.2%).

[0319] 1 H NMR (400MHz, CDCl3) δ7.43–7.18(m,5H),3.84(m,1H),3.78(s,2H),2.94(dd,J=9.8,6.7Hz,1H),2.82(dd,J=9.5,7.7Hz,1H),2.6 4(dd,J=9.5,8.4Hz,1H),2.60–2.44(m,2H),2.12(m,1H),1.89–1.72(m,3H),1.54(m,1H),1.47–1.35(m,1H),1.35–1.22(m,2H).

[0320] LC-MS(ESI):[M+H] + =232.31

[0321] Step 4: 2-Benzyloctahydro-5H-isoindol-5-one (Compound 7e)

[0322] Compound 7d (1.2 g, 12.97 mmol) was dissolved in anhydrous dichloromethane. Dess-Martin periodinane (11 g, 25.95 mmol) was added in an ice bath and allowed to react for 12 h. The reaction was quenched with a 1:1 mixture of saturated sodium bicarbonate and saturated sodium thiosulfate. The filtrate was filtered and extracted with dichloromethane. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Concentration afforded a crude product (1 g), which was used directly in the next reaction.

[0323] Step 5: 2-Benzyl-6-bromo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carbaldehyde (Compound 7f)

[0324] Dissolve N,N-dimethylformamide (1.01 mL, 13.08 mmol) in 2 mL of dichloromethane at 0°C. Slowly add phosphorus tribromide (1.13 mL, 11.77 mmol) dropwise and stir at 0°C for 1 hour. Add a dichloro solution of compound 7e (1 g, 2.62 mmol) dropwise to the above system, warm to room temperature and react for 10 hours. After the reaction is completed, place the reaction solution at 0°C and add saturated sodium bicarbonate until no bubbles are generated. Extract with dichloromethane. Wash the organic phase with saturated brine and dry it over anhydrous sodium sulfate. Concentrate to obtain a crude product, which is purified by column chromatography to obtain the target compound 7f (270 mg, 20%).

[0325] 1 H NMR (400MHz, CDCl3) δ10.04(s,1H),7.32(d,J=5.8Hz,5H),3.60(s,2H),3.21–3.10(m,2H),2.85–2.72(m,3H ),2.50–2.43(m,1H),2.33(dd,J=9.2,5.0Hz,1H),2.24–2.18(m,1H),1.83–1.74(m,2H).LC-MS(ESI):[M+H] + =320.16

[0326] Step 6: 2-Benzyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-6,7-dicarboxylic acid methyl ester (Compound 7g)

[0327] Compound 7f (270 mg, 0.84 mmol), dimethyl itaconate (133.4 mg, 0.84 mmol), palladium acetate (9.5 mg, 0.042 mmol), triphenylphosphine (22.11 mg, 0.084 mmol), and sodium acetate (207.5 mg, 2.53 mmol) were added sequentially to a pressure vessel, dissolved in tetrahydrofuran, replaced with nitrogen, and heated to 120°C for overnight reaction. After cooling the reaction system to room temperature, the tetrahydrofuran was dried, and then separated and purified by preparative liquid chromatography to obtain compound 7g (71 mg, 22%).

[0328] 1 H NMR (400MHz, CDCl3) δ7.52–7.39(m,7H),4.38–4.14(m,3H),3.91(d,J=2.8Hz,7H ),3.27(s,3H),2.94(d,J=12.0Hz,1H),2.85–2.72(m,3H),1.55(d,J=6.6Hz,1H).

[0329] LC-MS(ESI):[M+H] +=380.36

[0330] Step 7: 2-Benzyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-6,7-dicarboxylic acid (Compound 7h)

[0331] Compound 7g (71 mg, 0.19 mmol) was dissolved in methanol and water, and lithium hydroxide (90 mg, 3.74 mmol) was added. The mixture was reacted at room temperature for 20 h. After the reaction, the water and methanol were dried to obtain a crude product (62 mg, 95%). The crude product was used directly in the next step.

[0332] LC-MS(ESI):[M+H] + =352.34

[0333] Step 8: 7-Benzyl-2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione (Compound 7i)

[0334] Compound 7h (62 mg, 0.18 mmol) was dissolved in glacial acetic acid, and sodium acetate (43.2 mg, 0.53 mmol) and 3-amino-2,6-piperidinedione hydrochloride (44 mg, 0.26 mmol) were added. The mixture was reacted in an oil bath at 110°C overnight. Methanol and water were then evaporated, and the product was purified by preparative liquid chromatography to obtain compound 7i (39 mg, 49%).

[0335] 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.98–7.72(m,2H),7.64–7.41(m,5H),5. 14(dd,J=12.9,5.4Hz,1H),4.53–4.24(m,2H),4.01(dd,J=13.9,7.6Hz,1H),3. 76(s,3H),3.12(d,J=9.7Hz,1H),3.06–2.91(m,2H),2.92–2.76(m,3H),2.67–2 .54(m,2H),2.04(dd,J=12.5,6.2Hz,1H),1.90–1.59(m,2H).LC-MS(ESI):[M+H] + =444.41

[0336] Step 9: 2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione (E3 ligase inhibitor 7)

[0337] Compound 7i (39 mg, 0.088 mmol) was dissolved in 2 mL of methanol, 4 mg of palladium carbon was added, hydrogen was replaced, and the mixture was reacted at room temperature overnight. The palladium carbon was removed by filtration and the methanol was dried by spin drying. The E3 ligase inhibitor 7 (12 mg, 38%) was obtained by purification by preparative liquid chromatography.

[0338] 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.07–8.95(m,1H),7.95–7.68(m,2H),5.14 (dd,J=13.0,5.3Hz,1H),3.96–3.87(m,2H),3.51(m,2H),3.12(m,1H),3.04–2.82(m,4 H),2.72–2.55(m,2H),2.06(m,1H),1.86(m,1H),1.65–1.46(m,1H).LC-MS(ESI):[M+H] + =354.41

[0339] 8) Synthesis of E3 ligase inhibitor 8

[0340] Step 1: 1,4-dioxa-9,13-dithiadispiro[4.2.5 8 .2 5 ]pentadecane (Compound 8b)

[0341] Compound 8a (10.0 g, 64.0 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 1,3-propanedithiol (7.0 g, 64.0 mmol). 32 mmol of boron trifluoride etherate was added dropwise at -18°C. After the addition was complete, the mixture was stirred at -18°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, 500 mL of water was added, and the solid was filtered and purified by C18 column chromatography to yield compound 8b (2 g, 12.7%).

[0342] 1 H NMR(400MHz,DMSO-d6)δ3.85(s,4H),2.84–2.78(m,4H),2.06-1.98(m,4H),1.93–1.80(m,2H),1.70–1.59(m,4H).LC-MS(ESI):[M+H] + =247.07

[0343] Step 2: 1,5-dithiaspiro[5.5]undecan-9-one (Compound 8c)

[0344] Compound 8b (2.0 g, 8.0 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 100 mL of trifluoroacetic acid at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. After completion of the reaction, sodium bicarbonate (aq) solution was added to the system to adjust the pH to 7. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford compound 8c (1.5 g, 91.0%).

[0345] 1 H NMR(400MHz,DMSO-d6)δ2.93–2.84(m,4H),2.41–2.33(m,4H),2.31-2.25(m,4H),1.94–1.88(m,2H).LC-MS(ESI):[M+H] + =203.05

[0346] Step 3: Dimethyl 4-oxadispiro[chroman-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Compound 8d) Compound 8c (2.0 g, 9.9 mmol) was dissolved in 200 mL of tetrahydrofuran, followed by the addition of compound 4 (2.0 g, 9.8 mmol) and tetrahydropyrrole (2.0 g, 28.0 mmol) at room temperature. After the addition, the mixture was stirred at 70°C for 4 h. After completion of the reaction, the solvent was removed from the system under reduced pressure, and the residue was separated and purified by column chromatography to obtain compound 8d (2.0 g, 46.0%).

[0347] 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.35(s,1H),3.83(s,3H),3.81(s,3H),2.92( s,2H),2.90–2.85(m,2H),2.81–2.74(m,2H),2.14–2.10(m,2H),2.02–1.77(m,8H).

[0348] LC-MS(ESI):[M+H] + =437.10

[0349] Step 4: Dimethyl 4-hydroxydispiro[chroman-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Compound 8e) Compound 8d (2.0 g, 4.5 mmol) was dissolved in 50 mL of methanol and 50 mL of tetrahydrofuran, followed by the addition of sodium borohydride (350.0 mg, 9.0 mmol) at room temperature. After the addition, the mixture was stirred at 70°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography to obtain compound 8e (1.5 g, 75.0%).

[0350] 1 H NMR (600MHz, DMSO-d6) δ7.90 (s, 1H), 7.00 (s, 1H), 5.68 (d, J = 6.2Hz, 1H), 4.77-4.71 (m, 1H), 3.79 (s, 6H),2.96–2.72(m,4H),2.16–2.01(m,4H),1.93–1.79(m,5H),1.77–1.70(m,3H).LC-MS(ESI):[M+H] + =439.12

[0351] Step 5: Dimethyldispiro[chromene-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Compound 8f)

[0352] Compound 8e (700 mg, 1.5 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of triethylamine (480.0 mg, 4.5 mmol) and 4-dimethylaminopyridine (100.0 mg, 0.8 mmol) at room temperature. Sulfuryl chloride (720.0 mg, 6.0 mmol) was added dropwise at 0°C. After the addition, the mixture was stirred at 0°C for 4 h, and the reaction was monitored by TLC. Upon completion of the reaction, the solvent was removed under reduced pressure. After the addition, the residue was dissolved in 100 mL of toluene, followed by the addition of 1,8-diazabicycloundec-7-ene (1.6 g, 10.0 mmol) at room temperature. The mixture was stirred at 110°C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 8f (400 mg, 59.0%).

[0353] 1 H NMR (400MHz, DMSO-d6) δ7.58(s,1H),7.05(s,1H),6.59(d,J=9.9Hz,1H),5.95(d,J=11.4Hz,1H),3.78(s,3H),3.77(s, 3H),2.93–2.85(m,2H),2.82–2.73(m,2H),2.18-2.11(m,2H),2.09–1.96(m,2H),1.92–1.77(m,6H).LC-MS(ESI):[M+H] + =421.11

[0354] Step 6: Dispiro[chromene-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylic acid (Compound 8g)

[0355] Compound 8f (400.0 mg, 0.9 mmol) was dissolved in 50 mL of methanol, 50 mL of tetrahydrofuran, and 50 mL of water, followed by the addition of lithium hydroxide (120.0 mg, 4.5 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 16 h. After completion of the reaction, 1.0 M dilute hydrochloric acid was added to the system, and the pH was adjusted to 6. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford compound 8g (350 mg, 94.0%).

[0356] 1 H NMR (600MHz, DMSO-d6) δ12.90(s,2H),7.52(s,1H),6.99(s,1H),6.57(d,J=9.9Hz,1H),5.90(d,J=9.9Hz,1H) ,2.92–2.86(m,2H),2.83–2.73(m,2H),2.11(m,2H),2.09–1.97(m,2H),1.94–1.76(m,6H).LC-MS(ESI):[M+H] + =393.08

[0357] Step 7: 7-(2,6-dioxapiperidin-3-yl)-6H-dispiro[pyrano[2,3-f]isoindole-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,8(7H)-dione (Compound 8h)

[0358] Compound 8g (300.0 mg, 0.7 mmol) was dissolved in 100 mL of acetic acid, followed by the addition of 3-aminopiperidine-2,6-dione hydrochloride (170.0 mg, 1.3 mmol) and sodium acetate (360.0 mg, 2.1 mmol) at room temperature. After the addition, the mixture was stirred at 110°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 8h (280 mg, 75.0%).

[0359] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.72(s,1H),7.30(s,1H),6.70(d,J=8.0Hz,1H),6.03(d,J=8.8Hz,1H),5.13-5.07( m,1H),2.94–2.84(m,3H),2.84–2.76(m,2H),2.64-2.55(m,1H),2.18–1.98(m,6H),1.95–1.78(m,6H).LC-MS(ESI):[M+H] + =485.11

[0360] Step 8: 7'-(2,6-oxapiperidin-3-yl)-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione (Compound 8i)

[0361] Compound 8h (280.0 mg, 0.5 mmol) was dissolved in 50 mL of acetonitrile, followed by the addition of 50 mL of sodium bicarbonate solution and iodine (1.5 g, 5.0 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the solvent was removed under reduced pressure. The organic phase was then extracted, dried, concentrated, and purified by column chromatography to afford compound 8i (100 mg, 44.0%).

[0362] 1 H NMR (600MHz, DMSO-d6) δ11.13(s,1H),7.77(s,1H),7.45(s,1H),6.76(d,J=10.0Hz,1H),6.09(d,J=9.9Hz,1H),5.13-5.09 (m,1H),2.92-2.84(m,1H),2.78-2.70(m,2H),2.63-2.57(m,1H),2.26-2.15(m,4H),2.12–2.00(m,4H).LC-MS(ESI):[M+H] + =395.12

[0363] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione (E3 ligase inhibitor 8)

[0364] Compound 8i (280.0 mg, 0.7 mmol) was dissolved in 50 mL of tetrahydrofuran, followed by the addition of Pd / C (150.0 mg) at room temperature. After the addition, the mixture was stirred at 50°C under hydrogen for 4 h. Upon completion of the reaction, the reaction mixture was filtered through celite, the solvent was removed under reduced pressure, and the product was purified by preparative liquid chromatography to afford E3 ligase inhibitor 8 (195 mg, 70.0%).

[0365] 1 H NMR(600MHz,DMSO-d6)δ11.11(s,1H),7.68(s,1H),7.35(s,1H),5.12-5.06(m,1H),2.99-2.93(m,2H),2.92- 2.84(m,1H),2.68–2.55(m,3H),2.23-2.15(m,2H),2.13–2.00(m,4H),1.99-1.91(m,4H).LC-MS(ESI):[M+H]+ =397.13

[0366] 9) Synthesis of E3 ligase inhibitor 9

[0367] Step 1: 1'-(tert-Butyl)6,7-dimethyl-4,4-difluorospiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 9a)

[0368] Diethylaminosulfur trifluoride (4 mL) was added to compound 1e (2 g, 4.6 mmol), and the reaction solution was stirred at 85°C for 2 hours. The resulting mixture was poured into ice water and extracted three times with ethyl acetate. The organic phase was concentrated in vacuo and the mixture was purified by reverse-phase column chromatography to obtain compound 9a (0.5 g, 24%) as a yellow oily liquid.

[0369] 1 H NMR(600MHz,DMSO-d6)δ8.02(s,1H),7.29(s,1H),3.82(s,3H),3.81(s,3H),3.77–3.68(m,2H),3.22–3.02(m,2H),2. 72(t,J=14.7Hz,2H),1.85(d,J=13.9Hz,2H),1.70(td,J=14.0,11.6,4.7Hz,2H),1.40(s,9H).LC-MS(ESI):[M-tBu+H] + =400.31.

[0370] Step 2: 1'-(tert-Butyl)-4,4-difluorospiro[chroman-2,4'-piperidine]-6,7-dicarboxylic acid (Compound 9b)

[0371] To a solution of compound 9a (160 mg, 0.4 mmol) in methanol / tetrahydrofuran (2 ml) was slowly added lithium hydroxide (42 mg, 1.8 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted three times with dichloromethane / methanol (10:1) and the organic phase was concentrated in vacuo to afford compound 9b (0.1 g, 67%) as a white solid.

[0372] 1H NMR(600MHz,DMSO-d6)δ13.27(br s,2H),8.12(s,1H),7.36(s,1H),3.21–3.06(m, 2H),2.68(t,J=14.7Hz,2H),2.05–1.93(m,2H),1.84(d,J=13.8Hz,2H),1.68(td,J=14.0,12.9,4.7Hz,2H),1.40(s,9H).LC-MS(ESI):[M-tBu+H] + =372.27.

[0373] Step 3: 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[piperidine-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (E3 ligase inhibitor 9)

[0374] To a solution of compound 9b (100 mg, 0.23 mmol) in acetic acid (1 ml) were slowly added 3-aminopiperidine-2,6-dione hydrochloride (77 mg, 0.5 mmol) and sodium acetate (96 mg, 1.2 mmol). The reaction was stirred at 110°C for 2 hours. After completion of the reaction, the mixture was purified by reverse phase column to obtain the E3 ligase inhibitor 9 (50 mg, 51%) as a brown solid.

[0375] 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.10(s,1H),7.68(s,1H),5.16(dd,J=13.0,5.4Hz,1H),3.27–3.15(m,4H),2.92–2.82(m,3H),2.61(d t,J=17.2,3.4Hz,1H),2.56–2.51(m,1H),2.11(d,J=14.4Hz,2H),2.05(ddt,J=12.9,5.6,2.5Hz,1H),1.97–1.90(m,2H).LC-MS(ESI):[M+H] + =420.36.

[0376] 10) Synthesis of E3 ligase inhibitor 10

[0377] Step 1: 1-(tert-Butyl)6',7'-dimethyl-4',4'-difluorospiro[azetidine-3,2'-chromane]-1,6',7'-tricarboxylate (Compound 10b)

[0378] Diethylaminosulfur trifluoride (5 mL) was slowly added to compound 10a (1 g, 2.5 mmol). The reaction mixture was stirred at 50°C overnight. The resulting mixture was poured into ice water to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 0-40%) to afford compound 10b (500 mg, 47%) as a light yellow solid.

[0379] 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.34(s,1H),4.13(d,J=9.7Hz,2H),3.91(d,J=9.7Hz, 2H),3.83(s,3H),3.82(s,3H),3.04(t,J=13.4Hz,2H),1.39(s,9H).LC-MS(ESI):[M-Boc+H] + =328.30.

[0380] Step 2: 1-(tert-Butyloxycarbonyl)-4',4'-difluorospiro[azetidine-3,2'-chromane]-6',7'-dicarboxylic acid (Compound 10c)

[0381] Compound 10b (500 mg, 1.2 mmol) was dissolved in methanol (5 mL) and an aqueous solution of lithium hydroxide (140.1 mg, 5.9 mmol) was slowly added at room temperature. The reaction was stirred at room temperature for 2 h. The reaction solution was neutralized with acetic acid to pH 7. The product was concentrated under vacuum and extracted with ethyl acetate to yield a crude white solid, which was used directly in the next step without further purification.

[0382] LC-MS(ESI):[M+H] + =399.28.

[0383] Step 3: 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (E3 ligase inhibitor 10)

[0384] Under nitrogen, compound 10c (100 mg, 0.3 mmol) was dissolved in acetic acid (1 mL). Sodium acetate (61.6 mg, 0.8 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (64.5 mg, 0.5 mmol) were added, and the mixture was heated to 110°C and stirred for 3 h. After completion of the reaction, the mixture was purified via a C18 reverse-phase column to obtain E3 ligase inhibitor 10 (3.6 mg, 4%) as a white solid.

[0385] 1H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.13(s,1H),7.58(s,1H),5.18(dd,J=13.0,5.4Hz,1H),4.33(d,J=11.7Hz,2H),4.22(d,J=1 1.6Hz,2H),3.15(t,J=13.6Hz,2H),2.94–2.87(m,1H),2.65–2.59(m,1H),2.54–2.51(m,1H),2.10–2.05(m,1H).LC-MS(ESI):[M+H] + =392.30.

[0386] 11) Synthesis of E3 ligase inhibitor 11

[0387] Step 1: 1'-(tert-butyl)6,7-dimethyl-3,3-difluoro-4-oxospiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 11a)

[0388] Compound 1e (5 g, 11.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The temperature was lowered to -78°C and sodium bis(trimethylsilyl)amide (4.23 g, 23.07 mmol) was added dropwise. The reaction was incubated for 2 h. N-fluorobisbenzenesulfonamide (7.3 g, 23.1 mmol) was then added dropwise at -78°C. The reaction solution was stirred overnight at -78°C. The resulting mixture was poured into saturated ammonium chloride solution to quench the mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 0-40%) to give compound 11a (2.5 g, 46%) as a light yellow solid.

[0389] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.62(s,1H),3.94(d,J=11.6Hz,2H),3.85(s,3H),3.86(s,3H) ,3.08(s,2H),2.07(d,J=13.4Hz,2H),1.74(td,J=13.5,4.7Hz,2H),1.41(s,9H).LC-MS(ESI):[M+H] + =470.31.

[0390] Step 2: 1'-(tert-Butyl)6,7-dimethyl 3,3-difluoro-4-hydroxyspiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 11b)

[0391] Compound 11a (2.5 g, 5.3 mmol) was dissolved in ethanol (5 mL) and sodium borohydride (403 mg, 10.7 mmol) was slowly added at 0°C. The reaction was stirred at room temperature for 1 h. The reaction solution was quenched with acetone. After concentration under vacuum, the crude product was purified by column chromatography (PE:EA = 0-40%) to afford compound 11b (2.4 g, 95%) as a white solid.

[0392] 1 H NMR (400MHz, DMSO-d6) δ7.90(s,1H),7.23(s,1H),6.68(d,J=6.1Hz,1H),5.03(dt,J=16.1,7.0Hz,1H),3.97(d,J=14.1Hz,1H),3.91–3 .75(m,7H),3.04(d,J=55.0Hz,2H),1.99(d,J=13.3Hz,1H),1.84–1.74(m,2H),1.70–1.56(m,1H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] + =372.34.

[0393] Step 3: 1'-(tert-butyl)6,7-dimethyl-3,3-difluoro-4-(toluenesulfonyloxy)spiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylic acid (Compound 11c)

[0394] Compound 11b (1.5 g, 3.2 mmol) was dissolved in dichloromethane (30 mL). p-Toluenesulfonyl chloride (727 mg, 3.8 mmol) and triethylamine (642 mg, 6.4 mmol) were added under ice-cooling. The mixture was stirred at room temperature for 2 h. After vacuum concentration, the crude product was purified by column chromatography (PE:EA = 0-40%) to afford Compound 11c (1.0 g, 50%) as a white solid.

[0395] 1 H NMR (600MHz, DMSO-d6) δ7.98(d,J=8.2Hz,2H),7.56(d,J=8.1Hz,2H),7.41(s,1H),7.35(s,1H),6.25(dd,J=12.9,8.1Hz,1H),3.90(dd,J=21.4,8.9Hz, 2H),3.81(s,3H),3.79(s,3H),3.06(s,2H),2.48(s,3H),1.99–1.91(m,2H) ,1.67(dtd,J=39.4,13.3,4.7Hz,2H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] +=526.34.

[0396] Step 4: 1'-(tert-Butyl)-6,7-dimethyl-3,3-difluorospiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 11d): Compound 11c (1.0 g, 1.6 mmol) was dissolved in methanol (20 mL) and palladium on carbon (100 mg) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 12 h. Filtered, washed with methanol, and concentrated under vacuum to afford Compound 11d (700 mg, 96%) as a white solid.

[0397] 1 H NMR (600MHz, DMSO-d6) δ7.70(s,1H),7.28(s,1H),3.95–3.88(m,2H),3.86–3.74(m,8H),3.51(t,J=15 .8Hz,2H),1.81(d,J=13.2Hz,2H),1.69(td,J=13.6,4.9Hz,2H),1.42(s,9H).LC-MS(ESI):[M-tBu+H] + =400.44.

[0398] Step 5: 1'-(tert-Butyloxycarbonyl)-3,3-difluorospiro[chromane-2,4'-piperidine]-6,7-dicarboxylic acid (Compound 11e)

[0399] Compound 11d (700 mg, 1.5 mmol) was dissolved in methanol and water (10 mL). Lithium hydroxide (184 mg, 7.7 mmol) was added and stirred at room temperature for 2 h. Glacial acetic acid was added to neutralize the mixture to pH 7. Concentrate under vacuum and extract with ethyl acetate to obtain a crude white solid. The product was used directly in the next step without further purification. LC-MS (ESI): [M-Boc+H] + =328.32.

[0400] Step 6: 7'-(2,6-dioxapiperidin-3-yl)-3',3'-difluoro-3',4'-dihydro-6'H-spiro[piperidine-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (E3 ligase inhibitor 11)

[0401] Under nitrogen, compound 11e (600 mg, 1.4 mmol) was dissolved in acetic acid (10 mL). Sodium acetate (346 mg, 4.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (360 mg, 2.8 mmol) were added, and the mixture was heated to 110°C and stirred for 3 h. After completion of the reaction, the mixture was purified via a C18 reverse-phase column to obtain E3 ligase inhibitor 11 (70 mg, 12%) as a white solid.

[0402] 1 H NMR (400MHz, CD3OD) δ7.78(s,1H),7.55(s,1H),5.13(dd,J=12.6,5.4Hz,1H),3.60(t,J=15.5Hz,2 H),3.50–3.34(m,4H),2.93–2.82(m,1H),2.80–2.66(m,2H),2.24–2.09(m,5H).LC-MS(ESI):[M+H] + =420.41.

[0403] 12) Synthesis of E3 ligase inhibitor 12

[0404] Step 1: 1-(5-Bromo-2-hydroxy-4-methylphenyl)ethan-1-one (Compound 12b)

[0405] A mixture of 4-bromo-3-methylphenol 12a (5.0 g, 26.7 mmol) and acetyl chloride (10.5 g, 134 mmol) was stirred at 60°C for 1 hour, and then aluminum chloride (5.4 g, 40.1 mmol) was added at room temperature. After stirring at 160°C for 2 hours, the mixture was cooled to room temperature, poured into saturated ammonium chloride solution (50 mL), and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 12b as an off-white solid (5.5 g, 90%).

[0406] 1 H NMR (600MHz, DMSO-d6) δ11.81(s,1H),8.01(s,1H),7.00(s,1H),2.62(s,3H),2.34(s,3H).

[0407] Step 2: Methyl 5-acetyl-4-hydroxy-2-methylbenzoate (Compound 12c)

[0408] To a solution of compound 12b (5.5 g, 24.01 mmol) in methanol (50 mL) were added triethylamine (9.72 g, 96.04 mmol) and Pd(dppf)Cl2 (1.76 g, 2.40 mmol). The mixture was purged with CO three times and then stirred at 60°C overnight. After the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by column chromatography (PE:EA = 6:1) to afford 12c (3.26 g, 65%) as a white solid.

[0409] 1H NMR (600MHz, DMSO-d6) δ12.14(s,1H),8.34(s,1H),6.90(s,1H),3.82(s,3H),2.64(s,3H),2.53(s,3H).

[0410] Step 3: 1'-(tert-Butyl)6-methyl-7-methyl-4-oxaspiro[chroman-2,4'-piperidine]-1',6-dicarboxylate (Compound 12d) To a solution of 12c (3.1 g, 14.89 mmol) in ethanol (120 mL) were added N-tert-butyloxycarbonyl-3-azetidinone (2.8 g, 16.38 mmol) and tetrahydropyrrole (1.59 g, 22.33 mmol). The reaction was stirred at 80°C overnight. After the reaction was complete, the resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-20%) to afford 12d (1.9 g, 35%) as a yellow solid.

[0411] 1 H NMR(600MHz,DMSO-d6)δ8.25(s,1H),7.08(s,1H),3.82(s,3H),3.72(s,2H),3.14(s,2H),2.89( s,2H),2.55(s,3H),1.91-1.84(m,2H),1.69-1.61(m,2H),1.40(s,9H).LC-MS(ESI):[M-Boc+H] + =290.27.

[0412] Step 4: 1'-(tert-butyl)6-methyl-4-hydroxy-7-methylspiro[chroman-2,4'-piperidine]-1',6-dicarboxylate (Compound 12e)

[0413] To a solution of 12d (1.6 g, 4.43 mmol) in methanol (40 mL) was added sodium borohydride (504 mg, 13.28 mmol). The reaction was stirred at room temperature for 4 hours. After completion of the reaction, the resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to afford 12e (1.5 g, 93.23%) as a yellow solid.

[0414] 1H NMR (600MHz, DMSO-d6) δ8.01(s,1H),6.73(s,1H),5.52(d,J=4.7Hz,1H),4.68(s,1H),3.78(s,3H),3.68(dd,J=22.7,9.0Hz,2H),3.13( d,J=77.0Hz,2H),2.46(s,3H),2.13(dd,J=13.5,6.0Hz,1H),1.82-1.62(m,4H),1.59-1.50(m,1H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] + =292.30.

[0415] Step 5: 1'-(tert-Butyl)6-methyl7-methylspiro[chromene-2,4'-piperidine]-1',6-dicarboxylate (Compound 12f)

[0416] To a solution of 12e (1.5 g, 4.13 mmol) in toluene (40 mL) was added p-toluenesulfonic acid (712 mg, 4.13 mmol). The reaction was stirred at 110°C overnight. After completion of the reaction, the system was concentrated under vacuum to obtain a mixture, which was dissolved in tetrahydrofuran (40 mL). Triethylamine (2.23 g, 22.02 mmol) and di-tert-butyl dicarbonate (2.4 g, 11.01 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-30%) to afford 12f (1.1 g, 77%) as a yellow solid.

[0417] 1 H NMR (600MHz, DMSO-d6) δ7.64(s,1H),6.80(s,1H),6.55(d,J=9.9Hz,1H),5.80(d,J=9.8Hz,1H),3.78(s,3H),3.70(d,J= 13.0Hz,2H),3.30–3.11(m,2H),2.47(s,3H),1.84-1.78(m,2H),1.68-1.60(m,2H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] + =274.26.

[0418] Step 6: 1'-(tert-butyl)6-methyl7-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',6-dicarboxylate (Compound 12g)

[0419] To a solution of compound 12f (1 g, 2.90 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (620 mg, 3.47 mmol) and azobisisobutyronitrile (48 mg, 290 μmol). The reaction system was replaced with a nitrogen atmosphere and stirred at 80°C overnight. After completion of the reaction, the system was concentrated under vacuum, and the crude product was used directly in the next step.

[0420] Step 7: 3-(6'-oxa-6',8'-dihydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 12h)

[0421] The mixture from the previous step was dissolved in acetonitrile (40 mL), and diisopropylethylamine (1.12 g, 8.70 mmol) and 3-amino-2,6-piperidinedione (446 mg, 3.48 mmol) were added. The mixture was stirred at 80°C overnight. After concentration, acetic acid (10 mL) was added and the reaction continued for 2 hours. After the reaction was complete, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-50%) to obtain 12 g (285 mg, 22%) of a black solid.

[0422] 1 H NMR(600MHz,CD3OD)δ7.52(s,1H),7.13(s,1H),6.69(d,J=9.9Hz,1H),5.83(d,J=9.9Hz,1H),5 .13(dd,J=13.3,5.1Hz,1H),4.45(dd,J=35.2,17.3Hz,2H),3.48-3.40(m,2H),3.38-3.33(m,2 H),2.91(ddd,J=18.2,11.8,5.0Hz,2H),2.82-2.77(m,1H),2.49(ddd,J=17.9,12.7,3.8Hz,1H ),2.29-2.22(m,2H),2.17(tdd,J=13.4,6.7,4.2Hz,1H),2.03-1.95(m,2H).LC-MS(ESI):[M+H] + =368.38.

[0423] Step 8: 3-(6'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (E3 ligase inhibitor 12)

[0424] 12 g of the product from the previous step was dissolved in methanol (10 mL), palladium carbon (150 mg) was added thereto, and the reaction system was replaced with a hydrogen atmosphere and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum. The white solid E3 ligase inhibitor 12 (120 mg, two-step yield 35%) was purified by preparative high-performance liquid chromatography.

[0425] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),7.51(s,1H),7.05(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.9Hz,1H),4.22(d,J=16.9Hz,1H),3.26 -3.20(m,2H),3.16-3.08(m,2H),2.94-2.86(m,3H),2.63-2.57(m,1H),2. 41-2.33(m,1H),2.00-1.87(m,5H),1.85-1.77(m,2H).LC-MS(ESI):[M+H] + =370.39.

[0426] 13) Synthesis of Compound 13

[0427] Synthesis scheme:

[0428] Step 1: 1-(tert-Butyl)6'-methyl7'-methyl-4'-oxaspiro[azetidine-3,2'-chroman]-1,6'-dicarboxylate (Compound 13a)

[0429] To a solution of methyl 2-methyl-4-hydroxy-5-acetylbenzoate (3.1 g, 14.89 mmol) in ethanol (120 mL) were added N-tert-butyloxycarbonyl-3-azetidinone (2.8 g, 16.38 mmol) and tetrahydropyrrole (1.59 g, 22.33 mmol). The reaction was stirred at 80°C overnight. After completion of the reaction, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-20%) to afford 13a (1.9 g, 35%) as a yellow solid.

[0430] 1 H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.15(s,1H),4.00(d,J=8.7Hz,2H),3.89(d,J=8. 7Hz,2H),3.82(s,3H),3.20(s,2H),2.56(s,3H),1.38(s,9H).LC-MS(ESI):[M-Boc+H]+ =262.25.

[0431] Step 2: 1-(tert-Butyl)6'-methyl-4'-hydroxy-7'-methylspiro[azetidine-3,2'-chroman]-1,6'-dicarboxylate (Compound 13b)

[0432] To a solution of 13a (1.6 g, 4.43 mmol) in methanol (40 mL) was added sodium borohydride (504 mg, 13.28 mmol). The reaction was stirred at room temperature for 4 hours. After completion, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-40%) to afford 13b (1.5 g, 93.23%) as a yellow solid.

[0433] 1 H NMR (600MHz, CD3OD) δ8.02(s,1H),6.81(s,1H),4.82(t,J=5.2Hz,1H),4.28(d,J=9.6Hz,1H),4.04(dd,J=19.0,9.1Hz, 2H),3.95(d,J=9.7Hz,1H),3.87-3.84(m,3H),2.54(s,3H),2.32(d,J=5.2Hz,2H),1.47(s,9H).LC-MS(ESI):[M-Boc+H] + =264.27.

[0434] Step 3: 1-(tert-Butyl)6'-methyl7'-methylspiro[azetidine-3,2'-chromene]-1,6'-dicarboxylate (Compound 13c)

[0435] To a solution of 13b (1.5 g, 4.13 mmol) in toluene (40 mL) was added p-toluenesulfonic acid (712 mg, 4.13 mmol). The reaction was stirred at 110°C overnight. The resulting mixture was concentrated under vacuum, dissolved in tetrahydrofuran (40 mL), and triethylamine (2.23 g, 22.02 mmol) and di-tert-butyl dicarbonate (2.4 g, 11.01 mmol) were added. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-30%) to afford 13c (1.1 g, 77%) as a yellow solid.

[0436] 1H NMR (600MHz, DMSO-d6) δ7.67(s,1H),6.84(s,1H),6.65(d,J=9.9Hz,1H),6.16(d,J =9.9Hz,1H),4.04(s,4H),3.78(s,3H),2.47(s,3H),1.40(s,9H).LC-MS(ESI):[M-Boc+H] + =246.23.

[0437] Step 4: tert-Butyl 7'-(2,6-dioxapiperidin-3-yl)-6'-oxa-7',8'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-1-carboxylate (Compound 13d)

[0438] To a solution of compound 13c (1 g, 2.90 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (620 mg, 3.47 mmol) and azobisisobutyronitrile (48 mg, 290 μmol). The reaction system was replaced with a nitrogen atmosphere and stirred at 80°C overnight. The resulting mixture was concentrated under vacuum, dissolved in acetonitrile (40 mL), and diisopropylethylamine (1.12 g, 8.70 mmol) and 3-amino-2,6-piperidinedione (446 mg, 3.48 mmol) were added. The mixture was stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to afford 13d (285 mg, 22%) as a black solid.

[0439] 1 H NMR (600MHz, CD3OD) δ7.50 (s, 1H), 7.09 (s, 1H), 6.69 (d, J = 9.9Hz, 1H), 6.17 (d ,J=9.8Hz,1H),5.12(dd,J=13.2,5.2Hz,1H),4.50-4.40(m,2H),4.24-4.19(m ,2H),4.10(d,J=8.9Hz,2H),2.94-2.86(m,1H),2.82-2.77(m,1H),2.49(ddd, J=26.5,13.2,4.5Hz,1H),2.19-2.15(m,1H),1.48(s,9H).LC-MS(ESI):[M+H] + =440.38.

[0440] Step 5: 3-(6'-oxa-6',8'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 13e)

[0441] Compound 13d (285 mg, 648.5 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (636 mg, 6.49 mmol) was added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the solution was concentrated and used directly in the next step. LC-MS (ESI): [M+H] + =340.32.

[0442] Step 6: 3-(6'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (E3 ligase inhibitor 13)

[0443] The mixture from the previous step was dissolved in methanol (10 mL), and palladium on carbon (10%, 150 mg) was added thereto. The reaction system was replaced with a hydrogen atmosphere and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum. The mixture was purified by preparative high-performance liquid chromatography to obtain a white solid E3 ligase inhibitor 13 (120 mg, two-step yield 35%).

[0444] 1 H NMR(400MHz,CD3OD)δ7.57(s,1H),7.10(s,1H),5.11(dd,J=13.3,5.1Hz,1H ),4.50-4.35(m,2H),4.24(s,4H),2.97(t,J=5.8Hz,2H),2.91-2.84(m,1H) ,2.77(ddd,J=17.6,4.5,2.3Hz,1H),2.46(ddd,J=26.4,13.2,4.7Hz,1H),2 .28(t,J=6.1Hz,2H),2.14(dtd,J=12.7,5.2,2.3Hz,1H).LC-MS(ESI):[M+H] + =342.32.

[0445] 14) Synthesis of E3 ligase inhibitor 14

[0446] Step 1: 1-(4-Bromo-2-hydroxy-5-methylphenyl)ethan-1-one (Compound 14b)

[0447] 3-Bromo-4-methylphenol 14a (15.2 g, 81.27 mmol) was added to acetyl chloride (30 mL) and stirred at 60°C for 1 hour. After the reaction solution cooled to room temperature, aluminum chloride (16.25 g, 121.90 mmol) was slowly added. After completion, the reaction solution was stirred at 160°C for 3 hours. The resulting mixture was poured into ice water, filtered, and washed with saturated aqueous ammonium chloride. The mixture was concentrated under vacuum to obtain a mixture, which was then purified by column chromatography (PE:EA = 0-50%) to obtain 14b (18.0 g, 96%) as a yellow-brown solid.

[0448] 1 H NMR (600MHz, CDCl3) δ12.10(s,1H),7.57(s,1H),7.25(s,1H),2.63(s,3H),2.39(s,3H).

[0449] Step 2: Methyl 4-acetyl-5-hydroxy-2-methylbenzoate (Compound 14c)

[0450] To a solution of compound 14b (3.0 g, 13.1 mmol) in methanol (60 mL) were added triethylamine (1.99 g, 19.6 mmol) and Pd(dppf)Cl2 (1.42 g, 1.96 mmol). Under a carbon monoxide atmosphere, the reaction was stirred at 60°C overnight. After completion of the reaction, the filtrate was filtered and concentrated under vacuum. The resulting mixture was purified by column chromatography (PE:EA = 0-50%) to afford 14c (16.3 g, 51%) as a tan solid.

[0451] 1 H NMR (600MHz, CDCl3) δ11.88(s,1H),7.60(s,1H),7.49(s,1H),3.93(s,3H),2.68(s,3H),2.53(s,3H).

[0452] Step 3: 1'-(tert-Butyl)-7-methyl-6-methyl-4-oxaspiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Compound 14d): Compound 14c (10.11 g, 48.56 mmol), N-tert-butyloxycarbonyl-4-piperidone (9.67 g, 48.56 mmol), and tetrahydropyrrole (3.45 g, 48.56 mmol) were dissolved in methanol (50 mL) and refluxed at 80°C for 6 h. After the reaction was complete, the mixture was extracted, filtered, and concentrated to obtain the crude product, which was then purified by column chromatography (PE:EA = 0-50%) to obtain 14d (15.53 g, 82%) as a pale yellow solid.

[0453] 1H NMR (600MHz, DMSO-d6) δ7.64(s,1H),7.45(s,1H),3.85(s,3H),3.71(s,2H),3.12(d,J=50.1Hz,2H),2.88( s,2H),2.43(s,3H),1.90-1.84(m,2H),1.62(td,J=12.7,4.6Hz,2H),1.40(s,9H).LC-MS(ESI):[M-Boc+H] + =290.26.

[0454] Step 4: 1'-(tert-Butyl)7-methyl-4-hydroxy-6-methylspiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Compound 14e) was added to a solution of Compound 14d (15.53 g, 39.88 mmol) in methanol (70 mL) under ice-cooling conditions. Sodium borohydride (6.03 g, 159.51 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to afford 14e (15.39 g, 98%) as a yellow foam.

[0455] 1 H NMR (600MHz, CDCl3) δ7.40 (s, 1H), 7.32 (s, 1H), 4.83 (t, J = 7.0Hz, 1H), 3.90- 3.84(m,5H),3.31-3.05(m,2H),2.93(s,1H),2.49(s,3H),2.11(dd,J=13.6, 6.1Hz,1H),1.92-1.85(m,2H),1.78-1.72(m,1H),1.63(td,J=13.3,4.6Hz,1 H),1.52(ddd,J=24.7,12.6,7.9Hz,1H),1.46(s,9H).LC-MS(ESI):[M-Boc+H] - =292.27.

[0456] Step 5: Methyl 6-methylspiro[chroman-2,4'-piperidine]-7-dicarboxylate (Compound 14f)

[0457] Compound 14e (15.23 g, 38.91 mmol) and p-toluenesulfonic acid (6.7 g, 38.91 mmol) were dissolved in toluene and refluxed at 110°C overnight. The resulting mixture, 14f (8.6 g, 80%), was concentrated under vacuum to form a pale yellow oil. The crude product was used directly in the next step. LC-MS (ESI): [M-Boc+H] + =274.29.

[0458] Step 6: 1'-(tert-Butyl)7-methyl6-methylspiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Compound 14g)

[0459] Compound 14f (8.6 g, 31.46 mmol), di-tert-butyl dicarbonate (13.73 g, 62.93 mmol), and triethylamine (9.55 g, 94.39 mmol) were dissolved in dichloromethane (30 mL), and the mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-30%) to give 14 g (1.8 g, 83%) as a colorless solid.

[0460] 1 H NMR (600MHz, CDCl3) δ7.41(s,1H),6.85(s,1H),6.37(d,J=9.8Hz,1H),5.65(d,J=9.6Hz,1H),3.98-3.77(m,5H),3. 28(s,2H),2.50(s,3H),1.97(d,J=13.4Hz,2H),1.59(td,J=13.4,4.7Hz,2H),1.47(s,9H).LC-MS(ESI):[M-Boc+H] + =274.24.

[0461] Step 7: 1'-(tert-Butyl)7-methyl 6-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Compound 14h)

[0462] Compound 14g (5.11 g, 13.68 mmol), N-bromosuccinimide (2.73 g, 15.33 mmol), and azobisisobutyronitrile (0.112 g, 6.84 mmol) were dissolved in carbon tetrachloride (30 mL) and the reaction was refluxed at 80°C overnight under nitrogen. The mixture was extracted and dried to give 14h (1.32 g, 21%) as a colorless oil. The crude product was used directly in the next step.

[0463] Step 8: 3-(8'-oxa-6',8'-dihydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 14i)

[0464] Compound 14g (1.56 g, 3.45 mmol) was dissolved in acetonitrile (20 mL), and 3-aminopiperidine-2,6-dione hydrochloride (0.53 g, 4.14 mmol) and N,N-diisopropylethylamine (1.33 g, 10.35 mmol) were added. The reaction was stirred at 80°C overnight. The mixture was then spin-dried and acetic acid (1 mL) was added, and the mixture was refluxed at 110°C for 2 hours. After completion of the reaction, the mixture was purified by reverse phase column chromatography to obtain 14i (0.96 g, 75%) as a brown solid.

[0465] 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),7.36(s,1H),7.25(s,1H),6.68(d,J=9.8Hz,1H),5.99(d, J=9.8Hz,1H),5.08(dd,J=13.3,5.2Hz,1H),4.37(d,J=16.9Hz,1H),4.25(d,J=16.9Hz,1H),3.26 -3.19(m,4H),2.90(ddd,J=17.3,13.7,5.5Hz,1H),2.64-2.57(m,1H),2.39(qd,J=13.2,4.5Hz,1 H),2.10–2.03(m,2H),2.00(dtd,J=12.8,5.4,2.4Hz,1H),1.94–1.86(m,2H).LC-MS(ESI):[M+H] + =368.37.

[0466] Step 9: 3-(8'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (E3 ligase inhibitor 14)

[0467] Compound 14i (0.668 g, 1.82 mmol) was dissolved in methanol (15 mL) and palladium on carbon (0.2 g) was added. The reaction was stirred at room temperature overnight under hydrogen. The mixture was filtered and dried, and then purified by reverse phase column chromatography to obtain E3 ligase inhibitor 14 (0.536 g, 79%) as a white solid.

[0468] 1H NMR(600MHz,DMSO-d6)δ10.99(s,1H),7.36(s,1H),7.18(s,1H),5.07(dd,J= 13.3,5.1Hz,1H),4.34(d,J=16.6Hz,1H),4.21(d,J=16.5Hz,1H),3.25-3.11 (m,4H),2.94-2.87(m,3H),2.63-2.57(m,1H),2.39(qd,J=13.2,4.5Hz,1H), 2.01-1.95(m,1H),1.93-1.87(m,4H),1.82-1.74(m,2H).LC-MS(ESI):[M+H] + =370.36.

[0469] 15) Synthesis of E3 ligase inhibitor 15

[0470] Step 1: 1-(tert-Butyl)7'-methyl-6'-methyl-4'-oxaspiro[azetidine-3,2'-chroman]-1,7'-dicarboxylate (Compound 15a)

[0471] To a solution of compound 14c (12 g, 57.6 mmol) in ethanol (200 mL) were added 1-Boc-3-azetidinone (9.9 g, 57.6 mmol) and tetrahydropyrrole (4.1 g, 57.6 mmol). The reaction solution was stirred at 80 ° C for 4 hours. 1-Boc-3-azetidinone (9.9 g, 57.6 mmol) and tetrahydropyrrole (4.1 g, 57.6 mmol) were added to the reaction solution again, and the reaction solution was stirred at 80 ° C for 16 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to give compound 15a (8 g, 38%) as a yellow solid.

[0472] 1 H NMR (600MHz, CDCl3) δ7.74(s,1H),7.59(s,1H),4.09(d,J=9.6Hz,2H),3.97(d,J=9.5Hz,2H),3.94(s,3H),3.07(s,2H),2.53(s,3H),1.46(s,9H).

[0473] LC-MS(ESI):[M-Boc+H] + =262.28.

[0474] Step 2: 1-(tert-Butyl)7'-methyl-4'-hydroxy-6'-methylspiro[azetidine-3,2'-chroman]-1,7'-dicarboxylate (Compound 15b)

[0475] To a solution of compound 15a (5 g, 13.8 mmol) in methanol (100 mL) was slowly added sodium borohydride (786 mg, 20.8 mmol). The reaction solution was stirred at room temperature for 4 hours and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 15b (4.2 g, 83%) as a yellow oily liquid.

[0476] 1 H NMR (600MHz, CDCl3) δ7.50 (s, 1H), 7.24 (s, 1H), 4.89 (q, J = 5.2Hz, 1H), 4.36 (q, J = 7.2Hz, 1H), 4.27–4.23 (m, 1H), 4.10 (d, J = 9. 3Hz,1H),4.00(dd,J=17.3,9.6Hz,2H),3.90(s,3H),2.54(s,3H),2.35(d,J=5.3Hz,2H),1.47(s,9H).LC-MS(ESI):[M-Boc+H] + =264.27.

[0477] Step 3: Methyl 6'-methylspiro[azetidine-3,2'-chromene]-7'-carboxylate (Compound 15c)

[0478] To a solution of compound 15b (4 g, 13.8 mmol) in toluene (100 mL) was added hydrated p-toluenesulfonic acid (2.3 g, 12.1 mmol). The reaction mixture was stirred at 110°C for 18 hours. The reaction mixture was concentrated in vacuo to afford a crude yellow solid, which was used directly in the next step without further purification. LC-MS (ESI): [M+H] + =246.22.

[0479] Step 4: 1-(tert-Butyl)7'-methyl6'-methylspiro[azetidine-3,2'-chromene]-1,7'-dicarboxylate (Compound 15d)

[0480] To a solution of compound 15c (2 g, 8.2 mmol) in dichloromethane (30 mL) were added di-tert-butyl dicarbonate (2.1 g, 9.8 mmol) and triethylamine (3.2 mL). The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to afford compound 15d (2.5 g, 88%) as a colorless liquid.

[0481] 1H NMR (600MHz, CDCl3) δ7.45(s,1H),6.88(s,1H),6.47(d,J=9.8Hz,1H),6.06(d,J=9.7Hz,1H),4.24 (d,J=9.5,2H),4.01(d,J=9.5,2H),3.89(s,3H),2.51(s,3H),1.48(s,9H).LC-MS(ESI):[M-tBu+H] + =290.20

[0482] Step 5: 1-(tert-Butyl)7'-methyl 6'-(bromomethyl)spiro[azetidine-3,2'-chromene]-1,7'-dicarboxylate (Compound 15e)

[0483] To a solution of compound 15e (2 g, 5.8 mmol) in carbon tetrachloride (30 mL) were added NBS (1.2 g, 6.4 mmol) and AIBN (99 mg, 0.6 mmol). The reaction was stirred at 80°C for 12 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to afford a colorless crude liquid, which was used directly in the next step without further purification.

[0484] Step 6: tert-Butyl 7'-(2,6-dioxapiperidin-3-yl)-8'-oxa-7',8'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-1-carboxylate (Compound 15f)

[0485] To a solution of compound 15e (2 g, 0.7 mmol) in acetonitrile (15 mL) were added 3-amino-2,6-piperidinedione hydrochloride (173 mg, 1.05 mmol) and N,N-diisopropylethylamine (0.4 mL). The reaction was stirred at 80°C for 12 hours. The resulting mixture was concentrated under vacuum and purified on a C18 reverse-phase column to afford compound 15f (120 mg, 38%) as a gray solid.

[0486] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.35(s,1H),7.13(s,1H),6.71(d,J=9.9Hz,1H),6.33(d,J=9.8Hz,1H),5.08(dd,J=13.3 ,5.1Hz,1H),4.41–4.19(m,2H),4.15–3.96(m,4H),2.97–2.85(m,1H),2.66–2.55(m,1H),2.41–2.30(m,1H),2.03–1.95(m,1H), 1.40(s,9H).LC-MS(ESI):[M-tBu+H] + =384.35

[0487] Step 7: 3-(8'-oxa-6',8'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 15g)

[0488] Compound 15f (120 mg, 0.7 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. LC-MS (ESI): [M+H] + =340.34

[0489] Step 8: 3-(8'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (E3 ligase inhibitor 15)

[0490] Palladium on carbon (5 mg) was added to a solution of compound 15 g (50 mg, mmol) in methanol (3 mL). The reaction mixture was stirred at room temperature for 12 hours, filtered through celite, and the filtrate was concentrated. Preparative HPLC was performed to obtain E3 ligase inhibitor 15 (30 mg, 59%) as a white solid.

[0491] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.36(s,1H),7.11(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.8Hz,1H),4.21(d,J=16.8Hz,1H) ,4.15–4.04(m,4H),2.91(q,J=5.6,4.4Hz,2H),2.67–2.56(m,2H),2.40–2.31(m,1H),2.20(t,J=6.9Hz,2H),1.98(m,1H).LC-MS(ESI):[M+H] + =342.43

[0492] 16) Synthesis of E3 ligase inhibitor 16

[0493] Synthesis scheme:

[0494] Step 1: Methyl 4-fluoro-2-methylbenzoate (Compound 16b)

[0495] To a solution of compound 16a (5.5 g, 35.7 mmol) in methanol (100 mL) was slowly added concentrated sulfuric acid (15 mL). The reaction was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. Filtering and concentration under reduced pressure afforded compound 16b (5.0 g, 83%) as a colorless oil. The crude product was used in the next reaction without purification.

[0496] 1 H NMR (600MHz, DMSO-d6) δ7.90(dd,J=8.7,6.2Hz,1H),7.22(dd,J=10.1,2.8Hz,1H),7.15(td,J=8.5,2.7Hz,1H),3.82(s,3H),2.53(s,3H).LC-MS(ESI):[M+H] + =169.19.

[0497] Step 2: Methyl-4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Compound 16c): Boronic acid pinacol ester (5.7 g, 22.3 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.16 g, 0.59 mmol), and methoxy(cyclooctadiene)iridium dimer (0.20 g, 0.30 mmol) were added to a 10 mL solution of methyl tert-butyl ether. A solution of compound 16b (2.5 g, 14.9 mmol) in methyl tert-butyl ether (10 mL) was added, and the atmosphere was purged with nitrogen three times. The reaction was stirred at 85°C for 4 h. After completion of the reaction, the reaction was filtered through celite, and the filtrate was concentrated to obtain a crude product (4.0 g) that was used in the next step without purification.

[0498] 1 H NMR (600MHz, DMSO-d6) δ8.16(d,J=6.3Hz,1H),7.19(dd,J=10.4,3.2Hz,1H),3.83(s,3H),2.55(s,3H),1.30(s,12H).

[0499] Step 3: Methyl 4-fluoro-5-hydroxybenzoate (Compound 16d)

[0500] Potassium peroxymonosulfate (10.9 g) was added to a solution of compound 16c (4.0 g, 13.6 mmol) in acetonitrile (50 mL), and the reaction was stirred at room temperature overnight. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give compound 16d (2.0 g, 80%) as a white solid.

[0501] 1 H NMR (600MHz, DMSO-d6) δ10.04(s,1H),7.47(d,J=9.3Hz,1H),7.13(d,J=12.2Hz,1H),3.80(s,3H),2.41(s,3H).LC-MS(ESI):[M+H] - =183.21.

[0502] Step 4: 1'-(tert-Butyl)6-methyl-7-methyl-3H-spiro[benzo[b][1,4]dioxene-2,4'-piperidine]-1',6-dicarboxylate (Compound 16e)

[0503] Compound 16d (1.0 g, 5.4 mmol) was dissolved in 10 ml of ultra-dry N,N-dimethylformamide, followed by the addition of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.2 g, 5.3 mmol) and sodium hydride (196 mg, 4.9 mmol). The reaction was heated to 110°C and stirred overnight. The reaction mixture was purified by silica gel column chromatography to afford Compound 16e (1.4 g, 68%) as a white solid.

[0504] 1 H NMR (600MHz, DMSO-d6) δ7.37(s,1H),6.85(s,1H),4.04(s,2H),3.77(s,3H),3.73(d,J=13.4 Hz,2H),3.24–3.04(m,2H),2.42(s,3H),1.66–1.61(m,4H),1.41(s,9H).LC-MS(ESI):[M+H] + =278.29.

[0505] Step 5: 1'-(tert-Butyl)6-methyl7-(bromomethyl)-3H-spiro[benzo[b][1,4]dioxene-2,4'-piperidine]-1',6-dicarboxylate (Compound 16f)

[0506] To a solution of compound 16e (1.0 g, 2.7 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (613 mg, 3.4 mmol) and azobisisobutyronitrile (44 mg, 0.3 mmol). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 85°C overnight under nitrogen. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product (1.2 g), which was used in the next step without purification.

[0507] Step 6: 3-(6'-oxa-6',8'-dihydro-3'H,7'H-spiro[piperidin-4,2'-[1,4]dioxin[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (E3 ligase inhibitor 16)

[0508] To a solution of compound 16f (1.2 g, 2.7 mmol) in acetonitrile (10 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (655 mg, 4.0 mmol) and N,N-diisopropylethylamine (1.0 g, 8.0 mmol). The reaction was stirred at 80°C overnight. The solution was then concentrated, dissolved in acetic acid (10 mL), and stirred at 110°C for 2 h. The reaction solution was purified by reverse phase chromatography to afford E3 ligase inhibitor 16 (235 mg, 24%) as a white solid.

[0509] 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.22(s,1H),7.17(s,1H),5.06(dd,J=13.3,5. 1Hz,1H),4.32(d,J=16.8Hz,1H),4.20(d,J=16.8Hz,1H),4.19–4.11(m,2H),3.30–3.2 5(m,2H),3.18–3.08(m,2H),2.90(ddd,J=17.3,13.6,5.4Hz,1H),2.59(dt,J=16.6,3. 4Hz,1H),2.42–2.30(m,1H),2.00–1.93(m,1H),1.92–1.85(m,4H).LC-MS(ESI):[M+H] + =373.35.

[0510] 17) Synthesis of E3 ligase inhibitor 17

[0511] Step 1: Dimethyl 4-hydroxyphthalate (Compound 17b)

[0512] Under nitrogen, compound 17a (30 g, 165 mmol) was dissolved in methanol (300 mL). Concentrated sulfuric acid (36 mL) was slowly added to the system, and the temperature was raised to 66°C for 8 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. After adding water (200 mL), the mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. After concentration, the crude product, compound 17b (31 g, 89.5%), was obtained as a pale yellow solid. LC-MS (ESI): [M-OMe+H] + =179.12.

[0513] Step 2: Dimethyl 4-bromo-5-hydroxyphthalate (Compound 17c)

[0514] Under nitrogen, compound 17b (10 g, 47 mmol) was dissolved in trifluoroacetic acid (100 mL). N-bromosuccinimide (4.24 g, 47 mmol) was added to the reaction system and allowed to react overnight at room temperature. The resulting reaction system was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The mixture was washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The concentrated crude product was purified by reverse-phase column chromatography to yield compound 17c (4.6 g, 33%) as a pale yellow solid.

[0515] 1H NMR (600MHz, CD3OD) δ7.98(s,1H),7.07(s,1H),3.88(s,3H),3.86(s,3H).

[0516] LC-MS(ESI):[M+H] + =289.04.

[0517] Step 3: Dimethyl 4-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-5-bromobenzoate (Compound 17d). Under nitrogen, Compound 17c (8 g, 27 mmol, 1.0 eq), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (5.64 g, 27 mmol), and triphenylphosphine (7.2 g, 27 mmol) were dissolved in tetrahydrofuran (80 mL). Diethyl azodicarboxylate (4.08 mL, 27 mmol, 1.0 eq) was added and reacted at room temperature for 4 hours. The resulting reaction system was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography afforded Compound 17d (6 g, 46%) as a reddish-brown solid.

[0518] 1 H NMR(600MHz, CDCl3)δ8.04(s,1H),7.47(hd,J=5.4,1.9Hz,5H),7.09(s,1H),5.90(tt, J=3.2,1.5Hz,1H),4.67–4.55(m,2H),4.38(d,J=12.9Hz,1H),4.28(d,J=12.8Hz,1H),3 .98(d,J=16.7Hz,1H),3.93(s,3H),3.91(s,3H),3.78(dd,J=19.0,12.3Hz,1H),3.48( d,J=16.5Hz,1H),3.06(s,1H),2.75(s,1H),2.54(d,J=18.6Hz,1H).LC-MS(ESI):[M+H] + =474.26 / 476.27.

[0519] Step 4: 1'-benzyl-2H-spiro[benzofuran-3,4'-piperidine]-5,6-dicarboxylic acid dimethyl ester (Compound 17e)

[0520] Under nitrogen, compound 17d (8.4 g, 17 mmol), tri-n-butyltin hydroxide (10.2 g, 34 mmol), and azobisisobutyronitrile (574 mg, 3.4 mmol) were dissolved in toluene (84 mL) and heated to 110°C for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 times with 100 mL). The organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography afforded compound 17e (5 g, 71%) as a reddish-brown oil.

[0521] 1 H NMR (400MHz, CDCl3) δ7.67(s,1H),7.55–7.41(m,5H),6.97(s,1H),4.47(s,2H),4.27(s,2H),3.91(s,3H),3.89(s,3H ),3.70(d,J=12.3Hz,2H),2.78–2.63(m,2H),2.52(td,J=14.3,4.0Hz,2H),1.94(d,J=14.5Hz,2H).LC-MS(ESI):[M+H] + =396.40.

[0522] Step 5: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-5,6-dicarboxylic acid (Compound 17f)

[0523] Compound 17e (2.3 g, 5.8 mmol) was dissolved in methanol (20 mL) and water (2 mL), and lithium hydroxide (1.39 g, 58 mmol) was added. The reaction was allowed to react at room temperature for 4 hours. The reaction system was concentrated under reduced pressure, and reverse-phase purification was performed to obtain compound 17f (1.28 g, 60%) as a light reddish-brown solid.

[0524] 1 H NMR(600MHz,DMSO-d6)δ7.51(ddd,J=12.6,6.6,3.4Hz,6H),6.98(s,1H),4.64(s,2H),4.36(s,2H),3.39 (s,2H),3.13(t,J=13.4Hz,2H),2.15(dd,J=20.6,8.4Hz,2H),1.96(d,J=14.1Hz,2H).LC-MS(ESI):[M+H] + =368.34.

[0525] Step 6: 1'-Benzyl-6-(2,6-dioxopiperidin-3-yl)-6-hydro-2H,5H-spiro[[2,3-f]isoindole-3,4'-piperidine]-5,7-dione (Compound 17g)

[0526] Under nitrogen, compound 17f (3.0 g, 8 mmol), sodium acetate (3.3 g, 24 mmol), and 3-amino-2,6-piperidinedione hydrochloride (1.3 g, 10 mmol, 1.25 eq) were dissolved in acetic acid (30 mL) and reacted at 110°C for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The mixture was washed with saturated brine (80 mL), and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded compound 17g (1.8 g, 48%) as a pale yellow solid.

[0527] 1 H NMR(600MHz, CDCl3)δ7.69(s,1H),7.54–7.43(m,5H),7.25(s,1H),4.96(dd,J=12.7,5.4Hz,1H),4.56(s,2H),4.28(s,2H), 2.97–2.75(m,4H),2.70(t,J=13.6Hz,2H),2.63–2.53(m,2H),1.99(d,J=14.6Hz,2H),1.63–1.57(m,2H).LC-MS(ESI):[M+H] + =460.34.

[0528] Step 7: 6-(2,6-dioxopiperidin-3-yl)-6-hydro-2H,5H-spiro[[2,3-f]isoindole-3,4'-piperidine]-5,7-dione (E3 ligase inhibitor 17)

[0529] Under nitrogen, compound 17g (3.0 g, 6.5 mmol, 1.0 eq) was dissolved in methanol (30 mL), and 10% wet palladium on carbon (600 mg) was added. After hydrogen exchange three times, the mixture was allowed to react overnight at room temperature. The reaction system was filtered, and the filter cake was washed three times with methanol (15 mL). The filtrate was dried under reduced pressure, and the concentrated crude product was purified by reverse-phase column chromatography to yield E3 ligase inhibitor 17 (630 mg, 26%) as a white solid.

[0530] 1H NMR (600MHz, CD3OD) δ7.78(s,1H),7.26(d,J=0.6Hz,1H),5.14–5.10(m,1H),4.74(s,2H),3.38(dt,J=12.7,3.2Hz,2H),3.05(td,J=13.1 ,3.0Hz,2H),2.90–2.85(m,1H),2.78(dd,J=4.4,2.6Hz,1H),2.77–2.69(m,2H),2.14(ddt,J=13.2,11.0,4.1Hz,4H).LC-MS(ESI):[M+H] + =370.33.

[0531] 18) Synthesis of E3 ligase inhibitor 18

[0532] Step 1: Methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate (Compound 18a)

[0533] Under nitrogen, methyl 5-bromo-4-methoxy-2-methylbenzoate (5 g, 19.30 mmol), NBS (3.61 g, 20.30 mmol), and AIBN (316.9 mg, 1.90 mmol) were dissolved in carbon tetrachloride (50 mL) and heated to 75°C overnight. After TLC analysis, the reaction system was cooled to room temperature and saturated aqueous sodium thiosulfate was added. The mixture was stirred for 30 minutes, extracted with dichloromethane, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. After concentration, the crude product was purified by column chromatography to yield Compound 18a (6.9 g, 96.7%) as a white solid. LC-MS (ESI): [M+H] + =336.90

[0534] Step 2: 3-(6-bromo-5-methoxy-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound 18b)

[0535] Under nitrogen protection, compound 18a (7 g, 20.70 mmol) and 3-amino-2,6-piperidinedione hydrochloride (5.1 g, 31.10 mmol) were dissolved in acetonitrile (100 mL). N,N-diisopropylethylamine (13.4 g, 103.60 mmol) was added to the reaction system, and the reaction was allowed to proceed at 80°C overnight. The resulting reaction system was concentrated under reduced pressure, acetic acid (50 mL) was added, and the reaction was continued at 120°C for 2 hours. After TLC detection of the reaction completion, the reaction system was concentrated under reduced pressure and purified by reverse-phase column chromatography to obtain solid compound 18b (5.3 g, 72.5%). LC-MS (ESI): [M+H] +=353.15

[0536] Step 3: 3-(6-bromo-5-hydroxy-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound 18c)

[0537] Under nitrogen, compound 18b (5 g, 14.20 mmol) was dissolved in dichloromethane (10 mL). A dichloromethane solution of boron tribromide (1 M, 140 mL) was slowly added at 0°C. The mixture was brought to room temperature and allowed to react overnight. After TLC analysis, the reaction system was concentrated under reduced pressure to remove most of the boron tribromide. Dichloromethane (50 mL) was then added to the system and quenched with a small amount of methanol. The reaction system was concentrated under reduced pressure and purified by reverse-phase column chromatography to obtain compound 18c (3.6 g, 75.0%) as an off-white solid. LC-MS (ESI): [M+H] + =338.99

[0538] Step 4: 3-(5-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound 18d)

[0539] Under nitrogen, compound 18c (180 mg, 0.53 mmol), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (162 mg, 0.80 mmol), and triphenylphosphine (320 mg, 1.22 mmol) were dissolved in tetrahydrofuran (10 mL). Diethyl azodicarboxylate (0.2 mL, 1.2 mmol) was added and allowed to react at room temperature for 4 hours. After TLC analysis, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to yield compound 18d (147 mg, 53%) as a pale yellow solid.

[0540] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.90(s,1H),7.55-7.46(m,5H),7.42(s,1H),5.9 1(s,1H),5.08(dd,J=13.3,5.1Hz,1H),4.75(s,2H),4.45-4.34(m,3H),4.27(d,J=17.5H z,1H),3.71(s,2H),3.56(s,1H),3.17(s,1H),2.91(ddd,J=17.3,13.6,5.5Hz,1H),2.63 -2.57(m,1H),2.41(ddd,J=21.9,16.2,11.7Hz,3H),2.00(dtd,J=12.7,5.4,2.3Hz,1H).

[0541] LC-MS(ESI):[M+H] + =524.09

[0542] Step 5: 3-(1'-benzyl-5-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione (Compound 18e)

[0543] Under nitrogen, compound 18d (120 mg, 0.23 mmol), tri-n-butyltin hydroxide (80 mg, 0.27 mmol), and azobisisobutyronitrile (19 mg, 0.12 mmol) were dissolved in toluene (10 mL) and heated to 110°C for 2 hours. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Purification by reverse-phase column chromatography afforded compound 18e (51 mg, 50%) as a white solid.

[0544] 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),7.56-7.47(m,5H),7.42(s,1H),7.04(s,1H),5. 03(dd,J=13.2,4.9Hz,1H),4.64(q,J=9.3Hz,2H),4.39-4.33(m,3H),4.23(d,J=17.3Hz ,1H),3.33-3.24(m,2H),3.16(d,J=16.2Hz,2H),2.94-2.84(m,1H),2.59(d,J=16.7Hz ,1H),2.41-2.32(m,1H),2.16(t,J=12.4Hz,2H),2.00-1.92(m,3H).LC-MS(ESI):[M+H] + =446.35

[0545] Step 6: 3-(5-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione (E3 ligase inhibitor 18)

[0546] Under nitrogen, compound 18e (25 mg, 0.06 mmol) was dissolved in methanol (2 mL), and 10% wet palladium on carbon (24 mg) was added. After hydrogen exchange three times, the mixture was allowed to react overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed three times with methanol (5 mL). The filtrate was dried under reduced pressure, and the concentrated crude product was purified by reverse-phase column chromatography to yield E3 ligase inhibitor 18 (8.7 mg, 43%) as a white solid.

[0547] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),7.47(s,1H),7.04(s,1H),5.06(dd,J=13.3,5.1H z,1H),4.65-4.60(m,2H),4.36(d,J=17.2Hz,1H),4.24(d,J=17.2Hz,1H),3.36-3.34(m, 2H),3.04(d,J=8.5Hz,2H),2.95-2.86(m,1H),2.60(d,J=17.1Hz,1H),2.38(qd,J=13.2, 4.4Hz,1H),2.10-2.03(m,2H),2.00-1.95(m,1H),1.91-1.85(m,2H).LC-MS(ESI):[M+H] + =356.35

[0548] 19) Synthesis of E3 ligase inhibitor 19

[0549] Step 1: Methyl 2-hydroxy-6-methylbenzoate (Compound 19a)

[0550] Under nitrogen, 2-hydroxy-6-methylbenzoic acid (10 g, 65.79 mmol) was dissolved in methanol (30 mL), and concentrated sulfuric acid (10 mL) was added. The mixture was reacted at 80°C for 16 h. After TLC, the excess sulfuric acid was neutralized with 1 M / L NaOH solution, washed with water, and extracted with ethyl acetate. The combined organic phases were concentrated to yield compound 19a (10 g, 91.6%), which was carried on to the next step without purification.

[0551] 1 H NMR (600MHz, CDCl3) δ11.31(s,1H),7.31-7.28(m,1H),6.87-6.86(m,1H),6.75-6.74(m,1H),3.99(s,3H),2.56(s,3H).LC-MS(ESI):[M+H] + =167.13

[0552] Step 2: Methyl 2-hydroxy-3-iodo-6-methylbenzoate (Compound 19b)

[0553] Under nitrogen, compound 19a (10 g, 60.24 mmol) was dissolved in trifluoroacetic acid (20 mL) and NIS (16.2 g, 72.00 mmol) was added. The mixture was incubated at room temperature for 16 h. After TLC analysis, the reaction was quenched with saturated aqueous NaS₂O₃, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was then purified by reverse-phase purification to afford compound 19b (3.8 g, 21.6%).

[0554] 1 H NMR (600MHz, CDCl3) δ12.19(s,1H),7.77(d,J=8.0Hz,1H),6.56(dd,J=8.0,0.8Hz,1H),4.01(s,3H),2.54(s,3H).

[0555] Step 3: Methyl 3-acetyl-2-hydroxy-6-methylbenzoate (Compound 19c)

[0556] Under nitrogen, compound 19b (3.8 g, 13.02 mmol) and butyl vinyl ether (3.9 g, 39.00 mmol) were dissolved in methanol (20 ml). Pd(dppf)Cl2 (951 mg, 1.30 mmol) and TEA (3.95 g, 39.00 mmol) were added. The atmosphere was purged with nitrogen three times and the reaction was continued at 60°C for 16 h. The reaction was confirmed by TLC. The reaction mixture was dried by spin drying, dissolved in dichloromethane, and washed with 5 M / L HCl and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford compound 19c (2.0 g, 73.8%).

[0557] 1 H NMR (600MHz, CDCl3) δ12.74(s,1H),7.70(d,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),3.97(s,3H),2.64(s,3H),2.38(s,3H).LC-MS(ESI):[M-OCH3+H] + =177.14

[0558] Step 4: 1'-tert-Butyl 8-methyl-7-methyl-4-oxospiro[chroman-2,4'-piperidin]-1,8-dicarboxylate (Compound 19d). Under nitrogen, Compound 19c (1 g, 4.80 mmol) was dissolved in methanol (30 mL). Pyrrolidine (340 mg, 4.80 mmol) and N-tert-butyloxycarbonyl-4-piperidone (960 mg, 4.80 mmol) were slowly added to the mixture. The temperature was raised to 70°C and the reaction mixture was reacted for 12 hours. After TLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded Compound 19d (1.5 g, 80%) as a yellow solid.

[0559] 1 H NMR (600MHz, DMSO-d6) δ7.72(d,J=8.0Hz,1H),6.99(d,J=8.0Hz,1H),3.87(s,3H),3.78(br,2H),2.99(br,2H ),2.84(s,2H),2.28(s,3H),1.96-1.78(m,2H),1.59(td,J=13.3,4.8Hz,2H),1.40(s,9H).LC-MS(ESI):[M+H] + =390.35

[0560] Step 5: 1'-tert-Butyl 8-methyl 4-hydroxy-7-oxospiro[chroman-2,4'-piperidine]-1,8-dicarboxylate (Compound 19e)

[0561] Under nitrogen, compound 19d (1.5 g, 3.85 mmol) was dissolved in methanol (25 mL). NaBH₄ (340 mg, 7.7 mmol) was added to the reaction system and allowed to react at room temperature for 1 h. After TLC analysis, the resulting reaction system was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic phases were then washed with saturated brine and dried over anhydrous sodium sulfate. Concentration afforded the crude product, compound 19e (1.5 g, 99%).

[0562] 1H NMR (600MHz, DMSO-d6) δ7.37(d,J=7.8Hz,1H),6.80(d,J=7.9Hz,1H),5.44(d,J=5.5Hz,1H),4.67(q,J=6.7Hz,1H),3.80(s,3H),3.76(b r,2H),2.97(br,2H),2.17(s,3H),2.06(dd,J=13.5,6.2Hz,1H),1.85-1.66(m,3H),1.60-1.47(m,2H),1.41(s,9H).LC-MS(ESI):[M+H] + =392.40

[0563] Step 6: Methyl 7-methyloxospiro[chromene-2,4'-piperidine]-8-carboxylate (Compound 19f)

[0564] Under nitrogen, compound 19e (1.5 g, 3.83 mmol) was dissolved in toluene (25 mL), and p-toluenesulfonic acid (659.8 mg, 3.83 mmol) was added. The mixture was allowed to react at 110°C for 12 hours. After TLC analysis, the reaction mixture was concentrated under reduced pressure. The crude compound 19f (850 mg, 81%) was directly used in the next step. LC-MS (ESI): [M+H] + =274.25

[0565] Step 7: 1'-tert-Butyl 8-methyl 7-methylspiro[chromene-2,4'-piperidine]-1',8-dicarboxylate (Compound 19g)

[0566] Under nitrogen, compound 19f (850 mg, 3.11 mmol) was dissolved in dichloromethane (20 mL), and p-Boc2O (1.36 g, 6.22 mmol) and TEA (600 mg, 6.22 mmol) were added. The mixture was allowed to react at room temperature to 25°C for 1 hour. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded compound 19g (1 g, 86%) as a white solid.

[0567] 1H NMR (600MHz, DMSO-d6) δ7.07(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),6.48(d,J=9.8Hz,1H),5.72(d,J=9.8Hz,1H),3.83(s, 5H),3.07(s,2H),2.18(s,3H),1.81(dq,J=14.3,2.6Hz,2H),1.57(td,J=13.1,4.8Hz,2H),1.41(s,9H).LC-MS(ESI):[M+H] + =374.40

[0568] Step 8: 1'-tert-Butyl 8-methyl 7-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',8-dicarboxylate (Compound 19h)

[0569] Under nitrogen, compound 19g (1 g, 2.68 mmol) was dissolved in carbon tetrachloride (20 mL), and NBS (620 mg, 3.50 mmol) and AIBN (43 mg, 0.27 mmol) were added. The reaction was allowed to proceed at 85°C for 12 hours. After completion of the reaction, the reaction system was concentrated under reduced pressure, and the crude product, compound 19h, was directly used in the next step (1.2 g, 99%). LC-MS (ESI): [M+H] + =452.25.

[0570] Step 9: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-8',9'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 19i)

[0571] Under nitrogen, compound 19h (1.2 g, 2.65 mmol), DIPEA (1 g, 7.95 mmol), and 3-amino-2,6-piperidinedione hydrochloride (654.9 mg, 3.98 mmol) were dissolved in acetonitrile (30 mL) and reacted at 85°C for 16 hours. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Water was added, extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded compound 19i (400 mg, 32%) as a gray solid.

[0572] 1H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.31(d,J=7.5Hz,1H),7.04(d,J=7.5Hz,1H),6 .57(d,J=9.9Hz,1H),5.79(d,J=9.9Hz,1H),4.99(d,J=5.1Hz,1H),4.44-4.16(m,2H), 3.79(s,2H),3.19(d,J=22.8Hz,4H),2.87(ddd,J=18.2,13.6,5.4Hz,1H),2.73-2.56( m,1H),2.51(p,J=1.9Hz,1H),2.06-1.56(m,3H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] + =368.19.

[0573] Step 10: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-4',7',8',9'-tetrahydro-3'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 19j)

[0574] Under nitrogen protection, compound 19i (400 mg, 0.85 mmol) was dissolved in THF (10 mL), and 10% wet palladium on carbon (250 mg) was added to the system. After hydrogen replacement three times, the reaction was allowed to react at 50°C overnight. After TLC, the reaction system was filtered, and the filter cake was washed three times with methanol (15 mL). The resulting filtrate was dried under reduced pressure, and the concentrated crude solid compound 19j was directly used in the next step (380 mg, 94%). LC-MS (ESI): [M-Boc+H] + =370.29

[0575] Step 11: 3-(9'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[piperidin-4,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (E3 ligase inhibitor 19)

[0576] Under nitrogen, compound 19j (380 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction was allowed to react at 25°C for 1 h. After TLC, the reaction solution was evaporated to dryness under reduced pressure. Pre-HPLC analysis yielded the E3 ligase inhibitor 19 (290 mg, 97%) as a yellow solid.

[0577] 1H NMR (600MHz, DMSO-d6) δ10.98(s,1H),7.34(d,J=7.7Hz,1H),7.04(d,J=7.6Hz,1H),4.97(dd,J=13.3,5.2,1H),4.43–4.20(m,2H),3.30-3.08( m,4H),2.97-2.78(m,3H),2.61(dt,J=17.1,3.7Hz,1H),2.47-2.31(m,1H),2.04-1.88(m,5H),1.80(tt,J=12.6,5.0Hz,2H).LC-MS(ESI):[M+H] + =370.39

[0578] 20) Synthesis of E3 ligase inhibitor 20

[0579] Synthesis scheme:

[0580] Step 1: 1-tert-Butyl 8'-methyl 7'-methyl-4'-oxospiro[azetidine-3,2'-chroman]-1,8'-dicarboxylate (Compound 20a)

[0581] Under nitrogen, compound 19c (2.0 g, 9.61 mmol) was dissolved in ethanol (15 mL), and 1-Boc-3-azetidinone (1.63 g, 9.61 mmol) and tetrahydropyrrole (682 mg, 9.61 mmol) were added. The mixture was reacted at 70°C for 4 h. After TLC analysis, additional 1-Boc-3-azetidinone (0.82 g, 4.81 mmol) and tetrahydropyrrole (340 mg, 4.81 mmol) were added and the reaction continued at 70°C for 16 h. After completion of the reaction, the reaction mixture was evaporated to dryness to obtain the crude product, which was then purified by column chromatography to afford compound 20a (1.0 g, 28.8%).

[0582] 1 H NMR (600MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),4.09(d,J=9.5Hz,2H),3.99 (s,3H),3.96(d,J=9.5Hz,2H),3.06(s,2H),2.39(s,3H),1.46(s,9H).LC-MS(ESI):[M-Boc+H] + =262.17

[0583] Step 2: 1-tert-Butyl 8'-methyl 4'-hydroxy-7'-methyl spiro[azetidine-3,2'-chroman]-1,8'-dicarboxylate (Compound 20b)

[0584] Under nitrogen, compound 20a (1.0 g, 2.77 mmol) was dissolved in methanol (15 mL), and NaBH4 (157 mg, 4.16 mmol) was added. The mixture was allowed to react at room temperature for 2 h. After TLC, the reaction was quenched by adding saturated NH4Cl, washed with water, extracted with ethyl acetate, washed with saturated brine, and dried to give compound 20b (900.0 mg, 89.5%), which was directly used in the next step without purification. LC-MS (ESI): [M-Boc+H] + =264.17

[0585] Step 3: 7'-methylspiro[azetidine-3,2'-chromene]-8'-carboxylic acid methyl ester (Compound 20c)

[0586] Under nitrogen, compound 20b (900.0 mg, 2.48 mmol) was dissolved in toluene (10 mL), and TsOH (471 mg, 2.48 mmol) was added. The mixture was reacted at 110°C for 2 h. After TLC analysis, the reaction mixture was evaporated to dryness to obtain crude compound 20c (1.1 g, 181.1%), which was directly used in the next step without purification. LC-MS (ESI): [M+H] + =246.11

[0587] Step 4: 1-tert-Butyl 8'-methyl 7'-methylspiro[azetidine-3,2'-chromene]-1,8'-dicarboxylate (Compound 20d). Under nitrogen, Compound 20c (1.1 g, 1 eq) was dissolved in dichloromethane (15 mL). (Boc)2O (1.95 g, 2.0 eq) and TEA (1.36 g mg, 3.0 eq) were added and reacted at room temperature for 2 h. After completion of the reaction, the reaction mixture was spin-dried and filtered through a column to yield Compound 20d (300.0 mg, 19.4%).

[0588] 1 H NMR (600MHz, CDCl3) δ6.95(d,J=7.6Hz,1H),6.76(d,J=7.6Hz,1H),6.45(d,J=9.8Hz,1H),5.93(d,J=9.8Hz,1H ),4.24(d,J=9.5Hz,2H),3.99(d,J=9.5Hz,2H),3.96(s,3H),2.30(s,3H),1.48(s,9H).LC-MS(ESI):[M-Boc+H] + =256.17

[0589] Step 5: 1-tert-Butyl 8'-methyl 7'-(bromomethyl)spiro[azetidine-3,2'-chromene]-1,8'-dicarboxylate (Compound 20e) Under nitrogen protection, compound 20d (400.0 mg, 1 eq) was dissolved in CCl4 (10 mL), and AIBN (19 mg, 0.1 eq) and NBS (268 mg, 1.3 eq) were added to the reaction solution. The reaction was stirred at 85°C for 16 h. After the reaction was completed, the reaction solution was dried to obtain crude compound 20e (600 mg) without purification and directly used in the next step. LC-MS (ESI): [M-Boc+H] + =324.07

[0590] Step 6: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-8',9'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 20f)

[0591] Under nitrogen, compound 20e (600 mg, 1 eq) was dissolved in ACN (10 mL). 3-Aminopiperidine-2,6-dione hydrochloride (287 mg, 1.5 eq) and DIEA (448 mg, 3.0 eq) were added to the reaction mixture, and the mixture was allowed to react at 80°C for 16 h. After TLC analysis, the reaction mixture was dried and filtered through a column to obtain compound 20f (60 mg, 21.4% yield over two steps).

[0592] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.34(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),6 .67(d,J=9.9Hz,1H),6.20(d,J=9.9Hz,1H),4.99(dd,J=13.2,5.2Hz,1H),4.37(d,J= 17.6Hz,1H),4.25(d,J=17.6Hz,1H),4.04-4.01(m,4H),2.93-2.87(m,1H),2.62-2.5 7(m,1H),2.41-2.33(m,1H),2.00-1.96(m,1H),1.41(s,9H).LC-MS(ESI):[M-Boc+H] + =340.19

[0593] Step 7: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-4',7',8',9'-tetrahydro-3'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 20g)

[0594] Under nitrogen, compound 20f (60.0 mg, 1 eq) was dissolved in THF (10 mL), and Pd / C (60 mg, 1 eq) was added. The mixture was replaced with hydrogen three times and allowed to react at 50°C for 16 h. After TLC analysis, the reaction mixture was dried to give crude compound 20g (80 mg), which was directly used in the next step without purification. LC-MS (ESI): [M-Boc+H] + =342.17

[0595] Step 8: 3-(9'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (E3 ligase inhibitor 20)

[0596] Under nitrogen protection, compound 20g (80 mg, 1 eq) was dissolved in dichloromethane (5 mL), TFA (1 mL) was added, and the mixture was allowed to react at room temperature for 2 h. After TLC analysis, the reaction solution was spin-dried, separated, and lyophilized to obtain E3 ligase inhibitor 20 (15 mg, two-step yield 24.3%).

[0597] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),7.35(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),4.97(dd,J=13.2,5.2Hz,1H),4.35(d,J=17.3Hz,1H),4.23(d,J =17.3Hz,1H),4.14-4.10(m,4H),2.93–2.85(m,3H),2.62–2.58(m,1H),2. 42-2.35(m,1H),2.22–2.19(m,2H),1.99-1.95(m,1H).LC-MS(ESI):[M+H] + =342.29

[0598] 21) Synthesis of E3 ligase inhibitor 21

[0599] Synthesis scheme:

[0600] Step 1: Methyl 3-hydroxy-2-methylbenzoate (Compound 21b)

[0601] To a solution of 3-hydroxy-2-methylbenzoic acid 21a (10 g, 65.73 mmol) in methanol (100 mL) was slowly added thionyl chloride (15.64 g, 131.45 mmol). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was dried to give a gray solid 21b (10.0 g, 91.56%).

[0602] 1 H NMR (600MHz, DMSO-d6) δ9.71(s,1H),7.19(dd,J=7.7,1.3Hz,1H),7.09(t,J=7.9Hz,1H),7.02(dd,J=8.0,1.4Hz,1H),3.80(s,3H),2.29(s,3H).

[0603] LC-MS(ESI):[M+H] + =167.23.

[0604] Step 2: Methyl 3-hydroxy-4-iodo-2-methylbenzoate (Compound 21c)

[0605] To a solution of 3-hydroxy-2-methylbenzoic acid 21b (10.0 g, 60.18 mmol) in trifluoroacetic acid (80 mL) and methanol (40 mL) was slowly added N-iodosuccinimide (17.6 g, 78.23 mmol). The reaction was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give 21c (4 g, 22.76%) as a white solid.

[0606] 1 H NMR (600MHz, DMSO-d6) δ9.36 (s, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.03 (d, J = 8.2Hz, 1H), 3.80 (s, 3H), 2.38 (s, 3H). LC-MS (ESI): [M+H] + =364.22.

[0607] Step 3: Methyl 4-acetyl-3-hydroxy-2-methylbenzoate (Compound 21d)

[0608] Under nitrogen, compound 21c (5.4 g, 18.49 mmol), butyl vinyl ether (5.56 g, 55.47 mmol), and Pd(dppf)Cl2 (1.35 g, 1.85 mmol) were dissolved in methanol (80 mL). Triethylamine (5.61 g, 55.47 mmol) was added, and the mixture was heated to 60°C and stirred for 4 h. After the reaction, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (PE:EA = 20%) afforded 21d (3 g, 77.93%) as a yellow oil.

[0609] 1 H NMR (600MHz, CD3OD) δ7.28(d,J=8.2Hz,1H),7.18(d,J=8.3Hz,1H),3.87(s,3H),2.38(s,3H),1.59(s,3H).LC-MS(ESI):[M+H] + =209.15.

[0610] Step 4: 1'-(tert-butyl)7-methyl-8-methyl-4-oxospiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Compound 21e)

[0611] Compound 21d (3.0 g, 14.41 mmol), N-Boc-4-piperidone (3.16 g, 15.85 mmol), and tetrahydropyrrole (1.13 g, 15.85 mmol) were dissolved in methanol (60 mL), and the mixture was stirred at 70°C overnight. The mixture was dried and purified by column chromatography (PE:EA = 30%) to give 21e (5 g, 89.11%) as a yellow solid.

[0612] 1 H NMR (600MHz, DMSO-d6) δ7.65(d,J=8.2Hz,1H),7.33(d,J=8.2Hz,1H),3.86(s,3H),2.89(s,2H),2.38(s,3H),1.92(d, J=2.5Hz,1H),1.89(q,J=2.8Hz,1H),1.64(td,J=13.1,4.8Hz,2H),1.43(s,4H),1.40(s,9H).LC-MS(ESI):[M-Boc+H] + =290.18.

[0613] Step 5: 1'-(tert-Butyl)7-methyl-4-hydroxy-8-methylspiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Compound 21f)

[0614] Sodium borohydride (0.97 g, 25.68 mmol) was added to a solution of compound 21e (5.0 g, 12.84 mmol) in methanol (80 mL) under ice-bath conditions. The reaction was stirred at 25°C for 1 hour. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The solvent was dried to obtain a yellow oil 21f (5.5 g) which was used directly in the next reaction. LC-MS (ESI): [M-Boc+H] + =292.28.

[0615] Step 6: 8-methylspiro[chromene-2,4'-piperidine]-7-carboxylic acid methyl ester (Compound 21g)

[0616] Compound 21f (5.5 g, 14.05 mmol) and p-toluenesulfonic acid (2.66 g, 15.45 mmol) were dissolved in toluene (80 mL), and the mixture was stirred at 110°C for 5 hours. Concentration under vacuum afforded a brown oil 21 g (3.84 g) which was used directly in the next reaction. LC-MS (ESI): [M+H] + =274.47.

[0617] Step 7: 1'-(tert-Butyl)7-methyl8-methylspiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Compound 21h)

[0618] Compound 21g (3.84g, 14.05mmol) and Boc anhydride (6.13g, 28.10mmol) were dissolved in dichloromethane (100mL) and triethylamine (4.26g, 442.15mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction, the mixture was dried and purified by column chromatography (PE:EA = 25%) to obtain 21h (5g, 95.30%) as a yellow oil.

[0619] 1 H NMR (600MHz, CD3OD) δ7.37(d,J=7.9Hz,1H),6.94(d,J=7.9Hz,1H),6.48(d,J=9.8Hz,1H),5.77(d,J=9.7Hz,1H),3.87(s,3H),2. 45(s,3H),1.97–1.93(m,2H),1.66(td,J=13.9,12.2,4.8Hz,2H),1.58(s,2H),1.53(s,2H),1.49(s,9H).LC-MS(ESI):[M-Boc+H] + =274.17.

[0620] Step 8: 1'-(tert-Butyl)7-methyl8-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Compound 21i)

[0621] Compound 21h (3.3 g, 8.84 mmol), N-bromosuccinimide (1.89 g, 10.60 mmol), and azobisisobutyronitrile (145.11 mg, 883.65 μmol) were dissolved in carbon tetrachloride (50 mL). The reaction was stirred at 80°C overnight. Concentration under vacuum afforded a brown solid 21i (4 g), which was used directly in the next reaction. LC-MS (ESI): [M+H] + =316.08.

[0622] Step 9: 8'-(2,6-dioxopiperidin-3-yl)-7'-oxo-8',9'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 21j)

[0623] Compound 21i (4 g, 8.84 mmol) was dissolved in acetonitrile (100 mL), and 3-aminopiperidine-2,6-dione hydrochloride (2.18 g, 13.26 mmol) and N,N-diisopropylethylamine (3.43 g, 26.53 mmol) were added. The reaction was stirred at 80°C overnight. After completion of the reaction, the mixture was purified by normal phase column chromatography (100% EA) to obtain 21j (1 g, 24.19%) as a blue solid.

[0624] LC-MS(ESI):[M-tBu+H] + =412.29.

[0625] Step 10: 8'-(2,6-dioxopiperidin-3-yl)-7'-oxo-4',7',8',9'-tetrahydro-3'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 21k)

[0626] Compound 21j (90 mg, 192.50 μmol) was dissolved in tetrahydrofuran (5 mL), palladium on carbon (20 mg) was added, and the hydrogen atmosphere was replaced three times. The reaction was stirred at 50°C overnight. After completion of the reaction, the mixture was filtered to obtain 21k (90 mg, 99.57%) as a white solid. LC-MS (ESI): [M-tBu+H] + =414.39.

[0627] Step 11: 3-(7'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[piperidin-4,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidin-2,6-dione (E3 ligase inhibitor 21)

[0628] Compound 21k (90 mg, 191.68 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was spin-dried and purified by preparative liquid chromatography to obtain E3 inhibitor 21 (50 mg, 70.61%) as a white solid.

[0629] 1 H NMR (400MHz, CD3OD) δ7.36(d,J=7.8Hz,1H),7.32(d,J=7.8Hz,1H),5.18(dd, J=13.3,5.2Hz,1H),4.55–4.40(m,2H),3.38(dd,J=12.5,3.3Hz,4H),3.03–2 .89(m,3H),2.81(m,J=17.6,4.6,2.4Hz,1H),2.51(m,J=13.3,4.7Hz,1H),2. 24–2.09(m,3H),2.02(t,J=6.8Hz,2H),1.98–1.87(m,2H).LC-MS(ESI):[M+H] + =370.39

[0630] 22) Synthesis of E3 ligase inhibitor 22

[0631] Step 1: 5-Bromo-4-iodoisobenzofuran-1(3H)-one (Compound 22b)

[0632] 22a (1 g, 4.69 mmol) was dissolved in trifluoromethanesulfonic acid (10 mL). The solution was protected with nitrogen and cooled to 0°C. N-iodosuccinimide (1.16 g, 5.16 mmol) was added to the reaction solution at 0°C. The reaction solution was warmed to room temperature and reacted overnight. The resulting mixture was poured into ice water and filtered. The filter cake was washed with water and purified by column chromatography (EA:PE = 0%-15%) to afford 22b (800 mg, 50.28%) as a white solid.

[0633] 1 H NMR(600MHz, DMSO-d6)δ7.94–7.91(m,1H),7.78(dd,J=8.1,1.1Hz,1H),5.21(s,2H).LC-MS(ESI):[MH] - =230.86.

[0634] Step 2: 5-Bromo-4-hydroxyisobenzofuran-1(3H)-one (Compound 22c)

[0635] To a solution of compound 22b in N,N-dimethylaniline (3.5 mL) was added a solution of sodium hydroxide (413.04 mg, 10.33 mmol) in water (7 mL). Cuprous oxide (59.11 mg, 413.07 μmol) was added to the above solution. The reaction was heated to 80°C and stirred overnight. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was concentrated under vacuum and the resulting mixture was purified by column chromatography (EA:PE = 0%-35%) to give 22c (249 mg, 52.64%) as a white solid.

[0636] 1 H NMR (600MHz, DMSO-d6) δ10.91(s,1H),7.73(d,J=8.0Hz,1H),7.24(d,J=8.0Hz,1H),5.35(s,2H).LC-MS(ESI):[MH] - =230.86.

[0637] Step 3: 4-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-5-bromoisobenzofuran-1(3H)-one (Compound 22d)

[0638] Under nitrogen, compound 22c (100 mg, 436.63 μmol) and (1-benzyl 1,2,3,6-tetrahydropyridin-4-yl)methanol (106.51 mg, 523.95 μmol) were dissolved in tetrahydrofuran (1.0 mL). The system was cooled to 0°C, triphenylphosphine (229.05 mg, 873.25 μmol) was added, and diethyl azodicarboxylate (152.08 mg, 873.25 μmol) was slowly added. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was purified by preparative column chromatography to afford 22d (105 mg, 58.05%) as a yellow oil. 1 H NMR (600MHz, DMSO-d6) δ7.83(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.37–7.30(m,4H),7.29–7.19(m,1H),5.84( s,1H),5.68(s,2H),4.64(s,2H),3.56(s,2H),2.93(s,2H),2.57(t,J=5.7Hz,2H),2.25(s,2H).LC-MS(ESI):[M+H] + =414.20.

[0639] Step 4: 1'-Benzyl-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidin]-6(8H)-one (Compound 22e)

[0640] Compound 22d (100 mg, 241.37 μmol), azobisisobutyronitrile (79.27 mg, 482.74 μmol), and tri-n-butyltin hydride (210.77 mg, 724.11 μmol) were dissolved in toluene (1.0 mL), and the mixture was stirred at 110°C overnight. The reaction mixture was concentrated in vacuo and purified on a C18 reverse phase column to afford 22e (27 mg, 33.35%) as a yellow oil.

[0641] 1 H NMR(600MHz, CDCl3)δ7.56(d,J=7.7Hz,1H),7.52–7.46(m,6H),5.26(s,2H),4.54(s,2H),4.29(s ,2H),2.73(t,J=13.1Hz,2H),2.60(td,J=14.6,4.0Hz,2H),2.12–1.91(m,4H).LC-MS(ESI):[MH] - =336.30.

[0642] Step 5: 1'-Benzyl-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (Compound 22f)

[0643] To a solution of compound 22e (202 mg, 602.26 μmol) in tetrahydrofuran (2.0 mL) was added a solution of sodium hydroxide (120.44 mg, 3.01 mmol) in water (2.0 mL). The reaction was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and purified by reverse column chromatography to afford 22f (98 mg, 46.04%) as a white solid. LC-MS (ESI): [MH] - =354.59.

[0644] Step 6: 1'-benzyl-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (Compound 22g)

[0645] Compound 1f (20 mg, 56.59 μmol) and IBX (31.69 mg, 113.18 μmol) were dissolved in a 20:1 ratio of tetrahydrofuran and dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred at 80°C for 2 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was used directly in the next step without purification. LC-MS (ESI): [M+H]+ =352.30.

[0646] Step 7: 3-(1'-benzyl-6-oxo-6,8-dihydro-2H,7Hspiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Compound 22h)

[0647] Compound 22g (48 mg, 136.60 μmol) and 3-aminopiperidine-2,6-dione hydrochloride (44.96 mg, 273.19 μmol) were dissolved in tetrahydrofuran and dimethyl sulfoxide (DMSO) (20:1) (1.0 mL), and one drop of N,N-diisopropylethylamine was added. The reaction was stirred at 50°C for 1 h. The mixed solution was cooled to room temperature, and sodium triacetoxyborohydride (86.85 mg, 409.79 μmol) and one drop of acetic acid were added. The temperature was raised to 50°C and the reaction was allowed to react for 1 h. The mixture was concentrated under vacuum and purified by reverse-phase HPLC to yield 22h (16 mg, 26.29%) as a white solid.

[0648] 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),7.46-7.56(m,5H),7.34(d,J=7.6Hz,1H),7.26(d,J=7 .7Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.67(t,J=6.3Hz,2H),4.43–4.34(m,3H),4.24(d,J= 17.1Hz,1H),3.16(d,J=14.4Hz,2H),2.91(ddd,J=18.0,13.7,5.4Hz,1H),2.64–2.56(m,1H) ,2.44(td,J=13.2,4.6Hz,2H),2.12(d,J=15.4Hz,2H),2.03–1.89(m,4H).LC-MS(ESI):[M+H] + =446.35.

[0649] Step 8: 3-(6-oxo-6,8-dihydro-2H,7Hspiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (E3 ligase inhibitor 22)

[0650] Compound 22h (150 mg, 336.69 μmol) was dissolved in hexafluoroisopropanol (4.5 mL) and 20% palladium hydroxide on carbon (75 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred at room temperature under hydrogen for 5 hours. After completion of the reaction, the reaction solution was filtered, concentrated under reduced pressure, and purified by reverse-phase HPLC to obtain E3 ligase inhibitor 22 (35 mg, 29.25%) as a white solid.

[0651] 1 H NMR (600MHz, CD3OD) δ7.46–7.40(m,2H),5.16(dd,J=13.4,5.2Hz,1H),4.70(s,2H),4.52–4.40(m,2H),3.54–3.47(m,2H),3.24–3.14(m,2H) ,2.96–2.87(m,2H),2.80(m,J=17.7,4.6,2.2Hz,1H),2.52(m,J=13.3,4.6Hz,1H),2.25–2.16(m,3H),2.05–2.01(m,1H).LC-MS(ESI):[M+H] + =356.29.

[0652] 23) Synthesis of E3 ligase inhibitor 23

[0653] Synthesis scheme:

[0654] Step 1: Dimethyl 4-acetyl-3-hydroxyphthalate (Compound 23b)

[0655] Under nitrogen, dimethyl 4-bromo-3-hydroxyphthalate (10 g, 34.59 mmol) was dissolved in MeOH (100 mL), and 1-(vinyloxy)butane (13.86 g, 138.87 mmol), Pd(dppf)Cl2 (2.53 g, 3.46 mmol), and triethylamine (10.50 g, 103.78 mmol) were added. The reaction was stirred at 70°C for 12 h. After completion of the reaction, HCl-1,4-dioxane (100 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was then extracted three times with EA. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to afford the crude yellow oil, Compound 23b (8 g, 91.6%), which was used directly in the next step. LC-MS (ESI): [M-32+H] + =211.06.

[0656] Step 2: 1'-(tert-butyl)7,8-dimethyl4-oxospiro[chroman-2,4'-piperidine]-1',7,8-tricarboxylate (Compound 23c)

[0657] Compound 23b (8.0 g, 31.72 mmol), N-tert-butyloxycarbonyl-4-piperidone (7.72 g, 31.72 mmol), and tetrahydropyrrole (2.26 g, 31.72 mmol) were dissolved in 80 mL of ethanol and reacted at 85°C for 12 h. After the reaction, the mixture was concentrated and purified by column chromatography (EA:PE = 29%) to afford compound 23c (4.3 g, 31.28%) as a yellow oil.

[0658] 1 H NMR (600MHz, CDCl3) δ7.93(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),4.00(s,3H),3.95(s,3H),3.30(t,J=9.7 Hz,2H),3.17(t,J=9.7Hz,2H),3.14(s,2H),2.47(t,J=9.7Hz,2H),2.06(t,J=9.7Hz,2H).LC-MS(ESI):[M+H] + =334.19

[0659] Step 3: 1'-(tert-butyl)7,8-dimethyl 4-hydroxyspiro[chroman-2,4'-piperidine]-1',7,8-tricarboxylate (Compound 23d)

[0660] Compound 23c (4.30 g, 9.92 mmol) was dissolved in 40 mL of MeOH. Sodium borohydride (1.13 g, 29.76 mmol) was added under ice-cooling and stirred overnight. After the reaction was completed, the mixture was concentrated, added with water, extracted with ethyl acetate, and dried to give a crude yellow oil, compound 23d (2.8 g, 64.81%). This was used directly in the next step. LC-MS (ESI): [M+H] + =336.29

[0661] Step 4: Spiro[chromene-2,4'-piperidine]-7,8-dicarboxylic acid dimethyl ester (Compound 23e)

[0662] Compound 23d (2.80 g, 6.43 mmol) was dissolved in 3 mL of toluene, and p-toluenesulfonic acid (2.21 g, 12.86 mmol) was added. The mixture was refluxed at 110°C overnight. After the reaction was complete, the mixture was concentrated, extracted with ethyl acetate, and dried by spin drying. The mixture was then purified by column chromatography to obtain compound 23e (1.4 g, 68.6%) as a yellow oil. LC-MS (ESI): [M+H] + =318.38

[0663] Step 5: Spiro[chroman-2,4'-piperidine]-7,8-dicarboxylic acid dimethyl ester (Compound 23f)

[0664] Compound 23e (1.40 g, 4.41 mmol) was dissolved in MeOH, and Pd / C (700 mg) was added. The mixture was replaced with hydrogen and stirred under hydrogen for 4 hours. After completion of the reaction, the mixture was filtered and concentrated to afford Compound 23f (1.3 g, 93.8%) as a yellow oil. The crude product was directly used in the next step. LC-MS (ESI): [M+H] + =320.58

[0665] Step 6: Spiro[chroman-2,4'-piperidine]-7,8-dicarboxylic acid (Compound 23g)

[0666] Compound 23f (1.4 g, 4.38 mmol) was dissolved in a mixture of THF:H2O (4:1), and LiOH (629.87 mg, 26.30 mmol) was added and stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude yellow oil (1.35 g, 96.84%). LC-MS (ESI): [M+H] + =306.58

[0667] Step 7: 8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione (E3 ligase inhibitor 23)

[0668] Compound 23g (1.50 g, 4.91 mmol), 3-aminopiperidine-2,6-dione hydrochloride (970.30 mg, 5.90 mmol), and sodium acetate (806.02 mg, 9.83 mmol) were dissolved in acetic acid (5 mL). The mixture was stirred at 110°C for 5 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by prep-HPLC (Phase A = water, Phase B = ACN, 0.1% TFA, B% = 0% to 50% in 30 min) to afford E3 ligase inhibitor 23 (0.55 g, 31.3%) as a white solid.

[0669] 1H NMR (600MHz, DMSO-d6) δ11.11(s,1H),7.62(d,J=7.5Hz,1H),7.39(d,J=7.4Hz,1H),5.08(dd,J=12.9,5.5Hz,1H),3.28(t,J=11.8Hz,2H),3. 09(t,J=11.8Hz,2H),2.96(t,J=12,4Hz,2H),2.91–2.78(m,3H),2.63–2.52(m,2H),2.05–1.94(m,3H),1.91–1.81(m,2H).LC-MS(ESI):[M+H] + =384.19.

[0670] 24) Synthesis of E3 ligase inhibitor 24

[0671] Synthesis scheme:

[0672] Step 1: Dimethyl 4-acetyl-3-hydroxyphthalate (Compound 24b)

[0673] Under nitrogen protection, dimethyl 4-bromo-3-hydroxyphthalate (2.40 g, 8.30 mmol), butyl vinyl ether (4.15 g, 41.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (610 mg, 834.47 mmol) and triethylamine (2.53 g, 25.04 mmol) were dissolved in methanol and stirred in an oil bath at 70°C overnight. After the reaction, the reaction solution was spin-dried and the crude product was purified by silica gel column chromatography (EA / PE = 28%) to synthesize compound 24b (418 mg, 20.3%) as a yellow oil.

[0674] 1 H NMR (600MHz, DMSO-d6) δ10.70(s,1H),7.48(d,J=7.5Hz,1H),7.12(d,J=7.4Hz,1H),3.88(s,3H),3.87(s,3H),2.42(s,3H).LC-MS(ESI):[M-32+H] + =221.16

[0675] Step 2: 1-benzyl 7',8'-dimethyl 4'-oxospiro[azetidine-3,2'-chroman]-1,7',8'-tricarboxylate (Compound 24c)

[0676] Compound 24b (325 mg, 1.58 mmol) was dissolved in methanol, and tetrahydropyrrole (125 mg, 1.76 mmol) was added. The mixture was stirred overnight in an oil bath at 80°C. After the reaction, the mixture was dried by rotary evaporation. The crude product was purified by silica gel column chromatography (EA / PE = 30%) to afford compound 24c (310 mg, 44.5%) as a yellow oil with a purity greater than 90%.

[0677] 1 H NMR (600MHz, CDCl3) δ7.99 (dd, J=8.2, 0.9Hz, 1H), 7.71 (dd, J=8.2, 1.0Hz, 1H), 7.42–7.32 (m, 5H), 5.13 (s, 2 H),4.20(d,J=9.7Hz,2H),4.06(d,J=9.7Hz,2H),4.00(s,3H),3.95(s,3H),3.14(s,2H).LC-MS(ESI):[M+H] + =438.20

[0678] Step 3: 1-benzyl 7',8'-dimethyl 4'-hydroxyspiro[azetidine-3,2'-chroman]-1,7',8'-tricarboxylate (Compound 24d)

[0679] Compound 24c (310 mg, 705.48 μmol) was dissolved in methanol. Sodium borohydride (80 mg, 2.11 mmol) was added portionwise in an ice-water bath and stirred at room temperature for 3 hours. After the reaction, the mixture was dried by rotary evaporation. The crude product was purified on a silica gel column (DCM / MeOH = 5%) to afford compound 24d (180 mg, 57%) as a yellow oil.

[0680] 1 H NMR (600MHz, DMSO-d6) δ7.63(d,J=7.5Hz,1H),7.44(d,J=7.0Hz,1H),7.42–7.30(m,5H),5.11(s,2H),4.50(s,1 H),4.25-4.15(m,1H),4.10(d,J=9.7Hz,4H),3.88(s,3H),3.86(s,3H),2.60(d,J=17.6,2H).LC-MS(ESI):[M+H] + =442.29

[0681] Step 4: Spiro[azetidine-3,2'-chromene]-7',8'-dicarboxylic acid dimethyl ester (Compound 24e)

[0682] Compound 24d (180 mg, 407.76 μmol) was dissolved in trifluoroacetic acid, followed by the addition of triethylsilane (330 mg, 2.84 mmol). The mixture was stirred in an oil bath at 100°C for 6 hours and then cooled to room temperature. Another portion of triethylsilane (330 mg, 2.84 mmol) was then added. Upon completion of the reaction, the mixture was spin-dried to dryness. The crude product was dissolved in methanol, stirred for 1 hour, and then spin-dried to dryness. The supernatant was discarded, and the product was obtained as a yellow oil, Compound 24e (160 mg, 96.6%), without purification, which was used directly in the next step. LC-MS (ESI): [M+H] + =289.98

[0683] Step 5: Spiro[azetidine-3,2'-chroman]-7',8'-dicarboxylic acid dimethyl ester (Compound 24f)

[0684] Under nitrogen, compound 24e (160 mg, 409.28 μmol) was dissolved in methanol, and Pd / C (50 mg, 10%) was added. The mixture was replaced with hydrogen and stirred at room temperature overnight. After the reaction, the mixture was filtered and the filtrate was dried to give compound 24f (130 mg, 81.3%) as a yellow oil, which was used directly in the next step without purification. LC-MS (ESI): [M+H] + =292.18

[0685] Step 6: Spiro[azetidine-3,2'-chroman]-7',8'-dicarboxylic acid (Compound 24g)

[0686] Compound 24f (130 mg, 410.57 μmol) was dissolved in a 1:1:5 mixture of tetrahydrofuran / methanol / water. Lithium hydroxide (150 mg, 6.26 mmol) was added under ice-water conditions and stirred overnight at room temperature. After the reaction, the pH was adjusted to 7 with aqueous hydrochloric acid. The filtrate was then dried to give Compound 24g (140 mg, 105%) as a yellow oil, which was used directly in the next step without purification. LC-MS (ESI): [M+H] + =264.17

[0687] Step 7: 8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione (E3 ligase inhibitor 24)

[0688] Compound 24g (200 mg, 1.22 mmol) and sodium acetate (200 mg, 2.44 mmol) were dissolved in acetic acid and stirred overnight in an oil bath at 120°C. After spin drying, the product was dissolved in methanol and purified by reverse phase purification using ACN / H2O (0-20% over 40 min) to afford E3 ligase inhibitor 24 (80 mg, 18.4%) as a white solid.

[0689] 1 H NMR (600MHz, DMSO-d6) δ11.13(s,1H),7.63(d,J=7.5Hz,1H),7.44(d,J=7.0Hz,1H),5.09(dd,J=12.9,5.5Hz,1H),4.15(s, 4H),2.96(t,J=6.5Hz,2H),2.94-2.87(m,1H),2.60-2.54(m,2H),2.31–2.20(m,2H),2.03-1.94(m,1H).LC-MS(ESI):[M+H] + =356.30

[0690] 25) Synthesis of E3 ligase inhibitor 25

[0691] Step 1: Dimethyl 3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-bromophthalate (Compound 25b)

[0692] Under nitrogen, dimethyl 4-bromo-3-hydroxyphthalate (1.80 g, 6.23 mmol) was dissolved in tetrahydrofuran (10 mL). (1-Benzyl 1,2,3,6-tetrahydropyridin-4-yl)methanol (1.90 g, 9.34 mmol) and triphenylphosphine (3.27 g, 12.45 mmol) were added, followed by the slow dropwise addition of diisopropyl azodicarboxylate (2.52 g, 12.45 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed in vacuo, and the crude product was purified by column chromatography (H₂O:ACN = 0-30%) to afford the title compound as a yellow oil (2.10 g, 71.10%).

[0693] 1 H NMR (600MHz, DMSO-d6) δ7.95(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.58-7.45(m,5H),5.87-5.83(m,1H),4.45(s,2H ),3.84(s,3H),3.83(s,3H),3.81(s,2H),3.47–3.30(m,2H),3.25–3.10(m,2H),2.47–2.34(m,2H).LC-MS(ESI):[M+H] + =474.09

[0694] Step 2: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-6,7-dicarboxylic acid dimethyl ester (Compound 25c)

[0695] Under nitrogen, compound 25b (2.10 g, 4.43 mmol) was dissolved in toluene (25 mL), and azobisisobutyronitrile (2.18 g, 13.28 mmol) and tri-n-butyltin hydroxide (2.58 g, 8.85 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the solvent was removed in vacuo, and the crude product was purified by column chromatography (H₂O:ACN = 0-30%) to afford the title compound as a yellow oil (1.50 g, 85.68%).

[0696] 1 H NMR (600MHz, DMSO-d6) δ7.55-7.47(m,5H),7.46(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),4.65(s,2H),4.35(s,2H),3.8 0(s,3H),3.78(s,3H),3.43–3.30(m,2H),3.15–3.06(m,2H),2.17–2.07(m,2H),2.01–1.94(m,2H).LC-MS(ESI):[M+H] + =360.29.

[0697] Step 3: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-6,7-dicarboxylic acid (Compound 25d)

[0698] Compound 25c (1.50 g, 3.79 mmol) was dissolved in a 3:1 mixture of methanol and water (15 ml), and lithium hydroxide (454.17 mg, 18.97 mmol) was added. The reaction was stirred at 50°C for 2 hours. After completion of the reaction, the filtrate was concentrated to obtain the crude product as a yellow solid (1.35 g) which was used in the next step without purification. LC-MS (ESI): [M+H] + =367.99

[0699] Step 4: 1'-Benzyl-7-(2,6-dioxopiperidin-3-yl)-7-hydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-6,8-dione (Compound 25e)

[0700] Compound 25d (1.35 g, 3.67 mmol) was dissolved in acetic acid (12 mL), and 3-aminopiperidine-2,6-dione hydrochloride (1.21 g, 7.35 mmol) and sodium acetate (1.21 g, 14.70 mmol) were added. The reaction was stirred at 115°C overnight. After completion of the reaction, the mixture was concentrated in vacuo, and the crude product was purified by column chromatography (H2O:ACN = 0-30%) to afford the compound as a purple oil (1.52 g, 90.02%).

[0701] 1 H NMR (600MHz, DMSO-d6) δ11.10(s,1H),7.62(d,J=7.4Hz,1H),7.55-7.47(m,5H),7.43(d,J=7.3Hz,1H),5.11(dd,J=13.0,5.4Hz,1H),4.81(s,2H),3. 96(s,2H),3.38(d,J=13.0Hz,2H),3.09–3.01(m,2H),2.91–2.84(m,1H),2 .63-2.58(m,2H),2.08–2.00(m,3H),1.98–1.90(m,2H).LC-MS(ESI):[M+H] + =460.49

[0702] Step 5: 7-(2,6-dioxopiperidin-3-yl)-7-hydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-6,8-dione (E3 ligase inhibitor 25)

[0703] Compound 25e (489 mg, 1.06 mmol) was dissolved in methanol, and palladium on carbon (180 mg) was added. The atmosphere was then replaced with hydrogen two to three times. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through celite. The organic phase was dried and concentrated, and the crude product was purified by column chromatography (H₂O:ACN = 15-55%) to afford E3 ligase inhibitor 25 (170 mg, 43.25%).

[0704] 1 H NMR (600MHz, DMSO-d6) δ11.12(s,1H),7.61(d,J=7.4Hz,1H),7.49(d,J=7.3Hz,1H),5.11(dd,J=13.0,5.4Hz,1H),4.81(s,2H),3.38( d,J=13.0Hz,2H),3.09–3.00(m,2H),2.92–2.85(m,1H),2.62-2.59(m,2H),2.09–2.01(m,3H),1.98–1.91(m,2H).LC-MS(ESI):[M+H] + =370.09

[0705] 26) Synthesis of E3 ligase inhibitor 26

[0706] Step 1: 6-Bromo-2-fluoro-3-methylbenzoic acid (Compound 26b)

[0707] To a solution of lithium diisopropylamide (1.3M in THF / hexane, 6.9 mL, 13 mmol) in tetrahydrofuran (10.6 mL) at -78°C was added compound 26a (2.0 g, 10.6 mmol). The mixture was allowed to react for 2 hours at this temperature and then quickly poured into dry ice. After warming to room temperature, the solvent was evaporated to afford compound 26b (2.84 g, 115%) as a white solid, which was used directly in the next step. LC-MS (ESI): [MH] - =230.95

[0708] Step 2: Methyl 6-bromo-2-fluoro-3-methylbenzoate (Compound 26c)

[0709] To a solution of compound 26b (2.1 g, 8.9 mmol) in N,N-dimethylformamide (12 mL) were added iodomethane (2.5 g, 17.8 mmol) and potassium carbonate (3.7 g, 26.7 mmol). The reaction was allowed to proceed at 80°C for 1 hour. Upon completion, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was then spin-dried and purified by column chromatography (PE:EA = 0-20%) to afford compound 26c (1.9 g, 86%) as a yellow oil.

[0710] 1 H NMR (600MHz, CDCl3) δ7.27(d,J=9.2Hz,1H),7.14–7.09(m,1H),3.97(s,3H),2.25(d,J=1.9Hz,3H).LC-MS(ESI):[M+H] + =247.66.

[0711] Step 3: Methyl 6-bromo-3-(bromomethyl)-2-fluorobenzoate (Compound 26d)

[0712] Under a nitrogen atmosphere, N-bromosuccinimide (1.6 g, 9.2 mmol) and azobisisobutyronitrile (62.8 mg, 0.38 mmol) were added to a solution of compound 26d (1.9 g, 7.6 mmol) in carbon tetrachloride (98 mL). The mixture was allowed to react at 85°C overnight. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-30%) to afford compound 26d (219.9 mg, 8%) as a yellow oil.

[0713] 1 H NMR (600MHz, CDCl3) δ7.39 (d, J = 8.4Hz, 1H), 7.35–7.31 (m, 1H), 4.45 (s, 2H), 3.98 (s, 3H).

[0714] Step 4: tert-Butyl 4-(4-bromo-2-fluoro-3-(methoxycarbonyl)benzyl)-4-formylpiperidine-1-carboxylic acid methyl ester (Compound 26e)

[0715] Under a nitrogen atmosphere, potassium tert-butoxide (75.7 mg, 0.67 mmol) was added to a solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (158.4 mg, 0.74 mmol) in tetrahydrofuran (4 mL) at -30°C. The mixture was allowed to react for 1 hour. Compound 26d (219.9 mg, 0.67 mmol) in tetrahydrofuran (3 mL) was then slowly added. The reaction was continued for 2 hours at the same temperature and then allowed to react at room temperature overnight. The solvent was evaporated and the mixture was purified by column chromatography (PE:EA = 0-40%) to afford Compound 26e (147.6 mg, 48%) as a colorless oil.

[0716] 1 H NMR(600MHz, CDCl3)δ9.55(s,1H),7.30(d,J=8.3Hz,1H),7.00–6.95(m,1H),3.96(s,3H),4.00–3.75(m,2H),2 .95–2.70(m,2H),2.77(s,2H),1.94(d,J=13.0Hz,2H),1.58–1.46(m,2H),1.43(s,9H).LC-MS(ESI):[M-Boc+H] + =358.19.

[0717] Step 5: tert-Butyl 4-(4-bromo-2-fluoro-3-(methoxycarbonyl)benzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Compound 26f)

[0718] Sodium borohydride (1.9 g, 51.4 mmol) was slowly added portionwise to a solution of compound 26e (4.7 g, 10.3 mmol) in methanol (50 mL) at 0°C. The mixture was then allowed to react at room temperature for 2 hours. The reaction was quenched by slowly adding water, dried, and purified by column chromatography (PE:EA = 0-50%) to afford compound 26f (4.14 g, 88% yield) as a colorless oil.

[0719] 1H NMR(600MHz,DMSO-d6)δ7.51(d,J=8.3Hz,1H),7.41–7.36(m,1H),4.78(t,J=5.0Hz,1H),3.90(s,3H),3.46 –3.39(m,2H),3.20(d,J=4.5Hz,4H),2.66(s,2H),1.99(s,2H),1.42–1.32(m,11H).LC-MS(ESI):[M-Boc+H] + =360.29.

[0720] Step 6: 1'-(tert-butyl)8-methyl7-bromospiro[chroman-3,4'-piperidine]-1',8-dicarboxylate (Compound 26g)

[0721] Under a nitrogen atmosphere, compound 26f (125 mg, 0.27 mmol) was slowly added to a solution of sodium hydride (11.9 mg, 0.27 mmol, 60% dispersion in liquid paraffin) in N,N-dimethylformamide (1 mL). The mixture was heated to 110°C and allowed to react for 1 hour. After cooling to room temperature, the reaction was quenched by the slow addition of water (2 mL). After adding water (10 mL), the mixture was extracted with ethyl acetate (20 mL x 3) and washed with saturated brine (40 mL). The combined organic phases were purified by column chromatography (PE:EA = 0-40%) to afford compound 26g (73.0 mg, 61%) as a white solid.

[0722] 1 H NMR (600MHz, CDCl3) δ7.03(d,J=8.2Hz,1H),6.92(d,J=8.2Hz,1H),3.92(s,3H),3.90(s,2H),3 .59-3.47(m,2H),3.37–3.28(m,2H),2.61(s,2H),1.50–1.40(m,13H).LC-MS(ESI):[M-Boc+H] + =339.99

[0723] Step 7: 1'-(tert-butyl(8-methyl-7-vinylspiro[chroman-3,4'-piperidine]-1',8-dicarboxylate (Compound 26h)

[0724] Under a nitrogen atmosphere, compound 26g (73.0 mg, 0.17 mmol) was dissolved in a tetrahydrofuran / water mixture (10:1, 1.1 mL). Potassium vinyl trifluoroborate (33.5 mg, 0.25 mmol), palladium acetate (7.5 mg, 0.033 mmol), triphenylphosphine (6.1 mmol, 0.023 mmol), and cesium carbonate (108.2 mg, 0.33 mmol) were then added. The mixture was reacted in an 85°C oil bath overnight. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford compound 26h (38.9 mg, 45%) as a white solid.

[0725] 1 H NMR (600MHz, CDCl3) δ7.08(d,J=7.9Hz,1H),7.04(d,J=7.8Hz,1H),6.63(dd,J=17.4,11.0Hz,1H),5.69(d,J=17.4Hz,1H),5.28(d, J=11.0Hz,1H),3.96–3.88(m,5H),3.60–3.50(m,2H),3.38–3.29(m,2H),2.67(s,2H),1.52–1.42(m,13H).LC-MS(ESI):[M-Boc+H] + =288.18.

[0726] Step 8: 1'-(tert-Butyl)8-methyl7-formylspiro[chroman-3,4'-piperidine]-1',8-dicarboxylate (Compound 26i)

[0727] Sodium periodate (64.9 mg, 0.3 mmol) and potassium osmate dihydrate (1.4 mg, 0.003 mmol) were added to a solution of compound 26h (29.4 mg, 0.076 mmol) in acetone / water (5:1, 2.7 mL) and allowed to react overnight at room temperature. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford compound 26i (8.9 mg, 30%) as a white solid.

[0728] 1 H NMR(600MHz, CDCl3)δ9.89(s,1H),7.37(d,J=7.7Hz,1H),7.25(d,J=6.4Hz,1H),4.00–3.94(m,5H),3.59–3 .48(m,2H),3.42–3.33(m,2H),2.75(s,2H),1.54–1.48(m,2H),1.48–1.41(m,11H).LC-MS(ESI):[M-Boc+H] + =290.18.

[0729] Step 9: tert-Butyl 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-4',7',8',9'-tetrahydro-2'H-spiro[piperidine-4,3'-pyrano[2,3-e]isoindole]-1-carboxylate (Compound 26j)

[0730] Compound 26i (500 mg, 1.3 mmol) and 3-amino-2,6-piperidinedione hydrochloride (316 mg, 1.9 mmol) were mixed in a 1 / 2 dichloromethane / methanol mixture (39 mL). After reacting at room temperature for 1 hour, sodium cyanoborohydride (241 mg, 3.8 mmol) was added and the reaction continued overnight at room temperature. The solvent was evaporated, and the mixture was purified by reverse-phase column chromatography to yield compound 26j (233 mg, 39%) as a white solid.

[0731] 1 H NMR(600MHz,DMSO-d6)δ10.95(s,1H),7.28(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),5 .02(dd,J=13.3,5.1Hz,1H),4.30(d,J=17.2Hz,1H),4.17(d,J=17.1Hz,1H),4.01(s,2 H),3.50–3.43(m,2H),3.30–3.25(m,2H),2.94–2.87(m,1H),2.73(s,2H),2.60–2.55 (m,1H),2.38–2.30(m,1H),1.99–1.91(m,1H),1.45–1.35(m,11H),1.35–1.29(m,2H).

[0732] LC-MS(ESI):[M+H] + =470.40

[0733] Step 10: 3-(9'-oxo-7',9'-dihydro-2'-spiro[piperidin-4,3'-pyrano[2,3-e]isoindol]-8'(4'H)-yl)piperidine-2,6-dione (E3 ligase inhibitor 26)

[0734] Trifluoroacetic acid (2 mL) was added to a dichloromethane solution (5 mL) of compound 26j (230 mg, 0.49 mmol) and the reaction was allowed to proceed at room temperature for 1.5 hours. The solvent was evaporated and the mixture was purified by preparative column chromatography to afford E3 ligase inhibitor 26 (151.2 mg, 84%) as a white solid.

[0735] 1H NMR(600MHz,DMSO-d6)δ10.96(s,1H),7.30(d,J=7.6Hz,1H),7.04(d,J=7.4Hz,1H ),5.01(dd,J=13.2,4.9Hz,1H),4.31(d,J=17.1Hz,1H),4.18(d,J=17.2Hz,1H),4 .11–4.04(m,2H),3.20–3.06(m,4H),2.94–2.86(m,1H),2.77(s,2H),2.60–2.53m ,1H),2.39–2.30(m,1H),1.98–1.91(m,1H),1.69–1.53(m,4H).LC-MS(ESI):[M+H] + =370.29

[0736] 27) Synthesis of E3 ligase inhibitor 27

[0737] Step 1: Dimethyl 3-bromo-4-hydroxyphthalate (Compound 27a)

[0738] Compound 1b (33.6 g, 160 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (100 mL). N-bromosuccinimide (34.2 g, 192 mmol, 1.2 eq) was added to the reaction system and allowed to react overnight at room temperature. The resulting reaction system was concentrated under reduced pressure, water (100 mL) was added, and extraction was performed with ethyl acetate (100 ml x 3). The product was washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The concentrated crude product was purified by reverse-phase column chromatography to obtain compound 27a (9.8 g, 21.3%) as a pale yellow solid.

[0739] 1 H NMR (600MHz, DMSO-d6) δ11.68(s,1H),7.87(d,J=12.0Hz,1H),7.10(d,J=12.0Hz,1H),3.84(s,3H),3.79(s,3H).

[0740] LCMS(ESI):[MH] - =287.09.

[0741] Step 2: Dimethyl 4-((1-benzyl 1,2,3,6-tetrahydropyridin-4-yl)methoxy)-3-bromophthalate (Compound 27b)

[0742] Compound 27a (9.8 g, 33.9 mmol, 1.0 eq), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (10.3 g, 50.8 mmol, 1.5 eq), and triphenylphosphine (33.3 g, 127 mmol, 2.5 eq) were dissolved in tetrahydrofuran (80 mL). Diethyl azodicarboxylate (22.1 g, 127 mmol, 2.5 eq) was added and reacted at room temperature for 4 hours. The resulting reaction system was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 times with 100 mL). The mixture was washed with saturated brine (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain Compound 27b (8.7 g, 51.3%) as a reddish-brown solid.

[0743] 1 H NMR (600MHz, DMSO-d6) δ8.00(d,J=8.8Hz,1H),7.40-7.29(m,5H),7.27-7.24(m,1H),5.84(tt,J=3.4,1.6Hz,1H),4.68( s,2H),3.86(s,3H),3.81(s,3H),3.54(s,2H),2.93-2.92(m,2H),2.54(t,J=5.7Hz,2H),2.16(s,2H).LCMS(ESI):[M+H] + =474.09.

[0744] Step 3: 1'-benzyl-2H-spiro(benzofuran-3,4'-piperidine)-4,5-dicarboxylic acid dimethyl ester (Compound 27c)

[0745] Compound 27b (8.7 g, 18.3 mmol, 1.0 eq), tri-n-butyltin hydroxide (10.6 g, 36.6 mmol, 2.0 eq), and azobisisobutyronitrile (0.6 g, 3.7 mmol, 0.2 eq) were dissolved in toluene (84 mL) and reacted at 110°C under nitrogen for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain compound 27c (4.7 g, 64.8%) as a reddish-brown oil.

[0746] 1H NMR (600MHz, DMSO-d6) δ7.84(d,J=8.5Hz,1H),7.38-7.29(m,4H),7.29-7.23(m,1H),7.00(d,J=8.5Hz,1H),4.52(s,2H),3.86 (s,3H),3.78(s,3H),3.48(s,2H),2.75(dd,J=11.6,3.7Hz,2H),2.08~1.93(m,4H),1.58(d,J=12.2Hz,2H).LCMS(ESI):[M+H] + =395.71

[0747] Step 4: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-4,5-dicarboxylic acid (Compound 27d)

[0748] Compound 27c (4.7 g, 11.9 mmol, 1.0 eq) was dissolved in methanol (10 mL) and water (10 mL). Potassium hydroxide (33.3 g, 594 mmol, 50 eq) was added to the mixture. The mixture was reacted at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 27d (4.3 g, 92.1%) as a white solid.

[0749] 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=8.5Hz,1H),7.60-7.65(m,2H),7.44-7.39(m,3H),6.94(d,J=8.5H z,1H),4.61(s,2H),4.25(s,2H),3.16(s,4H),2.39(s,2H),1.78(d,J=12.2Hz,2H).LCMS(ESI)[M+H] + =368.30

[0750] Step 5: 1'-Benzyl-2-(2,6-dioxopiperidin-3-yl)-2-hydro-1H,7H-spiro[furo[3,2-e]isoindole-8,4'-piperidine]-1,3-dione (Compound 27e)

[0751] Compound 27d (4.3 g, 11.7 mmol, 1.0 eq), sodium acetate (3.8 g, 46.8 mmol, 4.0 eq), and 3-amino-2,6-piperidinedione hydrochloride (2.99 g, 23.4 mmol, 2.0 eq) were dissolved in acetic acid (30 mL) and reacted at 110°C for 12 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine (80 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain Compound 27e (2.5 g, 47.2%) as a white solid.

[0752] 1 H NMR (400MHz, CD3OD) δ7.79(d,J=8.2Hz,1H),7.69-7.44(m,5H),7.19(d,J=8.1Hz,1H),5.13(dd,J=12.6,5.4Hz,1H),4.80(s,2H),4.38(s,2H) ,3.55(d,J=13.0Hz,2H),3.35–3.36(m,1H),3.17(t,J=13.4Hz,2H),2.97-2.85(m,2H),2.81-2.65(m,2H),2.17-1.98(m,3H).LCMS(ESI)[M+H] + =460.29

[0753] Step 6: 2-(2,6-dioxopiperidin-3-yl)-2-hydro-1H,7H-spiro[furo[3,2-e]isoindole-8,4'-piperidine]-1,3-dione (E3 ligase inhibitor 27)

[0754] Compound 27e (50 mg, 1.1 mmol, 1.0 eq) was dissolved in methanol (50 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol, 0.1 eq) was added. The atmosphere was replaced with hydrogen three times, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed three times with methanol (10 mL). The filtrate was dried under reduced pressure, and the concentrated crude product was purified by reverse-phase column chromatography to afford E3 ligase inhibitor 27 (16 mg, 26.2%) as a white solid.

[0755] 1H NMR (600MHz, CD3OD) δ7.79(dd,J=8.2,1.2Hz,1H),7.19(dd,J=8.1,1.3Hz,1H),5.15(dd,J=12.9,5.4Hz,1H),4.78(s,2H),3.49(dt,J=13.3, 2.7Hz,2H),3.14(td,J=13.7,2.8Hz,2H),2.94-2.87(m,3H),2.80-2.70(m,2H),2.18-2.14(m,1H),2.04(d,J=14.3Hz,2H).LCMS(ESI)[M+H] + =370.39

[0756] 28) Synthesis of E3 ligase inhibitor 28

[0757] Step 1: 1-Bromo-2-(bromomethyl)-3-fluorobenzene (Compound 28b)

[0758] Under a nitrogen atmosphere, N-bromosuccinimide (1.2 g, 6.9 mmol) and azobisisobutyronitrile (173.7 mg, 1.1 mmol) were added to a solution of compound 28a (1 g, 5.3 mmol) in carbon tetrachloride (20 mL). The mixture was allowed to react overnight at 80°C. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-30%) to afford compound 28b (1.3 g, 90%) as a colorless oil.

[0759] 1 H NMR (600MHz, CDCl3) δ7.39 (d, J = 8.1Hz, 1H), 7.21–7.15 (m, 1H), 7.08–7.03 (m, 1H), 4.65 (d, J = 1.7Hz, 2H).

[0760] Step 2: tert-Butyl 4-(2-bromo-6-fluorobenzyl)-4-formylpiperidine-1-carboxylate (Compound 28c)

[0761] Under a nitrogen atmosphere, potassium tert-butoxide (592.5 mg, 5.3 mmol) was added to a solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (1.3 g, 4.8 mmol) in tetrahydrofuran (10 mL) at -30°C. The mixture was allowed to react for 1 hour. Compound 28b (1.3 g, 4.8 mmol) in tetrahydrofuran (10 mL) was then slowly added. The reaction continued for 2 hours at the same temperature and then allowed to react at room temperature overnight. The solvent was evaporated and the mixture was purified by column chromatography (PE:EA = 0-20%) to afford Compound 28c (710.7 mg, 37%) as a colorless oil.

[0762] 1 H NMR(600MHz, CDCl3)δ9.65(d,J=2.9Hz,1H),7.37(d,J=8.0Hz,1H),7.14–7.08(m,1H),7.04–6.98(m,1H),4.15–3.70(m,2 H),3.02(d,J=2.4Hz,2H),2.90–2.60(m,2H),2.18–1.94(m,2H),1.76–1.62(m,2H),1.44(s,9H).LC-MS(ESI):[M-Boc+H] + =300.06.

[0763] Step 3: tert-Butyl 4-(2-bromo-6-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Compound 28d)

[0764] Sodium borohydride (1.9 g, 51.4 mmol) was slowly added portionwise to a solution of compound 28c (4.7 g, 10.3 mmol) in methanol (50 mL) at 0°C. The mixture was then allowed to react at room temperature for 2 hours. The reaction was quenched by slowly adding water, dried, and purified by column chromatography (PE:EA = 0-50%) to afford compound 28d (4.14 g, 88% yield) as a colorless oil.

[0765] 1 H NMR(600MHz, CDCl3) δ7.39(d,J=8.0Hz,1H),7.12–7.07(m,1H),7.05–6.99(m,1H),3.80–3.65(m,2H),3.62(d,J=6.2Hz,2H),3.11(t, J=11.0Hz,2H),2.94(d,J=2.6Hz,2H),1.67–1.62(m,2H),1.62–1.59(m,1H),1.55–1.47(m,2H),1.44(s,9H).LC-MS(ESI):[M-Boc+H] + =301.98.

[0766] Step 4: tert-Butyl 5-bromospiro[chroman-3,4'-piperidine]-1'-carboxylate (Compound 28e)

[0767] Under a nitrogen atmosphere, compound 28d (659.4 mg, 1.64 mmol) was slowly added to a solution of sodium hydride (72.1 mg, 1.8 mmol, 60% dispersion in liquid paraffin) in N,N-dimethylformamide (7 mL). The mixture was heated to 110°C and allowed to react for 1 hour. After cooling to room temperature, the reaction was quenched by the slow addition of water (10 mL). After adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL x 3) and washed with saturated brine (80 mL). The combined organic phases were purified by column chromatography (PE:EA = 0-10%) to afford compound 28e (583.1 mg, 93%) as a white solid.

[0768] 1 H NMR(400MHz, CDCl3) δ7.15(dd,J=7.9,1.1Hz,1H),7.02–6.95(m,1H),6.78(dd,J=8.2,1.1Hz,1H),3.85 (s,2H),3.64–3.51(m,2H),3.45–3.32(m,2H),2.64(s,2H),1.52–1.44(m,13H).LC-MS(ESI):[M-tBu+H] + =325.98.

[0769] Step 5: 1'-(tert-Butyl)5-methylspiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Compound 28f)

[0770] Under a carbon monoxide atmosphere, triethylamine (2.5 g, 24.6 mmol) and Pd(dppf)2Cl2 CH2Cl2 (670.7 mg, 0.8 mmol) were added to a 60 mL methanol solution of compound 28e (3.1 g, 8.2 mmol). The mixture was then heated to 65°C and allowed to react overnight. After completion of the reaction, the mixture was spin-dried and purified by column chromatography (PE:EA = 0-20%) to afford compound 28f (2.7 g, 90%) as a colorless oil.

[0771] 1 H NMR(400MHz, CDCl3) δ7.52(d,J=7.5Hz,1H),7.20–7.11(m,1H),6.99(d,J=8.0Hz,1H),3.90(s,2H),3.88 (s,3H),3.60–3.46(m,2H),3.46–3.34(m,2H),3.00(s,2H),1.55–1.40(m,13H).LC-MS(ESI):[M-Boc+H] + =262.17.

[0772] Step 6: 1'-(tert-Butoxycarbonyl)spiro[chroman-3,4'-piperidine]-5-carboxylic acid (Compound 28g)

[0773] To a 1 / 1 methanol / tetrahydrofuran solution of compound 28f (40 mL, 40 mL) at 0°C was added a 20 mL aqueous solution of potassium hydroxide (1.5 g, 37 mmol). The mixture was moved to a 60°C oil bath and allowed to react overnight. The solution was dried by evaporation, and 1 M hydrochloric acid solution (50 mL) was added. The mixture was extracted with ethyl acetate (3 times with 40 mL), washed with saturated brine (80 mL), and the combined organic phases were dried by evaporation to afford compound 28f (2.5 g, 97%) as a white solid, which was used directly in the next step. LC-MS (ESI): [MH] - =346.20.

[0774] Step 7: 1'-(tert-Butoxycarbonyl)-6-iodospiro[chroman-3,4'-piperidine]-5-carboxylic acid (Compound 28h)

[0775] To a solution of compound 28g (84.9 mg, 0.244 mmol) in N,N-dimethylformamide (1 mL) under air was added iodine (62.0 mg, 0.244 mmol), diethyl iodate (78.7 mg, 0.244 mmol), and palladium acetate (2.7 mg, 0.012 mmol). The mixture was reacted in an 80°C oil bath for half an hour. The mixture was extracted with ethyl acetate (10 mL x 3) and washed with saturated brine (20 mL). The combined organic phases were spin-dried and lyophilized to yield compound 28h (72.3 mg, 65%) as a white solid.

[0776] 1 H NMR(400MHz, CDCl3) δ7.54(d,J=8.6Hz,1H),6.63(d,J=8.5Hz,1H),3.89(s,2H),3.64 –3.45(m,2H),3.45–3.26(m,2H),2.71(s,2H),1.52–1.36(m,13H).LC-MS(ESI):[MH] - =472.10.

[0777] Step 8: 1'-(tert-Butyl)5-methyl6-iodospiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Compound 28i)

[0778] To a solution of compound 28h (200.0 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) were added iodomethane (120 mg, 0.85 mmol) and potassium carbonate (175.2 mg, 1.27 mmol). The reaction was allowed to proceed at 80°C for 1 hour. Upon completion, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine (40 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The residue was then dried and purified by column chromatography (PE:EA = 0-20%) to afford compound 28i (203.9 mg, 99%) as a yellow oil.

[0779] 1 H NMR (600MHz, CDCl3) δ7.51 (d, J = 8.7Hz, 1H), 6.62 (d, J = 8.7Hz, 1H), 3.95 (s, 3H), 3. 88(s,2H),3.57–3.47(m,2H),3.40–3.27(m,2H),2.59(s,2H),1.49–1.41(m,13H).

[0780] LC-MS(ESI):[M-Boc+H] + =388.19.

[0781] Step 9: 1'-(tert-Butyl)5-methyl6-vinylspiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Compound 28j)

[0782] Under a nitrogen atmosphere, compound 28i (1.36 g, 2.8 mmol) was dissolved in a tetrahydrofuran / water mixture (10:1, 33 mL). Potassium vinyl trifluoroborate (560.7 mg, 4.2 mmol), palladium acetate (125.3 mg, 0.558 mmol), triphenylphosphine (102.5 mg, 0.391 mmol), and cesium carbonate (1.82 g, 5.58 mmol) were then added. The mixture was reacted in an 85°C oil bath overnight. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford compound 28j (790 mg, 73%) as a colorless oil, which was used directly in the next step.

[0783] LC-MS(ESI):[M+H] + =388.09.

[0784] Step 10: 1'-(tert-Butyl)5-methyl-6-formylspiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Compound 28k)

[0785] Sodium periodate (6.07 g, 28.4 mmol) and potassium osmate dihydrate (126.8 mg, 0.284 mmol) were added to a solution of compound 28j (2.75 g, 7.1 mmol) in acetone / water (5:1, 210 mL) and allowed to react overnight at room temperature. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford compound 28k (930 mg, 33%) as a white solid.

[0786] 1 H NMR(600MHz, CDCl3)δ9.83(s,1H),7.65(d,J=8.5Hz,1H),6.99(d,J=8.5Hz,1H),4.05–3.95(m,5H ),3.58–3.47(m,2H),3.40–3.31(m,2H),2.64(s,2H),1.55–1.29(m,13H).LC-MS(ESI):[M-tBu+H] + =334.19.

[0787] Step 11: tert-Butyl 2'-(2,6-dioxopiperidin-3-yl)-1'-oxo-1',2',3',9'-tetrahydro-7'-H-spiro[piperidin-4,8'-pyrano[3,2-e]isoindole]-1-carboxylate (Compound 281)

[0788] Compound 28k (451 mg, 1.16 mmol) and 3-amino-2,6-piperidinedione hydrochloride (286.2 mg, 1.74 mmol) were mixed in a 1 / 2 dichloromethane / methanol mixture (21 mL). After reacting at room temperature for 1 hour, sodium cyanoborohydride (218.5 mg, 3.5 mmol) was added and the reaction continued overnight at room temperature. The solvent was evaporated, and the mixture was purified by reverse-phase column chromatography to yield Compound 28l (30.2 mg, 5%) as a white solid.

[0789] 1H NMR (600MHz, DMSO-d6) δ10.99(s,1H),7.29(d,J=8.2Hz,1H),7.02(d,J=8.2Hz,1H),5.01(dd ,J=13.2,5.1Hz,1H),4.30(d,J=16.9Hz,1H),4.19(d,J=16.9Hz,1H),3.98(s,2H),3.47–3.38 (m,2H),3.31–3.24(m,2H),3.12–3.02(m,2H),2.92–2.85(m,1H),2.63–2.56(m,1H),2.42–2. 32(m,1H),2.00–1.94(m,1H),1.51–1.30(m,11H),1.38–1.30(m,2H).LC-MS(ESI):[M-Boc+H] + =370.29.

[0790] Step 12: 3-(1'-oxo-1',9'-dihydro-7'H-spiro[piperidin-4,8'-pyrano[3,2-e]isoindol]-2'(3'H)-yl)piperidine-2,6-dione (E3 ligase inhibitor 28)

[0791] Trifluoroacetic acid (1 mL) was added to compound 281 (30.2 mg, 0.064 mmol), and the reaction was allowed to proceed overnight at room temperature. The mixture was purified by preparative column chromatography to afford E3 ligase inhibitor 28 as a white solid (21.7 mg, 91%).

[0792] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.31(d,J=8.2Hz,1H),7.04(d,J=8.2Hz, 1H),5.01(dd,J=13.3,5.1Hz,1H),4.31(d,J=17.0Hz,1H),4.20(d,J=17.0Hz,1H ),4.05(s,2H),3.21–3.03(m,6H),2.94–2.84(m,1H),2.64–2.56(m,1H),2.38(q d,J=13.0,4.2Hz,1H),2.02–1.91(m,1H),1.70–1.52(m,4H).LC-MS(ESI):[M+H] + =370.29.

[0793] 29)

[0794] Step 1: Dissolve 2-1a (1 g, 4.69 mmol) in trifluoromethanesulfonic acid (10 mL), protect the solution with nitrogen and cool to 0°C.

[0795] N-iodosuccinimide (1.16 g, 5.16 mmol) was added to the reaction mixture at 0°C. The reaction mixture was allowed to warm to room temperature overnight. The resulting mixture was poured into ice water and filtered. The filter cake was washed with water and purified by column chromatography to afford 2-1b (800 mg, 50.28%) as a white solid.

[0796] 1 H NMR (600MHz, DMSO-d6) δ7.94–7.91 (m, 1H), 7.78 (dd, J = 8.1, 1.1Hz, 1H), 5.21 (s, 2H).

[0797] Step 2: To a solution of compound 2-1b in N,N-dimethylacetamide (3.5 mL) was added a solution of sodium hydroxide (413 mg, 10.33 mmol) in water (7 mL). Cuprous oxide (59 mg, 413.07 μmol) was added to the above solution. The reaction mixture was heated to 80°C and stirred overnight. The reaction mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was concentrated under vacuum, and the resulting mixture was purified by column chromatography to yield 2-1c (249 mg, 52.64%) as a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.91(s,1H),7.73(d,J=8.0Hz,1H),7.24(d,J=8.0Hz,1H),5.35(s,2H).

[0798] LC-MS(ESI):[M+H] + =230.86.

[0799] Step 3: Under nitrogen, compound 2-1c (11.85 g, 51.74 mmol) and butyl vinyl ether (6.74 g, 67.26 mmol) were dissolved in methanol (200 mL). Triethylamine (10.47 g, 103.48 mmol), palladium acetate (1.16 g, 5.17 mmol), and 1,1-bis(diphenylphosphino)ferrocene (4.30 g, 7.7 mmol) were added at room temperature. The reaction mixture was heated to 70°C and stirred overnight. The mixture was purified by preparative column chromatography to yield 2-1d (6.42 g, 45.20%) as a yellow oil.

[0800] 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.07(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),5.42(s,2H),2.73(s,3H).

[0801] LC-MS(ESI):[M+H] + =193.24.

[0802] Step 4: Dissolve compound 2-1d (6.28 g, 32.68 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (6.15 g, 35.96 mmol), and tetrahydropyrrole (2.58 g, 35.96 mmol) in methanol (100 mL), and stir the mixture at 70°C overnight. The reaction mixture was concentrated in vacuo and purified by normal phase column chromatography to afford 2-1e (2.52 g, 22.33%) as a yellow solid.

[0803] 1 H NMR (600MHz, DMSO-d6) δ7.93(d,J=7.9Hz,1H),7.54(d,J=7.9Hz,1H),5.51(s,2H),4.08–3.94(m,4H),3.32(s,2H),1.39(s,9H)

[0804] LC-MS(ESI):[M-tBu+H] + =290.16

[0805] Step 5: Dissolve compound 2-1e (2.52 g, 7.30 mmol) in methanol (30 mL) and add sodium borohydride (552 mg, 14.59 mmol) at room temperature. Stir the reaction at room temperature for 1 hour. Quench with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow solid 1f (2.5 g, 98.63%).

[0806] LC-MS(ESI):[M-tBu+H] + =292.08.

[0807] Step 6: Compound 2-1f (2.57 g, 7.39 mmol) and p-toluenesulfonic acid (2.54 g, 14.77 mmol) were dissolved in toluene (60 mL), and the mixture was stirred at 110°C for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was used directly in the next step without purification.

[0808] LC-MS(ESI):[M+H] + =230.46.

[0809] Step 7: Dissolve compound 2-1g (2.5g, 10.91mmol) in dichloromethane (30mL) and add triethylamine (5.51g, 54.55mmol). Add di-tert-butyl dicarbonate (7.14g, 32.72mmol) at 0°C and stir the reaction at room temperature for 1 hour. The mixture is concentrated under vacuum and purified by normal phase purification to give 2-1h as a white solid (800mg, 22.27%). LC-MS (ESI): [M-tBu+H] + =274.17

[0810] Step 8: Dissolve compound 2-1h (800 mg, 2.43 mmol) in hexafluoroisopropanol (20 mL) and add palladium hydroxide on carbon (1 g). Displace the hydrogen atmosphere three times and stir under hydrogen at room temperature for 5 hours. After completion of the reaction, filter the reaction mixture and concentrate under reduced pressure to obtain 2-1i (700 mg, 86.97%) as a white solid.

[0811] LC-MS(ESI):[M+H] + =276.27

[0812] Step 9: Dissolve diethylamine (353 mg, 4.83 mmol) in dry dichloromethane (5 mL) and add aluminum chloride (322 mg, 2.41 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, and compound 2-1i (200 mg, 603.56 μmol) was added. The mixture was stirred at room temperature overnight. Saturated ammonium chloride was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by normal phase column chromatography to obtain 2-1j (100 mg, 40.96%) as a white solid.

[0813] 1 H NMR (600MHz, DMSO-d6) δ7.04(d,J=7.7Hz,1H),6.65(d,J=7.7Hz,1H),4.56(t,J=5.6Hz,1H),4.38(d,J=86.7Hz,2H),3.91(s,4H),3.52(s,1 H),3.22–3.32(m,1H),3.08(s,2H),2.80(t,J=6.5Hz,2H),2.08(t,J=6.6Hz,2H),1.40(s,9H),1.14(t,J=7.0Hz,3H),0.97(t,J=7.1Hz,3H).

[0814] LC-MS(ESI):[M+H] + =405.40

[0815] Step 10: Dissolve compound 2-1j (80 mg, 197.77 μmol) in tetrahydrofuran (3 mL) and add 2-iodobenzoic acid (83 mg, 198.66 μmol). Stir the mixture at 70°C for 3 hours. After cooling, filter, and concentrate the filtrate in vacuo to obtain 2-1k (70 mg, 87.94%) as a white solid.

[0816] LC-MS(ESI):[M+H] + =403.35

[0817] Step 11: Dissolve compound 2-1k (300 mg, 745.36 μmol), 3-aminopiperidine-2,6-dione hydrochloride (184 mg, 1.12 mmol), and sodium acetate (92 mg, 1.12 mmol) in methanol (10 mL). Stir at room temperature for 30 minutes. Add sodium cyanoborohydride (94 mg, 1.49 mmol) and stir at room temperature overnight. Concentrate the reaction mixture in vacuo to obtain 2-1l (350 mg, 91.26%) as a blue solid.

[0818] LC-MS(ESI):[M+H] + =515.40

[0819] Step 12: Dissolve compound 2-11 (300 mg, 582.95 μmol) and glacial acetic acid (1.23 g, 20.40 mmol) in toluene (30 mL), and stir the mixture at 110°C overnight. Concentrate the reaction mixture in vacuo and purify it on a normal phase column to obtain 2-1m as a white solid (237 mg, 92.49%).

[0820] 1 H NMR (600MHz, DMSO-d6) δ10.99(s,1H),7.25(d,J=9.0Hz,2H),5.10(dd,J=13.4,5.1Hz,1H),4.39(d,J=17.3Hz,1H),4.23(d,J=17.3Hz,1H), 3.98(s,2H),3.88(s,2H),2.96–2.87(m,3H),2.57–2.61(m,1H),2.44(dd,J=13.2,4.5Hz,1H),2.15(s,2H),2.02–1.94(m,1H),1.40(s,9H).

[0821] LC-MS(ESI):[M-tBu+H] + =386.30

[0822] Step 13: Dissolve compound 2-1m (53 mg, 32.68 μmol) in dioxane (1 mL), add 4 M hydrochloric acid in dioxane (1 mL), and stir the mixture at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative chromatography to afford 2-1 (20 mg, 48.80%) as a white solid.

[0823] 1 H NMR (400MHz, Methanol-d4) δ7.39(d,J=7.7Hz,1H),7.32(d,J=7.8Hz,1H),5.18(dd,J=13.4,5.2Hz,1H),4.55–4.41(m,2H),4.32–4.22(m,4H),3.0 5–2.88(m,3H),2.81(ddd,J=17.6,4.7,2.4Hz,1H),2.50(qd,J=13.2,4.7 Hz,1H),2.33(dq,J=10.2,7.2Hz,2H),2.20(dtd,J=12.9,5.3,2.4Hz,1H).

[0824] LC-MS(ESI):[M+H] + =342.29

[0825] 30)

[0826] Step 1: Dissolve compound 2-2a (5.0 g, 33.30 mmol) in acetonitrile (50 mL). Add N-bromosuccinimide (8.89 g, 49.95 mmol) and trifluoroacetic acid (11.39 g, 99.89 mmol) to the reaction system. Warm the reaction mixture to 80°C and allow to react for 12 hours. Concentrate the resulting reaction mixture under reduced pressure. The resulting crude product is purified by reverse-phase column chromatography to afford compound 2-2b (1.41 g, 18.5%) as a pale yellow solid.

[0827] 1 H NMR (600MHz, DMSO-d6) δ11.63 (s, 1H), 7.70 (d, J = 8.3Hz, 1H), 7.13 (d, J = 8.3Hz, 1H), 5.25 (s, 2H).

[0828] LC-MS(ESI):[M+H] + =229.06.

[0829] Step 2: Dissolve compound 2-2b (2.6 g, 11.35 mmol), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (3.46 g, 17.03 mmol), and triphenylphosphine (7.44 g, 28.38 mmol) in tetrahydrofuran (60 mL). Cool the mixture to 0°C and add diethyl azodicarboxylate (4.44 g, 28.38 mmol). After the addition is complete, return the mixture to room temperature and react for 12 hours. The reaction mixture is concentrated under reduced pressure, and water (50 mL) is added. Extraction is performed with ethyl acetate (100 mL x 3), followed by washing with saturated brine (100 mL). The organic phases are combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases is purified by reverse-phase column chromatography to yield compound 2-2c (4.27 g, 90.79%) as a white solid.

[0830] 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=8.4Hz,1H),7.56-7.38(m,5H),7.35(d,J=8.5Hz,1H),5.87(d,J=3.8 Hz,1H),5.29(s,2H),4.79(s,2H),4.31–4.04(m,2H),3.52(s,2H),3.10(q,J=7.3Hz,2H),2.41(s,2H).

[0831] LC-MS(ESI):[M+H] + =414.19.

[0832] Step 3: Dissolve compound 2-2c (6.27 g, 15.13 mmol), tri-n-butyltin hydroxide (8.81 g, 30.26 mmol), and azobisisobutyronitrile (497 mg, 3.03 mmol) in toluene (200 mL) and react at 110°C under nitrogen for 12 hours. Cool the reaction system to room temperature, concentrate under reduced pressure, add water (100 mL), and extract with ethyl acetate (100 mL x 3). Wash with saturated brine (100 mL), and the combined organic phases are dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases is purified by column chromatography to yield compound 2-2d (3.0 g, 59.1%) as a yellow solid.

[0833] 1H NMR(600MHz,DMSO-d6)δ7.65(d,J=8.2Hz,1H),7.34(d,J=5.5Hz,4H),7.28–7.25(m,1H),7.00(d,J=8.3Hz,1 H),5.54(s,2H),4.58(s,2H),3.49(s,2H),2.02–1.95(m,4H),1.68(d,J=10.6Hz,2H),1.61(t,J=8.1Hz,2H)

[0834] LC-MS(ESI):[M+H] + =336.30.

[0835] Step 4: Dissolve aluminum trichloride (3.18 g, 23.85 mmol) in dichloromethane (15 mL). Cool the reaction system to 0°C and add diethylamine (3.49 g, 47.7 mmol) dropwise. Incubate at 0°C for 30 minutes. Add compound 2-2d (2.0 g, 5.96 mmol) dropwise. After the addition is complete, return the system to room temperature and react for 3 hours. Add saturated aqueous ammonium chloride (50 mL) to the reaction system and extract with dichloromethane (3 times 50 mL). Wash with saturated brine (100 mL). Combine the organic phases and dry over anhydrous sodium sulfate. Concentrate the organic phases to obtain the crude product, which is then purified by column chromatography to yield compound 2-2e (1.85 g, 75.9%) as a reddish-brown oil.

[0836] 1 H NMR (400MHz, DMSO-d6) δ7.57-7.25(m,5H),6.94(d,J=7.5Hz,1H),6.73(d,J=7 .5Hz,1H),4.81(t,J=4.6Hz,1H),4.51(d,J=4.6Hz,2H),4.46–4.26(m,2H),3. 63–3.43(m,3H),3.17(d,J=5.2Hz,1H),3.09(s,3H),2.80(s,1H),2.36(s,2H) ,1.98(s,2H),1.64–1.60(m,2H),1.13(t,J=7.5Hz,3H),0.98(t,J=7.1Hz,3H).

[0837] LC-MS(ESI):[M+H] + =409.49.

[0838] Step 5: Compound 2-2e (1.85 g, 4.53 mmol) was dissolved in dichloromethane (20 mL), and 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3(1H)-one (2.88 g, 6.79 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 2-2f (1.57 g, 85.3%). This crude product was directly used in the next reaction without further purification.

[0839] LC-MS(ESI):[M+H] + =407.69.

[0840] Step 6: Dissolve compound 2-2f (1.4 g, 3.44 mmol), 3-amino-2,6-piperidinedione hydrochloride (850 mg, 5.16 mmol), and sodium acetate (424 mg, 5.16 mmol) in methanol (30 mL). The mixture was allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (433 mg, 6.88 mmol) was added to the reaction system and allowed to react at room temperature for 12 hours. The reaction solution was concentrated, and acetic acid (7.0 mL) and toluene (40 mL) were added. The resulting reaction solution was reacted at 110°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 2-2g (1.32 g, 86.1%) as a light blue solid.

[0841] 1 H NMR (600MHz, Methanol-d4) δ7.64(d,J=8.2Hz,1H),7.49–7.34(m,5H),6.93(d,J=8.2Hz,1H),5.15(dd,J=13.4,5.2Hz,1H),4.65(dd,J=12.8,5.2Hz,2H),4 .60(d,J=5.0Hz,2H),3.86–3.78(m,2H),3.18–3.13(m,2H),2.82–2.75(m,2H) ,2.70–2.65(m,2H),2.47–2.40(m,2H),2.31–2.23(m,2H),2.18–2.12(m,2H).

[0842] LC-MS(ESI):[M+H] + =446.29.

[0843] Step 7: Dissolve compound 2-2g (500mg, 1.12mmol) in hexafluoroisopropanol (15mL) and add palladium hydroxide on carbon (394mg) to the system. After hydrogen substitution three times, react at room temperature for 12 hours. The reaction system is filtered, and the filter cake is washed three times with hexafluoroisopropanol (15mL). The filtrate is concentrated under reduced pressure, and the crude product is purified by reverse column chromatography to obtain compound 2-2 (277mg, 69.4%) as a white solid.

[0844] 1 H NMR (600MHz, Methanol-d4) δ7.69(d,J=8.2Hz,1H),6.99(d,J=8.2Hz,1H),5.18(dd,J=13.4,5.1Hz,1H),4.69(s,2H),4.66–4.53 (m,2H),3.50(d,J=13.1Hz,2H),3.20–3.12(m,2H),2.99–2.91(m,1H),2.85–2.78(m,1H),2.53–2.42(m,1H),2.41–2.29(m,2H), 2.25–2.19(m,1H),2.07(d,J=14.5Hz,2H).

[0845] LC-MS(ESI):[M+H] + =356.39

[0846] 31)

[0847] Step 1: Dissolve compound 2-3a (5.00 g, 21.64 mmol), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (6.60 g, 32.46 mmol), and diphenyl-2-pyridinylphosphine (5.71 g, 21.62 mmol) in ultra-dry tetrahydrofuran (50 mL). Add diisopropyl azodicarboxylate (4.40 g, 21.67 mmol) dropwise to the reaction system under nitrogen protection and in an ice bath. After the addition is complete, warm the mixture to room temperature and stir overnight. The resulting reaction system is concentrated under reduced pressure. The crude product is purified by normal column chromatography to afford compound 2-3b (8.61 g, 95.5%) as a white solid.

[0848] LC-MS(ESI):[M+H] + =416.20.

[0849] Step 2: Compound 2-3b (7.61 g, 18.28 mmol) was dissolved in toluene (100 mL), followed by the addition of azobisisobutyronitrile (6.00 g, 36.58 mmol) and tributyltin hydride (10.64 g, 36.56 mmol). The mixture was heated to 110°C and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the crude product obtained from the concentrated organic phase was purified by normal phase column chromatography to afford compound 2-3c (5.15 g, 83.5%) as a yellow oil.

[0850] 1 H NMR (600MHz, DMSO-d6) δ7.57(dd,J=7.8,1.3Hz,1H),7.54–7.48(m,5H),7.31(d,J=1.1Hz,1H),7.25(t,J=6.5Hz,1H),4.59(d,J=7.5Hz,2H), 4.36(d,J=4.0Hz,2H),3.83(s,3H),3.38(d,J=12.5Hz,2H),3.14(dd,J=22.5,10.7Hz,2H),2.11(td,J=14.2,3.9Hz,2H),1.98–1.91(m,2H).

[0851] LC-MS(ESI):[M+H] + =338.35.

[0852] Step 3: Dissolve compound 2-3c (5.15 g, 15.26 mmol) and p-toluenesulfonic acid (5.26 g, 30.53 mmol) in toluene (200 mL). Add N-bromosuccinimide (3.80 g, 21.37 mmol) and react at 60°C overnight. After cooling the reaction system to room temperature, concentrate under reduced pressure. The resulting crude product was purified by column chromatography to afford compound 2-3d (3.93 g, 61.5%) as a yellow solid.

[0853] 1 H NMR(600MHz,DMSO-d6)δ7.57(s,1H),7.54–7.48(m,5H),7.17(s,1H),4.58(s,2H),4.34(s,2H),3.82(s,3H) ,3.16–3.06(m,2H),2.33–2.24(m,1H),2.09(dd,J=17.0,7.4Hz,2H),1.98–1.92(m,2H),1.90–1.83(m,1H).

[0854] LC-MS(ESI):[M+H] + =416.25.

[0855] Step 4: Dissolve compound 2-3d (3.93 g, 9.44 mmol), methylboronic acid (1.70 g, 28.32 mmol), potassium carbonate (2.61 g, 18.88 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (890 mg, 1.21 mmol) in 1,4-dioxane and water (100 / 15 mL). Heat the reaction system to 105°C and stir overnight. Concentrate the reaction mixture to obtain a crude product, which was purified by reverse-phase column chromatography to afford compound 2-3e (1.53 g, 46.1%) as a white solid.

[0856] 1 H NMR (600MHz, DMSO-d6) δ7.51(t,J=6.3Hz,5H),7.19(s,1H),7.00(s,1H),4.54(s,2H),4.37–4.34(m,2H),3.80(d,J=3. 4Hz,3H),3.37(d,J=12.8Hz,2H),3.16–3.08(m,2H),2.44(d,J=4.0Hz,3H),2.13–2.05(m,2H),1.92(d,J=14.0Hz,2H).

[0857] LC-MS(ESI):[M+H] + =351.89

[0858] Step 5: Dissolve compound 2-3e (1.83 g, 5.21 mmol) and aqueous ammonia (0.5 mL) in ultra-dry methanol (50 mL). Add palladium hydroxide on carbon (900 mg) and palladium on carbon (900 mg). Replace the atmosphere with hydrogen. Heat the reaction system to 40°C and stir overnight. Filter and spin dry to obtain crude product 2-3f (1.23 g, 90.4%). LC-MS (ESI): [M+H] + =261.87

[0859] Step 6: Dissolve compound 2-3f (1.23 g, 4.71 mmol) in dichloromethane (50 mL), then add di-tert-butyl dicarbonate (2.05 g, 9.41 mmol) and triethylamine (1.43 g, 14.12 mmol). Stir at room temperature for one hour. Concentrate the reaction mixture to obtain a crude product, which was purified by normal phase column chromatography to afford compound 2-3f (940 mg, 55.2%) as a white solid.

[0860] LC-MS(ESI):[Mt-Bu+H] + =306.25

[0861] Step 7: Dissolve compound 2-3g (940 mg, 2.60 mmol), N-bromosuccinimide (555 mg, 3.12 mmol), and azobisisobutyronitrile (130 mg, 792.68 mmol) in carbon tetrachloride (30 mL). Under nitrogen, heat to 80°C and stir overnight. Extract with dichloromethane (100 mL x 2). Combine the organic phases and dry over anhydrous sodium sulfate. Concentrate the organic phase to obtain a crude product (1.20 g).

[0862] Step 8: Dissolve compound 2-3h (1.20 g, 2.59 mmol), 3-amino-2,6-piperidinedione hydrochloride (1.28 g, 7.77 mmol), and N,N-diisopropylethylamine (1.67 g, 12.94 mmol) in acetonitrile (50 mL). Warm the mixture to 80°C and stir overnight. Concentrate the reaction mixture to obtain a crude product, which was purified by reverse-phase column chromatography to afford compound 2-3i (290 mg, 24.5%) as a blue solid.

[0863] 1 H NMR(600MHz,DMSO-d6)δ10.98(s,1H),7.50(s,1H),7.03(s,1H),5.08(dd,J=1 3.3,5.1Hz,1H),4.56–4.51(m,2H),4.34(d,J=16.9Hz,1H),4.21(d,J=16.9Hz, 1H),3.94(s,2H),2.95–2.87(m,2H),2.63–2.56(m,1H),2.38(dd,J=13.1,4.4 Hz,1H),2.03–1.94(m,2H),1.82–1.73(m,2H),1.72–1.65(m,2H),1.43(s,9H).

[0864] LC-MS(ESI):[M+H] + =456.29

[0865] Step 9: Dissolve compound 2-3i (25 mg, 54.88 mmol) in dichloromethane (4 mL). Add trifluoroacetic acid (4 mL) to the reaction mixture and stir at room temperature for one hour. Concentrate the reaction mixture to obtain a crude product, which is then purified by reverse-phase column chromatography to afford compound 2-3 (10 mg, 51.2%) as a white solid.

[0866] 1H NMR(600MHz,DMSO-d6)δ10.99(s,1H),7.38(s,1H),7.07(s,1H),5.09(dd,J=13.3,5.1H z,1H),4.60(s,2H),4.38(d,J=16.8Hz,1H),4.26(d,J=16.8Hz,1H),3.36–3.32(m,2H), 3.04(q,J=11.7Hz,2H),2.91(ddd,J=17.3,13.6,5.4Hz,1H),2.62(dd,J=4.4,2.4Hz,1H ),2.38(qd,J=13.2,4.5Hz,1H),2.10–1.97(m,3H),1.89(ddt,J=11.9,9.4,2.6Hz,2H).

[0867] LC-MS(ESI):[M+H] + =356.30

[0868] 32)

[0869] Step 1: Dissolve 2-hydroxy-6-methylbenzoic acid (10 g, 65.73 mmol) in methanol (30 mL) and add thionyl chloride (23.6 mL, 328.65 mmol) at 0°C. Allow to react overnight at 60°C. The resulting reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to yield compound 2-4b (10.5 g, 96.1%) as a colorless liquid.

[0870] LC-MS(ESI):[M+H] + =167.13

[0871] Step 2: Dissolve compound 2-4b (6.6 g, 39.72 mmol) and N-bromosuccinimide (8.5 g, 47.66 mmol) in carbon tetrachloride (30 mL). Add azobisisobutyronitrile (1.4 g, 7.94 mmol) to the reaction system. Under nitrogen, react at 85°C overnight. The resulting reaction system was concentrated under reduced pressure to obtain crude product 2-4c (11.0 g), which was directly used in the next step without purification.

[0872] LC-MS(ESI):[M+H] + =247.07

[0873] Step 3: Dissolve crude compound 2-4c (11.0 g, 44.88 mmol) in acetonitrile (50 mL), add 3-aminopiperidine-2,6-dione hydrochloride (9.7 g, 67.33 mmol) and N,N-diisopropylethylamine (22 mL, 134.64 mmol), and react at 80°C overnight. The reaction system was concentrated under reduced pressure and purified by column chromatography to afford compound 2-4d (1.5 g, 12.8%) as a blue solid.

[0874] LC-MS(ESI):[M+H] + =261.17

[0875] Step 4: Dissolve compound 2-4d (1.0 g, 3.84 mmol) in tetrahydrofuran (15 mL), add triethylamine (1.65 mL, 11.52 mmol) and N-bromosuccinimide (820 mg, 7.68 mmol) in turn, and react at room temperature for 1 hour. After TLC detection, the resulting reaction system was directly subjected to the next step.

[0876] LC-MS(ESI):[M+H] + =419.00

[0877] Step 5: To the reaction system from the previous step, (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (760 mg, 3.73 mmol), triphenylphosphine (980 mg, 3.73 mmol), and diethyl azodicarboxylate (775 mg, 3.73 mmol) were added sequentially under nitrogen atmosphere at room temperature overnight. The reaction system was concentrated under reduced pressure. Purification by chromatography afforded compound 2-4f (820 mg, 43.7%) as a yellow oil.

[0878] 1 H NMR(600MHz,DMSO-d6)δ11.05(s,1H),8.20(s,1H),7.54–7.48(m,5H),5. 87–5.86(m,1H),5.10–5.06(m,1H),4.79–4.71(m,2H),4.43–4.34(m,3H) ,4.23(dd,J=18.1,6.0Hz,1H),3.70–3.64(m,2H),3.58–3.52(m,2H),3.2 1–3.15(m,1H),2.91–2.85(m,1H),2.62–2.60(m,3H),2.02–1.99(m,1H).

[0879] LC-MS(ESI):[M+H] + =604.08

[0880] Step 6: Dissolve compound 2-4f (820 mg, 1.36 mmol) in toluene (25 mL) and add azobisisobutyronitrile (2.3 g, 13.6 mmol) and tributyltin hydride (7.9 g, 27.2 mmol). React at 110°C overnight under nitrogen. Concentrate the reaction mixture under reduced pressure. Purify by chromatography and further slurry with methanol to obtain 2-4f (430 mg, 71.0%) as a white solid.

[0881] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),7.46(d,J=7.6Hz,1H),7.34(d,J=4.4Hz,

[0882] 4H),7.28–7.24(m,1H),7.02(d,J=7.6Hz,1H),5.05(dd,J=13.3,5.1Hz,1H),4.53(s, 2H),4.37(d,J=17.1Hz,1H),4.24(d,J=17.1Hz,1H),3.50(s,2H),2.90(ddd,J=17.2, 13.7,5.5Hz,1H),2.81(dt,J=11.8,4.0Hz,2H),2.63–2.55(m,1H),2.35(dd,J=13.2, 4.6Hz,1H),2.04(t,J=12.1Hz,2H),1.99–1.84(m,3H),1.65(tt,J=10.9,2.6Hz,2H).

[0883] LC-MS(ESI):[M+H] + =446.29

[0884] Step 7: Dissolve compound 2-4g (430 mg, 0.96 mmol) in methanol (25 mL). Add catalytic amounts of hydrochloric acid (5 drops), palladium on carbon (215 mg), and palladium hydroxide (215 mg). Replace the atmosphere with hydrogen three times and allow to react overnight at 40°C. Filter through celite and concentrate under reduced pressure. The crude product was purified by methanol slurry to yield 2-4 (260 mg, 75.8%) as a white solid.

[0885] 1H NMR (600MHz, DMSO-d6) δ10.97(s,1H),7.36(d,J=7.6Hz,1H),7.10(d,J=7.6H z,1H),5.05(dd,J=13.3,5.1Hz,1H),4.67(s,2H),4.41(d,J=17.3Hz,1H),4.2 7(d,J=17.3Hz,1H),3.36–3.34(m,2H),3.07–3.01(m,2H),2.94–2.88(m,1H) ,2.62–2.58(m,1H),2.40–2.33(m,1H),2.03–1.95(m,3H),1.89–1.85(m,2H).

[0886] LC-MS(ESI):[M+H] + =356.30

[0887] 33)

[0888] Step 1: Dissolve compound 2-5a (23.0 g, 151.2 mmol) in anhydrous methanol (120 mL) and slowly add concentrated sulfuric acid (12 mL) to the reaction system. Heat the reaction solution to 60°C and react at this temperature for 12 hours. Cool the resulting reaction system to room temperature, then pour the reaction solution into ice water and extract with ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless oil 2-5b (21.45 g, 85.4%). This product was used directly in the next step without further purification. LC-MS (ESI): [M+H] + =167.30.

[0889] Step 2: Dissolve compound 2-5b (5.0 g, 30.11 mmol) in acetonitrile (50 mL) and add N-bromosuccinimide (8.04 g, 45.16 mmol). Heat the reaction mixture to 80°C and allow to react for 12 hours. Concentrate the resulting reaction mixture under reduced pressure. The resulting crude product is purified by reverse-phase column chromatography to yield compound 2-5c (4.27 g, 58.13%) as a pale yellow solid.

[0890] Step 3: Compound 2-5c (1.00 g, 4.08 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). (1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (1.24 g, 6.12 mmol), triphenylphosphine (2.14 g, 8.16 mmol), and diisopropyl azodicarboxylate (1.65 g, 8.16 mmol) were added to the reaction mixture. The reaction mixture was allowed to react at room temperature under nitrogen for 12 hours. The reaction mixture was filtered and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by reverse-phase column chromatography to afford compound 2-5d (1.72 g, 97.9%) as a yellow oil.

[0891] 1 H NMR (600MHz, DMSO-d6) δ7.54–7.47(m,5H),7.26(d,J=8.5Hz,1H),7.14(d,J=8.5Hz,1H ),5.85(s,1H),4.65(s,2H),4.37(s,2H),3.87(s,3H),3.70(s,2H),3.58–3.52(m,1H), 3.19–3.12(m,1H),2.45(m,2H),2.18(s,3H).

[0892] LC-MS(ESI):[M+H] + =430.25.

[0893] Step 4: Dissolve 2-5d (1.72 g, 4.00 mmol), tri-n-butyltin hydride (2.3 g, 7.99 mmol), and azobisisobutyronitrile (1.97 g, 11.99 mmol) in toluene (15 mL) and react at 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography to afford compound 2-5e (1.11 g, 79.0%) as a yellow oil.

[0894] LC-MS (ESI) [M+H] + =352.49.

[0895] Step 5: Compound 2-5e (1.05 g, 2.99 mmol) was dissolved in anhydrous methanol (15 mL), palladium carbon (500 mg) was added, and the mixture was vented with hydrogen three times. The system was reacted at room temperature for 4 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 2-5f (570 mg, 73.1%). The crude product was directly used in the next step without further purification. LC-MS (ESI): [M+H] + =262.57.

[0896] Step 6: Dissolve compound 2-5f (570 mg, 2.19 mmol) in dichloromethane (16 mL). Add di-tert-butyl dicarbonate (718 mg, 3.29 mmol) and triethylamine (444 mg, 4.39 mmol). The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain compound 2-5g (570 mg, 72.1%) as a yellow oil.

[0897] LC-MS(ESI):[M-Boc+H] + =262.27.

[0898] Step 7: Dissolve compound 2-5g (521 mg, 1.44 mmol) in carbon tetrachloride (5 mL). Add N-bromosuccinimide (257 mg, 1.44 mmol) and azobisisobutyronitrile (24 mg, 0.14 mmol). The reaction mixture is incubated at 80°C under nitrogen for 2 hours. The reaction mixture is concentrated under reduced pressure to yield compound 2-5h (521 mg, 82.1%) as a yellow oil.

[0899] LC-MS(ESI):[M-tBu+H] + =384.27.

[0900] Step 8: Compound 2-5h (520 mg, 1.18 mmol) was dissolved in acetonitrile (12 mL). 3-Amino-2,6-piperidinedione hydrochloride (292 mg, 1.77 mmol) and N,N-diisopropylethylamine (459 mg, 3.55 mmol) were added to the reaction mixture. The reaction system was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography to obtain compound 2-5i (181 mg, 33.6%) as a yellow oil.

[0901] LC-MS(ESI):[M-tBu+H] + =400.35.

[0902] Step 9: Dissolve compound 2-5i (181 mg, 397.4 μmol) in dichloromethane (8 mL) and add trifluoroacetic acid (1 mL). The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative liquid chromatography to afford compound 2-5 (81 mg, 57.4%) as a white solid.

[0903] 1H NMR (600MHz, DMSO-d6) δ11.02(s,1H),7.40(d,J=8.2Hz,1H),7.09(d,J=8.2Hz,1H),4.95(dd,J=13.2,5.2Hz,1H),4.62(s,2H),4.46–4.33(m,2H) ,3.36–3.28(m,2H),3.02–2.92(m,2H),2.92–2.80(m,3H),2.66–2.59(m, 1H), 2.43 (qd, J=13.3, 4.5Hz, 1H), 2.07–1.95 (m, 1H), 1.84–1.77 (m, 2H).

[0904] LC-MS(ESI):[M+H] + =356.35

[0905] 34)

[0906] Step 1: Dissolve compound 2-8a (3.0 g, 21.14 mmol), N-bromosuccinimide (2.59 g, 14.57 mmol), and azobisisobutyronitrile (398 mg, 2.43 mmol) in carbon tetrachloride (30 mL). After nitrogen displacement three times, the system was heated to 80°C and reacted overnight. After cooling the reaction system to room temperature, it was concentrated under reduced pressure. The resulting crude product was purified by column chromatography to afford compound 2-8b (2.5 g, 63.18%) as a yellow oil.

[0907] Step 2: Dissolve compound 2-8b (2.36 g, 11.04 mmol) and potassium tert-butoxide (1.34 g, 11.96 mmol) in tetrahydrofuran (20 mL). After nitrogen replacement three times, cool the system to -30°C and react for 30 minutes. Dissolve tert-butyl 4-formylpiperidine-1-carboxylate (3.0 g, 13.2 mmol) in tetrahydrofuran and slowly add dropwise to the reaction system. Allow the system to react at -30°C for 2 hours. Concentrate the reaction system under reduced pressure, and the resulting crude product is purified by column chromatography to obtain compound 2-8c (1.75 g, 41.49%) as a yellow solid.

[0908] LC-MS(ESI):[M-Boc+H] + =358.18.

[0909] Step 3: Dissolve compound 2-8c (1.7 g, 3.71 mmol) in methanol (20 mL). Cool the reaction system to 0°C and add sodium borohydride (210 mg, 5.56 mmol). Allow the reaction to react overnight at room temperature. Concentrate under reduced pressure, add water (10 mL), and extract with ethyl acetate (20 mL x 3). Wash with saturated brine (20 mL). Combine the organic phases and dry over anhydrous sodium sulfate. The resulting crude product is purified by column chromatography to yield compound 2-8d (1.0 g, 57%) as a yellow oil.

[0910] LC-MS(ESI):[M-Boc+H] + =360.21.

[0911] Step 4: Dissolve compound 2-8d (750 mg, 1.63 mmol) and sodium hydride (120 mg, 1.96 mmol) in N,N-dimethylformamide (10 mL). Heat the mixture to 110°C and react for 5 hours. Cool the reaction mixture to room temperature, concentrate under reduced pressure, add water (10 mL), and extract with ethyl acetate (20 mL x 3). Wash with saturated brine (20 mL), and dry the combined organic phases over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography to afford compound 2-8e (300 mg, 41.82%) as a yellow oil.

[0912] Step 5: Compound 2-8e (550 mg, 1.25 mmol), 1,1-bis(diphenylphosphine)dichloroferroic palladium (493 mg,

[0913] A mixture of 2-8f (0.674 mmol) and triethylamine (1.37 g, 13.49 mmol) was dissolved in methanol (30 mL). After carbon monoxide was replaced three times, the system was heated to 70°C and allowed to react overnight. The reaction system was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to afford compound 2-8f (200 mg, 41.32%) as a yellow oil.

[0914] 1 H NMR(600MHz,DMSO-d6)δ7.42(s,1H),7.24(dd,J=17.5,11.0Hz,1H),7.15(s,1H),5.61(dd,J=17.5,1.4Hz,1H),5.21 (dd,J=11.0,1.3Hz,1H),3.95(s,2H),3.80(s,3H),3.60–3.43(m,2H),3.28(s,2H),2.75(s,2H),1.42–1.32(m,13H).

[0915] LC-MS(ESI):[M-tBu+H]+ =332.40.

[0916] Step 6: Compound 2-8f (200 mg, 0.52 mmol) was dissolved in dichloromethane (10 mL) and ozone was introduced. The system was cooled to -30°C and reacted for 30 minutes. Nitrogen was bubbled through the reaction system for 30 minutes. Dimethyl sulfide (15 mL) was added to the system and the reaction was allowed to proceed at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain Compound 2-8g (200 mg, 41.32%) as a yellow solid.

[0917] LC-MS(ESI):[M-tBu+H] + =334.36.

[0918] Step 7: Dissolve compound 2-8g (20 mg, 0.05 mmol), 3-aminopiperidine-2,6-dione hydrochloride (11 mg, 0.068 mmol), and triethylamine (0.2 mL) in dichloromethane (2 mL). The reaction was allowed to react at room temperature for 30 minutes. Sodium triacetoxyborohydride (9 mg, 0.136 mmol) and acetic acid (0.2 mL) were added. The reaction was allowed to react at room temperature for 3 hours. After concentration under reduced pressure, water (10 mL) was added and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography to afford compound 2-8h (5.0 mg, 21%) as a yellow oil.

[0919] 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),7.29(s,1H),7.04(s,1H),5.08(dd,J= 13.3,5.1Hz,1H),4.34(d,J=16.6Hz,1H),4.20(d,J=16.6Hz,1H),3.97(s,2H) ,3.40–3.54(m,2H),3.26–3.29(m,1H),2.85–2.95(m,1H),2.81(s,2H),2.60 (d,J=17.7Hz,1H),2.31–2.41(m,1H),1.95–2.03(m,2H),1.29–1.42(m,13H).

[0920] LC-MS(ESI):[M+H] + =470.43.

[0921] Step 8: Dissolve compound 2-8h (5 mg, 0.01 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (3 mL). Allow to react at room temperature for 1 hour. Concentrate the reaction mixture, and the resulting crude product is purified by high-pressure preparative liquid chromatography to yield compound 2-8 (3 mg, 76.26%) as a white solid.

[0922] 1 H NMR (600MHz, DMSO-d6) δ7.32(s,1H),7.08(s,1H),5.07–5.00(m,1H),4.34(d,J=16.8Hz,1H),4.21(d,J=16.7Hz,1H),4.04–3.96(m, 2H),3.18–3.06(m,4H),2.92–2.84(m,1H),2.85(s,2H),2.64–2.53(m,1H),2.42–2.31(m,1H),2.02–1.95(m,1H),1.66–1.52(m,4H).

[0923] LC-MS(ESI):[M+H] + =370.42.

[0924] 35)

[0925] first step:

[0926] Compound 2-6a (5.0 g, 25.11 mmol) was dissolved in methanol (50 mL). Palladium on carbon (4.0 g) was added to the reaction system. After hydrogen exchange three times, the reaction was allowed to proceed at room temperature for 12 hours. The reaction system was filtered, and the filter cake was washed three times with methanol (15 mL). The filtrate was concentrated under reduced pressure to obtain the crude product 2-6b (4.23 g, 99.59%). This crude product was directly used in the next step without further purification.

[0927] 1 H NMR (600MHz, DMSO-d6) δ6.58 (dd, J=9.4, 2.7Hz, 1H), 6.54 (dd, J=11.1, 2.7Hz, 1H), 5.37 (s, 2H), 2.14 (s, 3H).

[0928] LC-MS(ESI):[M+H] + =170.25.

[0929] Step 2:

[0930] Compound 2-6b (4.23 g, 25.01 mmol) was dissolved in a mixture of sulfuric acid and water (35 mL), rapidly heated to 90°C, stirred for 10 minutes, and then cooled to below 5°C. Sodium nitrite (1.90 g, 27.51 mmol) was then dissolved in a small amount of water (3 mL) and added. After stirring for 30 minutes, urea (750.90 mg, 12.50 mmol) was added. Finally, ice-cold sulfuric acid and water (5 mL) was added, and the mixture was heated to 90°C for 3 hours. After cooling the reaction system to room temperature, it was concentrated under reduced pressure, followed by addition of aqueous sodium hydroxide solution to adjust the pH to approximately 4-5, and extracted with ethyl acetate (50 mL x 3). The organic phases were washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the crude product 2-6c (3.72 g, 87.43%). This crude product was directly used in the next reaction without further purification.

[0931] 1 H NMR (600MHz, DMSO-d6) δ6.91 (dd, J=9.3, 2.6Hz, 1H), 6.83 (dd, J=10.3, 2.6Hz, 1H), 2.24 (s, 3H).

[0932] LC-MS(ESI):[MH] - =169.05.

[0933] Step 3: 5-fluoro-3-hydroxy-2-methylbenzoic acid methyl ester (Compound 2-6d)

[0934] Compound 2-6c (3.72 g, 21.86 mmol) was dissolved in methanol (16 mL), sulfuric acid (1.6 mL) was added, and the reaction temperature was raised to 60°C for 2 hours. After cooling the reaction system to room temperature, the organic phase was concentrated, and the reaction system was rapidly stirred by adding water. The filter cake was washed with water (50 mL), and the filtrate was concentrated at pH 7 to obtain crude product 2-6d (3.60 g, 89.40%). This crude product was directly used in the next reaction without further purification.

[0935] 1 H NMR (600MHz, Chloroform-d) δ7.75 (dd, J=8.3, 2.8Hz, 1H), 7.61 (dd, J=7.3, 2.8Hz, 1H), 3.95 (s, 3H), 2.59 (s, 3H).

[0936] LC-MS(ESI):[MH] - =183.24.

[0937] Step 4: 2,4-dibromo-3-fluoro-5-hydroxy-6-methylbenzoic acid methyl ester (Compound 2-6e)

[0938] Compound 2-6d (1.13 g, 6.14 mmol) was dissolved in acetonitrile (15 mL), and N-bromosuccinimide (2.40 g, 13.50 mmol) was added dropwise. Trifluoroacetic acid (1.5 mL) was then added dropwise. The temperature was raised to 50°C and the reaction mixture was allowed to react for 2 hours. The reaction mixture was then heated to 50°C and allowed to react for 12 hours. The resulting reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography to afford compound 2-6e (1.20 g, 57.19%) as a pale yellow solid.

[0939] 1 H NMR(600MHz,Chloroform-d)δ5.83(s,1H),3.96(s,3H),2.23(s,3H).

[0940] LC-MS(ESI):[M+H] + =340.88.

[0941] Step 5: tert-Butyl 4-((2,4-dibromo-3-fluoro-5-(methoxycarbonyl)-6-methylphenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 2-6f)

[0942] Dissolve triphenylphosphine (1.86 g, 7.08 mmol) in tetrahydrofuran (15 mL). Cool to 0°C, add diisopropyl azodicarboxylate (1.43 g, 7.08 mmol), and stir for 20 minutes. Then, add tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.13 g, 5.31 mmol). Stir for 30 minutes, then add compound 2-6e (1.21 g, 3.54 mmol). After complete addition, return to room temperature and react for 12 hours. The reaction solution was concentrated under reduced pressure, and water (25 mL) was added. Extraction was performed with ethyl acetate (50 mL x 3), followed by washing with saturated brine (50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by reverse-phase column chromatography to yield compound 2-6f (952 mg, 50.08%) as a white solid.

[0943] 1 H NMR(600MHz,DMSO-d6)δ5.88(s,1H),4.35(s,2H),3.92(s,3H),3.88(s,2H), 3.48(t,J=5.8Hz,2H),2.27–2.24(m,2H),2.20(d,J=1.2Hz,3H),1.41(s,9H).

[0944] LC-MS(ESI):[M-tBu+H] + =482.00.

[0945] Step 6:

[0946] Compound 2-6f (952 mg, 1.77 mmol), tri-n-butyltin hydroxide (1.03 g, 3.54 mmol), and azobisisobutyronitrile (873 mg, 5.32 mmol) were dissolved in toluene (10 mL) and reacted at 110°C under nitrogen for 12 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated brine (10 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield compound 2-6g (416 mg, 61.87%) as a yellow solid.

[0947] LC-MS(ESI):[M-Boc+H] + =280.28.

[0948] Step 7:

[0949] Compound 2-6g (416 mg, 1.10 mmol) was dissolved in carbon tetrachloride (8 mL). N-bromosuccinimide (195 mg, 1.10 mmol) and azobisisobutyronitrile (18 mg, 0.11 mmol) were added to the reaction system. The reaction solution was heated to 85°C and allowed to react at this temperature for 12 hours. The resulting reaction system was concentrated under reduced pressure to obtain a crude product 2-6h (416 mg, 82.79%). This crude product was directly used in the next reaction without further purification.

[0950] Step 8:

[0951] Compound 2-6h (416 mg, 0.91 mmol), 3-amino-2,6-piperidinedione hydrochloride (224 mg, 1.36 mmol), and N,N-diisopropylethylamine (352 mg, 2.72 mmol) were dissolved in acetonitrile (8 mL). The reaction mixture was heated to 85°C and allowed to react for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to afford compound 2-6i (55 mg, 12.80%) as a light blue solid.

[0952] LC-MS(ESI):[M+H] + =474.39.

[0953] Step 9: 3-(4-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Compound 2-6)

[0954] Compound 2-6i (55 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. The resulting filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography to afford compound 2-6 (10 mg, 23.06%) as a white solid.

[0955] 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),7.11(d,J=8.5Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.77–4.72(m,2H),4.38(d,J=17.1Hz,1H),4. 22(d,J=17.0Hz,1H),3.06–2.97(m,2H),2.95–2.87(m,1H),2.63–2.57(m,1H),2.46–2.38(m,1H),2.35–2.28(m,2H),2.03–1.95(m,4H).

[0956] LC-MS(ESI):[M+H] + =374.29.

[0957] 36)

[0958] first step:

[0959] Dissolve compound 2-7a (5.0 g, 32.4 mmol) in sulfuric acid (50 mL) and add N-bromosuccinimide (6.1 g, 34.1 mmol) with stirring at room temperature. Allow to react for 12 hours at room temperature. Quench the resulting reaction system with ice water and extract three times with ethyl acetate. The organic phase is concentrated to afford a crude white solid, compound 2-7b (5.0 g).

[0960] LC-MS(ESI):[MH] - =231.16.

[0961] Step 2: Methyl 3-bromo-6-fluoro-2-methylbenzoate (Compound 2-7c)

[0962] Compound 2-7b (5.0 g, 21.5 mmol) was dissolved in acetonitrile (50 mL). Cesium carbonate (10.5 g, 32.2 mmol) and iodomethane (6.1 g, 42.9 mmol) were added with stirring at room temperature. The reaction was allowed to react at room temperature for 12 hours. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound 2-7c (4.5 g, 85%) as a white solid.

[0963] 1 H NMR (600MHz, DMSO-d6) δ7.80 (dd, J=8.9, 5.4Hz, 1H), 7.21 (t, J=9.0Hz, 1H), 3.91 (s, 3H), 2.33 (s, 3H).

[0964] Step 3:

[0965] Compound 2-7c (2.0 g, 8.1 mmol), pinacol diboron (3.1 g, 12.1 mmol), and potassium acetate (2.4 g, 24.3 mmol) were dissolved in ultra-dry 1,4-dioxane (20 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (118 mg, 0.2 mmol) was added and the mixture was reacted at 90°C under nitrogen for 12 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography to afford compound 2-7d (1.8 g, 76%) as a white solid.

[0966] 1 H NMR (600MHz, DMSO-d6) δ7.77(dd,J=8.4,6.7Hz,1H),7.16(t,J=9.0Hz,1H),3.88(s,3H),2.45(s,3H),1.30(s,12H).

[0967] LC-MS(ESI):[M+H] + =295.28.

[0968] Step 4: Methyl 6-fluoro-3-hydroxy-2-methylbenzoate (Compound 2-7e)

[0969] Compound 2-7d (1.8 g, 6.1 mmol) was dissolved in acetonitrile:water (20:1) (20 mL). Potassium peroxymonosulfate (3.8 g, 6.1 mmol) was added under ice-cooling. The reaction was stirred at room temperature for 2 hours. The resulting reaction was quenched with ice-cold water and extracted three times with ethyl acetate. The organic phase was concentrated, and the resulting crude product was purified by column chromatography to obtain compound 2-7e (850 mg, 75%) as a white solid.

[0970] 1H NMR (600MHz, DMSO-d6) δ9.69 (s, 1H), 6.95 (t, J = 9.1Hz, 1H), 6.89 (dd, J = 8.9, 4.9Hz, 1H), 3.86 (s, 3H), 2.08 (s, 3H).

[0971] LC-MS(ESI):[MH] - =183.03.

[0972] Step 5: Methyl 4-bromo-6-fluoro-3-hydroxy-2-methylbenzoate (Compound 2-7f)

[0973] Compound 2-7e (500 mg, 2.7 mmol) was dissolved in acetonitrile (5 mL). Trifluoroacetic acid (0.5 mL) was added with stirring at room temperature, followed by N-bromosuccinimide (966 mg, 5.4 mmol). The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography to obtain compound 2-7f (500 mg, 70%) as a colorless oil.

[0974] 1 H NMR (600MHz, DMSO-d6) δ9.40 (s, 1H), 7.47 (d, J = 8.9Hz, 1H), 3.87 (s, 3H), 2.19 (s, 3H).

[0975] LC-MS(ESI):[M+H] - =263.17.

[0976] Step 6:

[0977] Compound 2-7f (300 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). Imidazole (155 mg, 2.28 mmol) and tert-butyldimethylsilyl chloride (258 mg, 1.7 mmol) were added under ice-cooling. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated, and the crude product was purified by column chromatography to obtain compound 2-7g (350 mg, 81%) as a white solid.

[0978] 1 H NMR (600MHz, DMSO-d6) δ7.57 (d, J = 8.8Hz, 1H), 3.88 (s, 3H), 2.20 (s, 3H), 1.01 (s, 9H), 0.26 (s, 6H).

[0979] Step 7:

[0980] Dissolve compound 2-7g (300 mg, 0.8 mmol) in carbon tetrachloride (5 mL), add N-bromosuccinimide (170 mg, 1.0 mmol) and azobisisobutyronitrile (13 mg, 0.08 mmol). Incubate at 85°C under nitrogen for 12 hours. Concentrate the reaction mixture to obtain the crude product, compound 2-7h, as a yellow oil.

[0981] Step 8:

[0982] Compound 2-7h (300 mg, 0.7 mmol) was dissolved in acetonitrile (5 mL), and 3-aminopiperidine-2,6-dione hydrochloride (162 mg, 1.0 mmol) and N,N-diisopropylethylamine (255 mg, 2.0 mmol) were added. The reaction was allowed to proceed at 80°C for 12 hours. The reaction mixture was concentrated, and the resulting crude product was purified by column chromatography to afford compound 2-7i (130 mg, 55%) as a light blue solid.

[0983] 1 H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.36(s,1H),7.59(d,J=8.4Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.41(d,J=17.8Hz,1H), 4.28(d,J=17.8Hz,1H),2.90(ddd,J=17.4,13.6,5.4Hz,1H),2.64–2.57(m,1H),2.35(qd,J=13.3,4.6Hz,1H),2.06–2.00(m,1H).

[0984] LC-MS(ESI):[M+H] + =359.09.

[0985] Step 9:

[0986] Compound 2-7i (100 mg, 0.3 mmol), tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (90 mg, 0.4 mmol), and triphenylphosphine (147 mg, 0.6 mmol) were dissolved in tetrahydrofuran (1 mL). The mixture was stirred at 0°C under nitrogen for 15 minutes. Diethyl azodicarboxylate (98 mg, 0.6 mmol) was slowly added dropwise to the reaction system. The reaction system was allowed to react at room temperature for 15 hours. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound 2-7j (50 mg, 32%) as a white solid.

[0987] LC-MS(ESI):[M-Boc+H] + =454.19.

[0988] Step 10:

[0989] Compound 2-7j (50 mg, 0.09 mmol) was dissolved in toluene (1 mL). Azobisisobutyronitrile (22 mg, 0.1 mmol) and tributyltin hydride (79 mg, 0.3 mmol) were added at room temperature and reacted at 110°C for 15 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography to obtain compound 2-7k (25 mg, 58%) as a white solid.

[0990] LC-MS(ESI):[M+H] + =474.39.

[0991] Step 11:

[0992] Compound 2-7k (20 mg, 0.04 mmol) was dissolved in dichloromethane:trifluoroacetic acid (10:1) (1 mL) and reacted at room temperature for 2 hours. The reaction system was concentrated, and the resulting crude product was purified by reverse-phase column chromatography to afford compound 2-7 (10 mg, 63%) as a white solid.

[0993] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.71(s,1H),7.18(d,J=8.8Hz,1H),5.05(dd,J=13.3,5.1Hz,1H),4.70–4.62(m,2H), 4.40(d,J=17.7Hz,1H),4.23(d,J=17.6Hz,1H),3.11–2.84(m,4H),2.66–2.55(m,1H),2.49–2.34(m,2H),2.05–1.86(m,5H).

[0994] LC-MS(ESI):[M+H] + =374.35.

[0995] The synthesis of Protacs molecules is carried out using the following general formula, wherein n1, n2, n3, and n4 are independently selected from integers at each occurrence, preferably selected from 1, 2, 3, 4, 5, and 6; in the following PROTACS synthesis general formula 1-82, R and R1 are commonly used substituents, which are independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8Cycloalkyl, OC 3-11 Heterocyclic group, CO-C 3-8 Cycloalkyl, CO-C 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 alkyl), N(C 1-8 Alkylene)(C 3-8 Cycloalkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group) (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2、Si(OH)3、Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, COO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 alkyl)2, CONH-C 1-8 Alkyl, CONH-C 3-8 Cycloalkyl, CONH-C 3-11 Heterocyclic group, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2、NHCONH(C 1-8Alkyl), NHCON(C 1-8 alkyl)2、NHCONH2、N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, and NH SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-8 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each independently substituted by one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; preferably, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-8 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently selected from F, Cl, Br, I, C 1-6 substituted by one or more substituents selected from alkyl, methoxy and ethoxy groups;

[0996] In addition: For the convenience of description, the present invention uses the E3 ligase inhibitor in the PROTACS synthesis formula 1-82

[0997] The synthetic formula is described as an example, which can be replaced by any E3 ligase inhibitor provided by the present invention, such as wait.

[0998] Intermediate synthesis formula 1

[0999] PROTACS synthesis formula 1

[1000] PROTACS synthesis formula 2

[1001] PROTACS synthesis formula 3

[1002] PROTACS synthesis formula 4

[1003] PROTACS synthesis formula 5

[1004] PROTACS synthesis formula 6

[1005] PROTACS synthesis general formula 7

[1006] PROTACS synthesis formula 8

[1007] PROTACS synthesis formula 9

[1008] PROTACS synthesis formula 10

[1009] PROTACS synthesis formula 11

[1010] PROTACS synthesis formula 12

[1011] PROTACS synthesis formula 13

[1012] PROTACS synthesis formula 14

[1013] PROTACS synthesis formula 15

[1014] PROTACS synthesis formula 16

[1015] PROTACS synthesis formula 17

[1016] PROTACS synthesis formula 18

[1017] PROTACS synthesis formula 19

[1018] PROTACS synthesis formula 20

[1019] PROTACS synthesis formula 21

[1020] PROTACS synthesis general formula 22

[1021] PROTACS synthesis formula 23

[1022] PROTACS synthesis formula 24

[1023] PROTACS synthesis formula 25

[1024] PROTACS synthesis of general formula 26

[1025] PROTACS synthesis of general formula 27

[1026] PROTACS synthesis formula 28

[1027] PROTACS synthesis formula 29

[1028] PROTACS synthesis formula 30

[1029] PROTACS synthesis formula 31

[1030] PROTACS synthesis formula 32

[1031] PROTACS synthesis formula 33

[1032] PROTACS synthesis formula 34

[1033] PROTACS synthesis formula 35

[1034] PROTACS synthesis formula 36

[1035] PROTACS synthesis general formula 37

[1036] PROTACS synthesis formula 38

[1037] PROTACS synthesis formula 39

[1038] PROTACS synthesis formula 40

[1039] PROTACS synthesis formula 41

[1040] PROTACS synthesis formula 42

[1041] PROTACS synthesis formula 43

[1042] PROTACS synthesis formula 44

[1043] Intermediate synthesis formula 2

[1044] PROTACS synthesis formula 45

[1045] PROTACS synthesis formula 46

[1046] PROTACS synthesis general formula 47

[1047] PROTACS synthesis formula 48

[1048] PROTACS synthesis formula 49

[1049] PROTACS synthesis formula 50

[1050] PROTACS synthesis formula 51

[1051] PROTACS synthesis formula 52

[1052] Intermediate synthesis formula 3

[1053] PROTACS synthesis formula 53

[1054] PROTACS synthesis formula 54

[1055] PROTACS synthesis formula 55

[1056] PROTACS synthesis formula 56

[1057] PROTACS synthesis general formula 57

[1058] PROTACS synthesis formula 58

[1059] Intermediate synthesis formula 4

[1060] PROTACS synthesis formula 59

[1061] PROTACS synthesis formula 60

[1062] PROTACS synthesis formula 61

[1063] PROTACS synthesis formula 62

[1064] PROTACS synthesis formula 63

[1065] PROTACS synthesis formula 64

[1066] Intermediate synthesis formula 5

[1067] PROTACS synthesis formula 65

[1068] PROTACS synthesis formula 66

[1069] PROTACS synthesis formula 67

[1070] PROTACS synthesis formula 68

[1071] PROTACS synthesis formula 69

[1072] PROTACS Synthesis Formula 70

[1073] PROTACS synthesis formula 71

[1074] PROTACS synthesis formula 72

[1075] PROTACS synthesis formula 73

[1076] PROTACS synthesis formula 74

[1077] PROTACS synthesis formula 75

[1078] PROTACS synthesis formula 76

[1079] PROTACS synthesis formula 77

[1080] PROTACS synthesis formula 78

[1081] PROTACS synthesis formula 79

[1082] PROTACS Synthesis Formula 80

[1083] PROTACS synthesis formula 81

[1084] Intermediate synthesis formula 6

[1085] PROTACS synthesis formula 82

[1086] Characterization of Protacs molecules

[1087] Example 427

[1088] first step:

[1089] Intermediate 2-18a (20 g, 92.9 mmol) was dissolved in tetrahydrofuran (100 mL) in a single-necked flask. The temperature was cooled to 0°C, and sodium hydroxide (8.36 g, 209.02 mmol) was slowly added. The temperature was maintained at 0°C and stirred for 1 hour. A solution of 2-chloro-4-fluorobenzonitrile (20 g, 92.9 mmol) in tetrahydrofuran (100 mL) was added to the single-necked flask and stirred at 0°C for 0.5 hours. The mixture was transferred to room temperature and stirred for 3 hours. After the reaction was complete, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (0-25% ethyl acetate) to obtain Intermediate 2-18b (21.92 g) as a white solid.

[1090] 1 H NMR (600MHz, MeOD) δ7.69(d,J=8.8Hz,1H),7.18(d,J=2.4Hz,1H),7.03(dd,J=8.8,2.4Hz,1H),4.43(tt,J=10.2, 4.1Hz,1H),3.42(dq,J=10.9,5.8Hz,1H),2.18–2.10(m,2H),2.07–1.97(m,2H),1.61–1.51(m,2H),1.46(s,9H).

[1091] Step 2:

[1092] Intermediate 2-18b (21.92 g, 62.48 mmol) was added to a single-necked flask containing dioxane (25 mL). A solution of hydrochloric acid in dioxane (25 mL) was added to the reaction flask. After addition, the mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated to yield a crude white solid Intermediate 2-18c (20.05 g).

[1093] 1 H NMR (600MHz, DMSO) δ8.18(s,3H),7.86(d,J=8.7Hz,1H),7.42(dd,J=2.5,0.9Hz,1H),7.14(ddd,J=8.8,2.4,1.0Hz,1H), 4.52(tt,J=9.6,4.2Hz,1H),3.10–3.01(m,1H),2.10(dd,J=12.6,4.4Hz,1H),2.00(d,J=11.8Hz,1H),1.58–1.41(m,1H).

[1094] Step 3:

[1095] To a single-necked flask, intermediate 2-18c (20.05 g, 79.97 mmol), triethylamine (32.37 g, 319.87 mmol), 1-propylphosphonic anhydride (12.2 g, 96 mmol), and dichloromethane (200 mL) were added sequentially and stirred at room temperature for 5 min. 6-Chloropyridazine-3-carboxylic acid (16.48 g, 103.96 mmol) was slowly added to the single-necked flask, and the temperature was raised to 30°C and stirred for 2.5 h. After completion of the reaction, the mixture was concentrated and purified by slurrying (petroleum ether:ethyl acetate = 1:1) to afford intermediate 2-18 (13.45 g) as a brown solid.

[1096] 1 H NMR (600MHz, DMSO) δ9.17(d,J=8.2Hz,1H),8.23(d,J=8.9Hz,1H),8.11(d,J= 8.9Hz,1H),7.87(d,J=8.7Hz,1H),7.41(d,J=2.4Hz,1H),7.15(dd,J=8.8,2.4 Hz,1H),4.54(td,J=10.5,5.1Hz,1H),3.91(dtd,J=11.5,7.7,4.1Hz,1H),2. 13(d,J=12.3Hz,2H),1.90(s,2H),1.71(q,J=13.4Hz,2H),1.57–1.48(m,2H).

[1097] Example 428

[1098] Step 1: Prepare according to the first step of Example 427.

[1099] Step 2: Prepare according to the second step of Example 427.

[1100] Step 3: Prepare according to the third step of Example 427.

[1101] 1 H NMR (600MHz, DMSO-d6) δ9.14(d,J=8.2Hz,1H),8.23(d,J=8.9Hz,1H),8.11(d,J=8.8Hz,1H),7.64–7.59(m,1H),6.73(d,J=8.1H z,2H),4.49(tt,J=10.5,4.2Hz,1H),3.90(s,4H),2.19–2.10(m,2H),1.95–1.88(m,2H),1.67-1.74(m,2H),1.49-1.55(m,2H).

[1102] Example 429

[1103] Step 1: Prepare according to the first step of Example 427 LC-MS: [M+H] + =375.49

[1104] Step 2: Prepare according to the second step of Example 427 LC-MS: [M+H] + =275.37

[1105] 1 H NMR (600MHz, DMSO-d6) δ8.48(d,J=6.0Hz,2H),7.64(d,J=8.6Hz,1H),6.63(d,J=2.2Hz,1H),6.53( dd,J=8.6,2.2Hz,1H),4.31(s,1H),3.90(s,3H),3.07(d,J=5.4Hz,1H),1.32(s,6H),1.11(s,6H).

[1106] Example 430

[1107] first step:

[1108] To a reaction flask, compound (S)-tert-butyl 3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (4 g, 15.72 mmol), 2-chloro-4-fluorobenzonitrile (4.89 g, 31.45 mmol), DIEA (6.1 g, 47.16 mmol), and DMSO (40 mL) were added sequentially. Stirring was carried out at 100°C under a nitrogen atmosphere for 4 h. After completion of the reaction, the temperature was lowered to 0°C, and extraction with water and ethyl acetate was added. The organic phase was concentrated under vacuum to obtain a residue, which was purified by normal phase chromatography (PE:EA = 4:1) to afford intermediate 2-11b (4.3 g, 70.13%) as a yellow solid.

[1109] LC-MS: [Mt-Bu+H] + =334.39

[1110] Step 2: (Intermediate 2-11c) Prepared by referring to the second step of Example 432

[1111] LC-MS: [M+H] + =290.38

[1112] Step 3: (Intermediate 2-11d)

[1113] Compound 2-11c (1 g, 3.45 mmol), tert-butyl 4-fluorobenzoate (1.02 g, 5.18 mmol), K2CO3 (2.4 g, 17.25 mmol), and DMSO (10 mL) were added sequentially to a reaction flask. Stirring was carried out at 100°C for 12 h under a nitrogen atmosphere. After completion of the reaction, the temperature was lowered to 0°C, and extraction with water and ethyl acetate was added. The organic phase was concentrated under vacuum to obtain a crude product, which was purified by normal phase chromatography (PE:EA = 4:1) to afford compound 2-11d (660 mg, 41.04%) as a yellow solid.

[1114] LC-MS: [M+H] + =466.39

[1115] Step 4: (Intermediate 2-11) Prepared by referring to the second step of Example 432

[1116] 1 H NMR(600MHz,DMSO-d6)δ7.74(d,J=8.9Hz,2H),7.58(d,J=8.8Hz,1H),6.98– 6.91(m,2H),6.78(d,J=2.4Hz,1H),6.64(dd,J=8.9,2.4Hz,1H),4.02(m,1H) ,3.44(s,2H),3.31(d,J=10.6Hz,4H),2.22(dd,J=12.8,7.7Hz,1H),1.77–1. 63(m,2H),1.56(dd,J=12.8,6.5Hz,1H),1.46(m,2H),1.19(d,J=6.1Hz,3H).

[1117] LC-MS: [M+H] + =410.30

[1118] Example 431

[1119] Step 1: (Compound 2-47-2)

[1120] To a MeOH (210 mL) solvent containing 4-formyl-N-Cbzpiperidine (21 g, 85 mmol) were added trimethyl orthoformate (27 g, 255 μmol) and hydrochloric acid (0.2 mL) in sequence. The mixture was stirred at 70°C under a nitrogen atmosphere for 2 h. After completion of the reaction, the mixture was concentrated to give compound 47-2 (22 g, 88.31%) as a colorless oil, which was used directly in the next step.

[1121] Step 2: (Compound 2-47-3)

[1122] Pd / C (500 mg, 10%) was added to a MeOH (210 mL) solvent containing compound 2-47-2 (5 g, 17 mmol), and the atmosphere was replaced with hydrogen three times. The mixture was stirred at 40 ° C for 12 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain a white solid compound 2-47-3 (2.5 g, 92.12%), which was used directly in the next step.

[1123] Step 3: (Compound 2-47-4)

[1124] Compound 2-47-3 (3 g, 18.84 mmol), 1,4-dibromobenzene (13.33 g, 56.52 mmol), Pd(OAc)2 (426 mg, 1.884 mmol), BINAP (2.3 g, 3.768 mmol) and Cs2CO3 (18.4 g, 56.52 mmol) were added to a glass bottle in sequence, and solvent Dioxane (30 mL) was added. Under a nitrogen atmosphere, the reaction was stirred at 110 ° C for 3 h. After the reaction was completed, the solution was filtered and the filtrate was purified by normal phase chromatography (PE: EA = 4: 1) to obtain a yellow solid compound 2-47-4 (1.7 g, 28.72%).

[1125] LC-MS: [M+H] + =316.38

[1126] Step 4: (Compound 2-47-5)

[1127] 11c (4.7 g, 16.22 mmol), compound 2-47-4 (6.12 g, 19.46 mmol),

[1128] Pd2(dba)3 (1.5 g, 1.622 mmol), X-phos (1.5 g, 3.244 mmol) and Cs2CO3 (15.8 g, 48.66 mmol) were added to the solvent Dioxane (47 mL) and stirred at 110 ° C under a nitrogen atmosphere for 3 h. After the reaction was completed, the mixture was filtered and the filtrate was purified by normal phase chromatography (PE: EA = 3: 1) to obtain a yellow solid compound 2-47-5 (4 g, 47.15%).

[1129] LC-MS: [M+H] + =523.49

[1130] Step 5: (Intermediate 2-47)

[1131] Compound 2-47-5 (4 g, 7.65 mmol) was added to the reaction flask, and solvent DCM / H2O (40 / 2 mL) was added, and TFA (8 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. After the reaction was completed, it was concentrated and the crude product was purified by normal phase chromatography (DCM:MeOH=20:1) to give a green solid intermediate 2-47 (2 g, 54.83%).

[1132] LC-MS: [M+H] + =477.40

[1133] 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),7.62(d,J=8.8Hz,1H),7.12(s,4H),6.81(d,J=2.3Hz,1H),6.67(dd,J=8.9,2.4Hz,1H),4.05(m, 1H),3.58(s,5H),3.17(s,2H),2.58(s,1H),2.25(s,1H),2.08(s,1H),1.99(s,2H),1.87(s,2H),1.63(s,6H),1.21(d,J=6.0Hz,4H).

[1134] Example 432

[1135] Step 1: Compound 4 (100.0 mg, 281.38 μmol) and tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (76.75 mg, 337.65 μmol) were added to the reaction flask in sequence, and solvent THF (2 mL) and Ti(O-iPr)4 (159.95 mg, 562.76 umol) were added. The mixture was stirred at 60 ° C for 1 h, and then NaBH3CN (53.05 mg, 844.13 umol) was added. The reaction was continued by stirring at 60 ° C for 1 h. After the reaction was completed, the mixture was concentrated and then purified by preparative thin layer plate chromatography (DCM: MeOH = 10: 1) to obtain a white solid compound 2-261-2 (50 mg, 31.36%).

[1136] LC-MS: [M+H] + =567.58

[1137] Step 2:

[1138] 2-261-2 (40.0 mg, 70.58 μmol) was added to the reaction flask, and solvent DCM (1 mL) was added, followed by TFA (1 mL). The reaction was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated and then purified by reverse phase column (MeCN in Water = 30%) to obtain a white solid compound 2-261-3 (30 mg, 91.09%).

[1139] LC-MS: [M+H] + =467.49

[1140] Step 3: 2-261-3 (20.0 mg, 42.86 μmol) and intermediate 10 (19.90 mg, 51.44 μmol) were added to the reaction flask in sequence, and solvent DMSO (1 mL) and DIEA (16.62 mg, 128.59 umol) were added. The mixture was stirred at 80°C for 2 h. After the reaction was completed, the mixture was concentrated and then purified by high performance liquid chromatography to obtain a white solid compound 2-261 (4 mg, 11.42%).

[1141] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),8.60(d,J=8.2Hz,1H),7.85(d,J=9.5Hz,1H ),7.62(d,J=8.8Hz,1H),7.39(d,J=9.6Hz,1H),7.33(d,J=7.5Hz,1H),7.12(d,J=3 .3Hz,1H),6.73(d,J=7.7Hz,2H),5.05(dd,J=13.3,5.1Hz,1H),4.67(d,J=6.7Hz,2 H),4.50(tt,J=9.8,4.3Hz,1H),4.41(d,J=17.3Hz,1H),4.27(d,J=17.3Hz,1H),4. 19–4.06(m,2H),3.89(s,3H),3.87–3.83(m,1H),3.59(s,2H),3.34(s,2H),3.27( d,J=11.5Hz,2H),3.17(s,1H),2.91(ddd,J=18.1,13.5,5.5Hz,1H),2.63–2.57(m, 1H),2.36(qd,J=13.2,4.5Hz,3H),2.26(s,1H),2.15–2.12(m,2H),1.98–1.88(m,5 H),1.64(qd,J=13.1,12.1,5.8Hz,6H),1.56–1.48(m,2H),1.28(d,J=12.2Hz,3H).

[1142] LC-MS: [M+H] + =817.66

[1143] Example 433

[1144] Step 1: (Compound 2-262) was prepared according to the third step of Example 432

[1145] 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),8.60(d,J=8.2Hz,1H),7.86(dd,J=9.1,5 .2Hz,2H),7.43–7.36(m,2H),7.33(d,J=7.5Hz,1H),7.13(ddd,J=16.7,8.3,2.7 Hz,2H),5.06(dd,J=13.3,5.0Hz,1H),4.67(d,J=8.0Hz,2H),4.55–4.53(m,1H), 4.41(d,J=17.3Hz,1H),4.26(s,1H),4.12(dt,J=13.9,4.7Hz,2H),3.87(dq,J=1 1.3,3.6Hz,1H),3.59(d,J=12.1Hz,2H),3.47(ddd,J=13.7,9.6,3.9Hz,2H),3. 44–3.20(m,4H),3.17(d,J=4.0Hz,2H),2.95–2.88(m,1H),2.63–2.57(m,1H),2. 35(td,J=13.3,4.4Hz,3H),2.31–2.18(m,1H),2.16–2.08(m,2H),1.97(qd,J=6. 2,5.7,2.9Hz,1H),1.90(t,J=7.1Hz,4H),1.72–1.57(m,6H),1.56–1.48(m,2H).

[1146] LC-MS: [M+H] + =821.56

[1147] Example 434

[1148] Step 1: (Compound 2-263-2)

[1149] Prepared according to the first step of Example 432

[1150] LC-MS: [M+H] + =583.48

[1151] Step 2: (Compound 2-263-3)

[1152] Prepared with reference to the second step of Example 432

[1153] LC-MS: [M+H] + =483.39

[1154] Step 3: (Compound 2-263)

[1155] Prepared with reference to the third step of Example 432

[1156] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),8.63(d,J=8.1Hz,1H),7.86(dd,J=7.3,4.4Hz,2H),7.44(d,J=9.3Hz,1H),7.39(d,J=2.7Hz,1H),7.31(dd,J =7.6,2.5Hz,1H),7.13(ddd,J=15.0,8.4,2.6Hz,2H),5.06(dd,J=13.3,5.1Hz,1H),4.68(s,2H),4.54(dd,J=9.8,5.3Hz,1H),4.41(d,J=17.3Hz,1H ),4.29(s,1H),4.26(s,2H),3.87(d,J=6.7Hz,1H),3.63(s,2H),3.33(d, J=11.6Hz,2H),3.30(s,3H),2.92(td,J=13.0,6.8Hz,1H),2.63–2.57(m, 1H),2.45–2.28(m,4H),2.14–2.09(m,2H),2.05–1.93(m,4H),1.90(d,J= 12.5Hz, 4H), 1.65 (q, J=12.2, 11.3Hz, 5H), 1.52 (dt, J=15.6, 10.8Hz, 3H).

[1157] LC-MS: [M+H] + =837.66

[1158] Example 435

[1159] Step 3: (Compound 2-264)

[1160] Prepared with reference to the third step of Example 432

[1161] 1H NMR (600MHz, DMSO-d6) δ10.98(s,1H),8.62(d,J=8.2Hz,1H),7.87(d,J=9.4 Hz,1H),7.62(d,J=8.6Hz,1H),7.44(d,J=9.6Hz,1H),7.31(d,J=7.4Hz,1H), 7.12(d,J=7.6Hz,1H),6.73(d,J=7.3Hz,2H),5.06(dd,J=13.3,5.1Hz,1H),4 .68(s,2H),4.49(dq,J=9.8,5.0,4.2Hz,1H),4.41(d,J=17.3Hz,1H),4.27(d d,J=17.1,7.5Hz,3H),3.90(s,3H),3.88–3.86(m,1H),3.65–3.62(m,2H),3 .40–3.36(m,2H),3.32(d,J=22.0Hz,6H),2.91(ddd,J=18.0,13.5,5.5Hz,1H ),2.63–2.57(m,1H),2.55(s,1H),2.43–2.26(m,3H),2.17–2.08(m,2H),2.0 8–1.81(m,7H),1.65(td,J=14.1,7.0Hz,4H),1.52(dt,J=13.9,10.1Hz,2H).

[1162] LC-MS: [M+H] + =833.66

[1163] Example 436

[1164] Step 1: (Compound 2-292-2)

[1165] Prepared according to the first step of Example 432.

[1166] LC-MS: [M+H] + =643.58

[1167] Step 2: (Compound 2-292-3)

[1168] Prepare with reference to the second step of Example 432.

[1169] LC-MS: [M+H] + =587.48

[1170] Step 3: (Compound 2-292)

[1171] Prepare with reference to the third step of Example 427.

[1172] 1 H NMR (600MHz, DMSO) δ10.97(s,1H),7.78(d,J=8.7Hz,2H),7.66(d,J=8.6Hz,1H),7.52(d,J=9.2Hz,1H),7.33(d,J=7.5Hz,1H),7.12(d,J=7.7Hz,1H), 7.01(d,J=8.8Hz,2H),6.65(d,J=1.9Hz,1H),6.55(dd,J=8.6,2.0Hz,1H), 5.06(dd,J=13.3,4.9Hz,1H),4.68(d,J=7.0Hz,2H),4.41(d,J=17.4Hz,1H) ,4.27(d,J=15.7Hz,2H),4.06(d,J=9.2Hz,1H),3.92(s,3H),3.57(d,J=13 .0Hz,4H),3.32(dd,J=51.3,10.8Hz,3H),3.20–3.12(m,4H),2.91(ddd,J= 22.6,12.1,5.3Hz,1H),2.60(d,J=17.0Hz,1H),2.43–2.32(m,3H),2.00–1 .86(m,3H),1.66(dd,J=41.4,11.3Hz,4H),1.28–1.20(m,8H),1.16(s,6H).

[1173] LC-MS: [M+H] + =843.76

[1174] Example 437

[1175] Step 1: (Compound 2-293-2)

[1176] Prepared according to the first step of Example 432.

[1177] LC-MS: [M+H] + =659.57

[1178] Step 2: (Compound 2-293-3)

[1179] Prepare with reference to the second step of Example 432.

[1180] LC-MS: [M+H] + =603.40

[1181] Step 3: (Compound 2-293)

[1182] Prepare with reference to the third step of Example 427.

[1183] 1 H NMR (600MHz, DMSO) δ10.97(s,1H),7.79(d,J=8.7Hz,2H),7.66(d,J=8.6Hz,1H),7.53(d,J=9.2Hz,1H),7.32(d,J=7.5Hz,1H),7.12(d,J=7.6Hz, 1H),7.02(d,J=8.9Hz,2H),6.65(d,J=2.1Hz,1H),6.55(dd,J=8.7,2.1Hz,1H),5.06(dd,J=13.3,5.1Hz,1H),4.69(s,2H),4.41(d,J=17.5Hz,1H ),4.27(d,J=16.8Hz,2H),4.07(d,J=9.2Hz,1H),3.92(s,3H),3.73–3.65(m,4H),3.38(s,2H),3.29(d,J=16.2Hz,5H),3.09(t,J=11.3Hz,2H),2 .91(ddd,J=22.6,12.5,5.3Hz,1H),2.63–2.57(m,1H),2.40–2.31(m,3H ),2.02–1.86(m,5H),1.70(t,J=10.4Hz,2H),1.23(s,6H),1.16(s,6H).

[1184] LC-MS: [M+H] + =859.66

[1185] Example 438

[1186] Step 1: (Compound 313-2)

[1187] Compound 4 (50.0 mg, 140.69 μmol) and tert-butyl 4-formylpiperidine-1-carboxylate (59.44 mg, 281.38 μmol) were added to the reaction flask in sequence, and solvent THF (1.6 mL) was added. The reaction was stirred at room temperature for 1 h, and then NaBH3CN (89.45 mg, 422.07 μmol) was added. The reaction was continued to stir at room temperature for 1 h. After the reaction was completed, the mixture was concentrated and then purified by preparative thin layer plate chromatography (DCM:MeOH=10:1) to obtain a white solid compound 2-313-2 (70 mg, 45.01%).

[1188] LC-MS: [M+H] + =553.49

[1189] Step 2: (Compound 2-313-3)

[1190] Prepared with reference to the second step of Example 432

[1191] LC-MS: [M+H] + =453.40

[1192] Step 3: (Compound 2-313)

[1193] Prepared with reference to the third step of Example 432

[1194] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),8.58(d,J=8.1Hz,1H),7.85(t,J=9.2Hz,2H),7.43–7.36(m,2H),7.33(d,J=7.5Hz,1H),7.15–7.08(m,2H), 5.05(dd,J=13.3,5.1Hz,1H),4.67(s,2H),4.60–4.48(m,J=11.9,11.2, 5.6Hz,3H),4.41(d,J=17.3Hz,1H),4.27(d,J=17.4Hz,1H),3.93–3.80(m ,J=11.8,8.3,4.0Hz,2H),3.15–3.01(m,6H),2.96–2.85(m,J=17.9,13. 5,5.4Hz,1H),2.63–2.55(m,1H),2.41–2.30(m,1H),2.20(d,J=15.0Hz,3 H),2.14–2.07(m,2H),2.00–1.83(m,8H),1.69–1.59(m,J=13.2,3.2Hz,2 H),1.57–1.46(m,J=12.9,9.3Hz,2H),1.33–1.20(m,J=13.6,4.7Hz,2H).

[1195] LC-MS: [M+H] + =807.55

[1196] Example 439

[1197] Step 3: (Compound 2-314)

[1198] Prepared with reference to the third step of Example 432

[1199] 1H NMR (600MHz, DMSO-d6) δ10.91(s,1H),8.52(d,J=8.1Hz,1H),7.79(d,J=9.5Hz,1H),7.58–7.54(m,1H),7.35(d,J=9.6Hz,1H),7.28(d,J=7.5Hz,1H) ,7.06(d,J=7.6Hz,1H),6.67(d,J=7.3Hz,2H),5.00(dd,J=13.3,5.1Hz,1H ),4.62(s,2H),4.50–4.41(m,3H),4.36(d,J=17.4Hz,1H),4.22(d,J=17.3 Hz,1H),3.84(s,3H),3.82–3.78(m,1H),3.09–2.98(m,J=14.7,10.2,5.6H z,6H),2.90–2.80(m,J=17.3,13.6,5.5Hz,1H),2.54(d,J=14.1Hz,1H),2. 36–2.26(m,1H),2.22–2.03(m,5H),1.97–1.76(m,8H),1.65–1.53(m,J=13 .2,3.2Hz,2H),1.52–1.40(m,2H),1.28–1.14(m,J=13.5,5.4,4.4Hz,3H).

[1200] LC-MS: [M+H] + =803.56

[1201] Example 440

[1202] Step 1: (Compound 2-315-2)

[1203] Compound 4 (50.0 mg, 140.69 μmol) and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (59.44 mg, 281.38 μmol) were added to the reaction flask in sequence, and solvent THF (1.6 mL) was added. The reaction was stirred at room temperatu...

Claims

1. A compound having the following chemical structure: CLM-L-PTM, or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates, in: PTM is the binding part that targets the estrogen receptor protein and has the following structure: R L0 is selected from a single bond, -O-, alkylene, and -C(=O)-; preferably, R L0 Selected from single bond, -O-, C 1-3 Alkylene, and -C(=O)-; R v Selected from R is Each time Q appears, it is independently selected from CR x and N; Q 1 Each occurrence is O, S or NR x ; R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x and R P7 each occurrence is independently selected from H, carboxyl, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; Preferably, R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , and R P7 Each occurrence is independently selected from H, carboxyl, a deuterium atom, a halogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 alkoxyl, a C1-C6 haloalkyl, a C1-C6 haloalkoxyl, a hydroxyl, a C1-C6 hydroxyalkyl, a nitro, a cyano, an amino, a C1-C6 alkylamino, a C1-C6 alkylacyl, a C1-C6 alkyloxyacyl, a C1-C6 alkylaminoacyl, a C3-C8 cycloalkyl, a 4-10 membered heterocyclyl, a C5-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 heteroaryl, and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 The heteroaryl and 5-10 membered heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C5-C 10 Heterocyclic group, 4-10 membered heterocyclic group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkylamino group, C1-C6 alkylacyl group, C1-C6 alkyloxyacyl group, C1-C6 alkylaminoacyl group, C6-C 10 Aryl, C5-C 10 is substituted by one or more substituents in heteroaryl and 5-10 membered heteroaryl; preferably R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , and R P7 Each occurrence is independently selected from H, carboxyl, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 heteroaryl, and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 The heteroaryl and 5-10 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C5-C 10 Heterocyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl, C5-C 10 is substituted by one or more substituents in heteroaryl and 5-10 membered heteroaryl; preferably R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , and R P7 Each occurrence is independently selected from H, carboxyl, hydroxyl, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; m13 is 0, 1, 2, 3, 4, or 5; m14 is 0, 1, 2, 3, 4, or 5; m15 is 0, 1, 2, 3, 4 or 5; m16 is 0, 1, 2, 3, 4, or 5; The PTM is preferably: L is a bond or chemical linking moiety that covalently links the CLM and the PTM, and The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures: in: W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O); G and Z are the same or different and are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , and R 3d are each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R d , R e , R f , R g , R D , R E , R F , and R G Each occurrence is independently C(R m )2. NR m , C(=O), O or S; W 3 and W 4 Each time it appears, it is independently CR m or N; R t and R T Each occurrence is N or CR independently 2h , and when R D , R E , R F , and R G Both are C(R m )2, R T CR 2h ; m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6; m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8; m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+m6≤7; m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+m8≤7; R m each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; R 2h Selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl and alkynyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; R 2 , R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and n is 0, 1, 2 or 3; Preferably, the compound is not:

2. A compound having the following chemical structure: CLM-L-PTM, or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates, in: PTM is the binding part that targets the estrogen receptor protein and has the following structure: R L0 is selected from a single bond, -O-, alkylene, and -C(=O)-; preferably, R L0 Selected from single bond, -O-, C 1-3 Alkylene, and -C(=O)-; R v Selected from R is Each time Q appears, it is independently selected from CR x and N; Q 1 O, S or NR x ; R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , and R x each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; m13 is 0, 1, 2, 3, 4, or 5; m14 is 0, 1, 2, 3, 4, or 5; m15 is 0, 1, 2, 3, 4 or 5; m16 is 0, 1, 2, 3, 4, or 5; The PTM is preferably: L is a bond or chemical linking moiety that covalently links the CLM and the PTM, and The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures: in: W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of C(=O); G and Z are the same or different and are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, an aryl group, and the heteroaryl group are each independently selected from halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, R d , R e , R f , R g , R D , R E , R F , and R G Each occurrence is independently C(R m )2. NR m , C(=O), O or S; W 3 and W 4 Each time it appears, it is independently CR m or N; R t and R T Each occurrence is N or CR independently 2h , and when R D , R E , R F , and R G Both are C(R m )2, R T CR 2h ; m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6; m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8; m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+m6≤7; m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+m8≤7; R m each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; R 2h Selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl and alkynyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; R 2 , R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and n is 0, 1, 2 or 3.

3. A compound having the following chemical structure: CLM-L-PTM, or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates, in: PTM is a binding moiety that targets the estrogen receptor protein and is selected from the following structures: L is a bond or chemical linking moiety that covalently links the CLM and the PTM, and The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures: in: Each time Q appears, it is independently selected from CR x and N; Q 1 O, S or NH; R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , and R x each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; m13 is 0, 1, 2, 3, 4, or 5; m14 is 0, 1, 2, 3, 4, or 5; m15 is 0, 1, 2, 3, 4 or 5; W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O); G and Z are the same or different and are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , and R 3d are each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R d , R e , R f , R g , R D , R E , R F , and R G Each occurrence is independently C(R m )2. NR m , C(=O), O or S; W 3 and W 4 Each time it appears, it is independently CR m or N; R t and R T Each occurrence is N or CR independently 2h , and when R D , R E , R F , and R G Both are C(R m )2, R T CR 2h ; m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6; m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8; m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+m6≤7; m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+m8≤7; R m each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; R 2h Selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl and alkynyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; R 2 , R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and n is 0, 1, 2 or 3.

4. The compound according to any one of claims 1 to 3, wherein: W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , R 3a , R 3b , R 3c , and R 3d Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 miscellaneous The aryl group is substituted by one or more substituents; preferably R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , R 3a , R 3b , R 3c , and R 3d Each independently selected from H, hydroxyl, deuterium atom, halogen, C1-C3 alkyl, and C1-C3 alkoxy; preferably R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , R 3a , R 3b , R 3c , and R 3d Each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; preferably R P1 , R P2 , R P3 , R P4 , R P5 , R P6 , R x , R 3a , R 3b , R 3c , and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R d , R e , R f and R g Each occurrence is independently C(R m )2 or 0; and / or R D , R E , R F and R G Each occurrence is independently C(R m )2 or 0; and / or W 3 and W 4 is CH; and / or R 2h is selected from the group consisting of H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R 2h is selected from H, deuterium atoms, halogens, C1-C3 alkyl groups, and C1-C3 alkoxy groups; preferably R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group; and / or m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3, preferably m1+m2=1 or m1+m2=2; and / or m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4 when they appear each time, and m7+m8≤4, preferably m7+m8=2, or m7+m8=3; and / or; R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 1 is selected from H, halogen, C1-C3 alkyl, and hydroxyl; R 1 Preferably selected from H, F, Cl, Br, I, C1-C3 alkyl and hydroxyl; and / or R 2 Selected from H, and C1-C3 alkyl; and / or n is 0 or 1.

5. The compound according to any one of claims 1 to 4, wherein the CLM is selected from the following structures: W 1 , W 2 , W 3 , W 4 , R 3a , R 3b , R 3c , R 3d , R d , R e , R f , R t , R g , R D , R E , R F , R T , R G , m3, m4, m5 and m6 are as defined in claim 1, 2, 3 or 4; preferably, R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; m1, m9 and m10 are each independently an integer of 0, 1, 2, 3, 4, or 5 when they appear, and m1+m9+m10≤5; preferably m1, m9 and m10 are each independently an integer of 0, 1, or 2 when they appear, and m1+m9+m10≤2, preferably m1+m9+m10=1 or m1+m9+m10=0; and m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1.

6. The compound according to any one of claims 1 to 5, wherein the CLM is selected from the following structures: in: W1, W2, R 3a , R 3b , R 3c , R 3d , R d , R e , R f , R t , R g , R D , R E , R F , R T , R G , m3, m4, m5 and m6 as defined in claim 1, 23, or 4; Preferably: R 3a , R 3b , R 3c , R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and / or m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or R d , R e , R f , R g , R D , R E , R F , and R G Each occurrence is independently C(R m )2 or O, R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and / or R t , and R T Each occurrence is N or CR independently 2h , R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents.

7. The compound according to any one of claims 1 to 6, wherein the CLM is selected from the following structures: in: W 1 , W 2 , W 3 , W 4 , R 3a , R 3b , R 3c , R 3d , R f , R t , R g , R F , R G , m1, m2, m3, m4, m5, m6, m7, and m8 are as defined in claim 1, 2, 3, or 4, preferably, R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; R 1d , R 1e , R 1D and R 1E Each occurrence is independently C(R m )2; R T N, or CR 2h , when R F and R G Both are C(R m )2, R T CR 2h ;and R 2h , and R m As defined in claim 1, 2, 3 or 4.

8. The compound according to any one of claims 1 to 7, wherein the CLM is selected from the following structures: in, W 1 , W 2 , R 3a , R 3b , R 3c , R 3d , R f , R t , R g , R F , R G , m3, m4, m5, and m6 are as defined in claim 1, 2, 3 or 4; R 1d , R 1e , R 1D , R 1E Each occurrence is independently C(R m )2; R T N or CR 2h And when R F and R G Both are C(R m )2, R T CR 2h ; and, R 2h and R m As defined in claim 1, 2, 3 or 4; Preferably: R 3a , R 3b , R 3c , R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and / or m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or R 1d , R 1e , R 1D , R 1E , R f , R g , R F , and R G Each occurrence is independently C(R m )2,R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and / or R t Each occurrence is N or CR independently 2h , R T Each time it appears, it is independently CR 2h , R 1h , R 2h , and R 3h Each is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents.

9. The compound according to any one of claims 1 to 8, wherein the CLM is selected from the following structures:

10. The compound according to any one of claims 1 to 9, wherein L is Key or -(B L ) q -: B L Each occurrence is the same or different and is independently selected from: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 ,CO,CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene, and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 Preferably, B L Each occurrence is independently selected from: CR L1 R L2 、O、S、SO、SO2、NR L3 , CO, C≡C, 3-16-membered cycloalkylene, 3-16-membered heterocyclylene, 6-10-membered arylene, or 5-10-membered heteroarylene, wherein the 3-16-membered cycloalkylene, 3-16-membered heterocyclylene, 6-10-membered arylene, or 5-10-membered heteroarylene is optionally substituted by 0, 1, 2, 3 or 4 R L1 and / or R L2 group substitution; R L1 , R L2 , R L3 , and R L4 Each occurrence is independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclic group, CO-C 3-8 Cycloalkyl, CO-C 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), N(C 1-8 Alkylene)(C 3-8 Cycloalkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, COO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CONH-C 3-8 Cycloalkyl, CONH-C 3-11 Heterocyclic group, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 Alkyl), N(C 1-8 alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 Alkyl), N(C 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, and NH SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-8 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; preferably, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-8 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently selected from F, Cl, Br, I, C 1-6 Substituted by one or more substituents selected from alkyl, methoxy and ethoxy groups; and q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; Preferably: B L Each occurrence is the same or different and is independently selected from: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 ,CO,CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene, and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 group substitution; R L1 , R L2 , R L3 , and R L4 Each occurrence is independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group (C 1-8 Alkyl), NH- Aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 Alkyl), N(C 1-8 alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 Alkyl), N(C 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, and NH SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 The heteroaryl groups are each independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; and q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

11. The compound of claim 10, wherein B L One or more selected from the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3) 2 -、-N(CH3)-、-N(CH2CH3)-、 For the connection point.

12. The compound of any one of claims 1 to 11, wherein L is selected from the following structures: Covalent bond, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -CO-(CH2) s -, -(CH2) p -O-(CH2) s -, -(CH2) y -CO-(CH2) j -CO-(CH2) s -, -(CH2) y -O-(CH2) j -O-(CH2) s -, -(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -, in, j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 at each occurrence; k, s, p and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; It is the connection point of CLM or PTM; L is preferably selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -CO-NH-CH2-, -CO-NH-(CH2)2-, -CO-NH-(CH2)3-, -CO-NH-(CH2)4-, -CO-NH-(CH2)5-, -CO-NH-(CH2)6-, -CO-NH-(CH2)7-, -CO-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -CO-NH-(CH2-CH2-O)-CH2-CH2-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-NH--CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH 2)3-、-CO-NH-CH2-CH2-(O-CH2-CH2)-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)3-、-CH2-CH2-(O-CH2-CH2)-NH-、-CH2-CH2-(O-CH2-CH2)2-NH-、-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-(O-CH2-CH2)-NH-、-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-NH-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-O-CH2-CH2-CO-、 -CO-CH2-CH2-O-CH2-CH2-NH-、-NH-(CH2)4-CO-、-NH-(CH2)5-CO-、-NH-(CH2)6-CO-、-CO-(CH2)4-NH-、-CO-(CH2)5-NH-、-CO-(CH2)6-NH-、-NH-(CH2-CH2-O)-(CH2)3-、 -NH-(CH2-CH2-O)-(CH2)4-、-NH-(CH2-CH2-O)-(CH2)5-、-NH-(CH2-CH2-O)-(CH2)6-、-(CH2)3-(O-CH2-CH2)-NH-、-(CH2)4-(O-CH2-CH2)-NH-、-(CH2)5-(O-CH2-CH2)-NH-、-(CH2)6-(O-CH2-CH2)-NH-、-CH2-CH2-O-(CH2)2-CO-、-CH2-CH2-O-(CH2)3-CO-、-CH2-CH2-O-(CH2)4-CO-、-CO-(CH2)2-O -CH2-CH2-、-CO-(CH2)3-O-CH2-CH2-、-CO-(CH2)4-O-CH2-CH2-、-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、-CO-(CH2)5-、-CO-(CH2)6-、-(CH2)2-CO-、-(CH2)3-CO-、-(CH2)4-CO-、-(CH2)5-CO-、-(CH2)6-CO-、-CO-(CH2)2-CO-、-CO-(CH2)3-CO-、-CO-(CH2)4-CO-、-CO-(CH2)5-CO-、-CO-(CH2)6-C O-、-CH2-CO-CH2-、-CH2-CO-(CH2)2-、-CH2-CO-(CH2)3-、-CH2-CO-(CH2)4-、-(CH2)2-CO-CH2-、-(CH2)2-CO-(CH2)2-、-(CH2)2-CO-(CH2)3-、-(CH2)2-CO-(CH2)4-、-(CH2)3-CO-CH2-、-(CH2)3-CO-CH2-、- (CH2)4-CO-(CH2)3-、-(CH2)4-CO-(CH2)4-、-CH2-O-CH2-、-CH2-O-(CH2)2-、-CH2-O-(CH2)3-、-CH2-O-(CH2)4-、-(CH2)2-O-CH2-、-(CH2)2-O-(CH2 )2-、-(CH2)2-O-(CH2)3-、-(CH2)2-O-(CH2)4-、-(CH2)3-O-CH2-、-(CH2)3-O-(CH2)2-、-(CH2)3-O-(CH2)3-、-(CH2)3-O-(CH2)4-、-(CH2)4-O-CH2-、-(CH2)4-O-(CH2)2-、-(CH2)4-O-(CH2)3-、-(CH2)4-O-(CH2)4-、 13. The compound according to any one of claims 1 to 12, wherein The PTM is selected from the following structures: R is selected from 14. A compound according to any one of claims 1 to 13, selected from the following compounds: R is selected from 15. A compound according to any one of claims 1 to 13, selected from the following compounds:

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15.

17. Use of the compound according to any one of claims 1 to 15, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for treating or preventing a disease that is treated by degrading estrogen receptor protein.

18. Use of a compound according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for treating or preventing a disease that is treated by binding to cerebellar protein in vivo.

19. Use of the compound according to any one of claims 1 to 15, or the pharmaceutical composition according to claim 16, in treating or preventing a disease associated with accumulation and / or aggregation of a target protein, wherein the target protein is an estrogen receptor.

20. The use according to any one of claims 17 to 19, wherein the disease is a tumor or cancer, preferably the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

21. A compound as claimed in any one of claims 1 to 15, or a pharmaceutical composition as claimed in claim 16, for use in the treatment or prevention of a condition to be treated by degradation of estrogen receptor protein.

22. A compound as claimed in any one of claims 1 to 145, or a pharmaceutical composition as claimed in claim 16, for use in the treatment or prevention of a condition which is treated by binding to cerebellin in vivo.

23. The compound of any one of claims 1 to 15, or the pharmaceutical composition of claim 14, for use in treating or preventing a disorder associated with accumulation and / or aggregation of a target protein, wherein the target protein is an estrogen receptor.

24. A compound for use according to any one of claims 21 to 23, or a pharmaceutical composition thereof, wherein the disease is a tumor or cancer, preferably the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

25. A method for treating or preventing a disease that is treated by degrading estrogen receptor protein, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16, to a subject in need thereof.

26. A method for treating or preventing a condition that is treated by binding to cerebellin in vivo, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16.

27. A method for treating or preventing a disorder associated with accumulation and / or aggregation of a target protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16, wherein the target protein is an estrogen receptor.

28. The method of any one of claims 25 to 27, wherein the disease is a tumor or cancer, preferably the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

29. A compound or its isomer, isotopic derivative, polymorph, prodrug, or pharmaceutically acceptable salt or solvate, wherein the compound is selected from any of the following structures:

30. A compound having the following chemical structure: CLM a ―L a ―PTM a , or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates, in: PTM a is a target protein binding portion; preferably, the target protein is B7.1 and B7, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDEIV phosphodiesterase type 4, PDEI I, PDEI II, PDE III, squalene epoxidase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (ie, Gq), histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and its analogs, HIV1 protease, HIV1 integrase, influenza neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug-resistant bacteria, protein P-glycoprotein, tyrosine kinase, CD23, CD124, tyrosinase p561ck, CD4, CD5, 1L-2 receptor, 1L-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, inosine monophosphate dehydrogenase, p38MAP kinase, Ras1Raf1MEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus, 3C protease, herpes simplex virus-I (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase 4 / 6, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y 1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor of NGF, beta-amyloid, tyrosine kinase Flk-II KDR, vitronectin receptor, integrin receptor, Her-21 nerve sheath, telomerase inhibition, cytosolic phospholipase A2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel, acetyl-CoA carboxylase, adenylate succinate synthetase, protoporphyrinogen oxidase, enolpyruvylshikimate phosphate synthetase, MYC protein, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, or bromodomain protein 4; L a is covalently linked to CLM a and the PTM a a bond or chemical linking moiety, and The CLM a is a cerebellin E3 ubiquitin ligase binding moiety selected from any of the following structures:

31. The compound of claim 30, in: PTM a To target the androgen receptor protein binding portion, L a With structure-(B La ) q1 -, B La Each occurrence is the same or different and each occurrence is independently selected from: a covalent bond, a CR La R Lb , O, S, SO, SO2, CO, C(=NCN), C(=CNO2), C2-C6 alkenylene, C2-C6 alkynylene, optionally with 0-6 R La and / or R Lb C3-C 11 Cycloalkylene, optionally substituted by 0-6 R La and / or R Lb A 3-11 membered heterocyclyl group substituted with 0-6 R La and / or R Lb The arylene group substituted by a group, optionally substituted by 0-6 R La and / or R Lb A heteroarylene group substituted with 0-6 R La and / or R Lb C6-C 16 spirocyclylene, and optionally 0-6 R La and / or R Lb a 6-16 membered spirocyclic group substituted with a radical; R La , and R Lb each independently represents H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, OH, CN, and NO2; and q1 is an integer greater than or equal to 1.

32. The compound of claim 30 or 31, in: B La Each occurrence is the same or different and is independently selected from: a covalent bond, a CR La R Lb , optionally 0-6 R La and / or R Lb C3-C 11 Cycloalkylene, optionally substituted by 0-6 R La and / or R Lb a 3- to 11-membered heterocyclylene group substituted with a radical; R La , and R Lb Each occurrence is independently selected from H, F, Cl, Br, I, C 1-8 Alkyl, C1-8 alkoxy, -OH, -NH2, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2; and / or q1 is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; preferably 1, 2, 3, 4, or 5; Preferably, B La One or more selected from the following structures: covalent bond, -(CH2) k1 -、 k1 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

33. A compound as described in any one of claims 30-32, wherein L a Select from the following structures: Covalent bond, -(CH2) j1 -、 in, j1 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p1 and y1 are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, L a Selected from 34. The compound of any one of claims 20-33, wherein PTM a Select from the following structures: Among them, F6, F 16 and F 21 Each occurrence is independently selected from a single bond, NH, SO, S, O, SO2, alkylene, haloalkylene, heteroalkylene, alkyleneoxy, heteroalkoxy, alkenylene, alkynylene, C(=O), OC(=O), C(=O)O, C(=O)NH, and NHC(=O) One or more combinations; wherein the alkylene, alkyleneoxy, alkenylene is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R c Preferably, F6, F 16 and F 21 is independently selected at each occurrence from a single bond, NH, O, C(═O), C(═O)O, and NHC(═O); F A1 are independently aryl or heteroaryl; the aryl or heteroaryl is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R A replace; F A3 Each occurrence is independently arylene or heteroarylene; said arylene or heteroarylene may be optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R c substituted, preferably by 0, 1, 2 or 3 R c replace; F A2 is cycloalkylene, spirocycloalkylene, heterocycloalkylene or spiroheterocycloalkylene, and is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R A replace; R c Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl, OH, NH2, CN and NO2, preferably H, F, Cl, Br, I, CH3, OCH3, CF3, OH, NH2, CN or NO2; R A Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl, oxo (=O), thio (=S), OH, NH2, CN and NO2, preferably oxo (=O), thio (=S), H, F, Cl, Br, I, CH3, OCH3, CF3, OH, NH2, CN or NO2.

35. The compound of claim 34, wherein F A1 0, 1, 2, 3 R c substituted phenyl; and / or F A2 Selected from 0, 1, 2, 3, 4 R A Replaced and / or F A3 Each occurrence is independently 6-10 membered arylene or 5-13 membered heteroarylene containing 1, 2, 3, 4, or 5 N, O, and / or S heteroatoms, said arylene or heteroarylene being optionally substituted by 0, 1, 2, 3, 4, 5, or 6 R c preferably, F A3 Selected from optionally 0, 1, 2, 3, 4, 5 or 6 R c Substituted with the following groups: That middle represents the connection site, when In the F A3 When the attachment site on the group is not fixed, Indicates that it can be connected to the F A3 Any atom on the group that can be attached.

36. The compound of any one of claims 30-35, wherein PTM a Selected from 37. A compound as described in any one of claims 30 to 36, wherein the compound is selected from 38. A pharmaceutical composition comprising a compound according to any one of claims 30 to 37.

39. The compound according to any one of claims 30 to 37, the pharmaceutical composition according to claim 38, for use as a medicament.

40. The compound according to any one of claims 30 to 37, or the pharmaceutical composition according to claim 38, for use as a drug for treating prostate cancer.

41. Use of the compound according to any one of claims 30 to 37 or the pharmaceutical composition according to claim 38 in the preparation of a drug for treating cancer, wherein the cancer is preferably prostate cancer.

42. A method for treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 30 to 37, or a pharmaceutical composition according to claim 38; preferably, the cancer is prostate cancer.