Estrogen receptor proteolysis-targeting chimera compound and use thereof

Abstract

Provided in the present disclosure are a new compound that binds to an estrogen receptor protein, an estrogen receptor proteolysis-targeting chimera compound, and the pharmaceutical use thereof. The compounds provided in the present disclosure can be used as an estrogen receptor degrader in the treatment of estrogen-dependent diseases.

Description

Estrogen receptor protein degradation targeting chimera compounds and uses thereof

[0001] This application claims priority to Chinese Patent Application No. CN2024107944455, filed on June 19, 2024, No. CN2024108679368, filed on July 1, 2024, No. CN2024110531335, filed on August 2, 2024, No. CN2024113898416, filed on October 8, 2024, No. CN2024119462167, filed on December 27, 2024, No. CN2025102685444, filed on March 7, 2025, No. CN202510726053X, filed on June 3, 2025, No. CN2024110572316, filed on August 2, 2024, No. CN2024111197892, filed on August 15, 2024, No. CN2024119467368, filed on December 27, 2024, No. CN2025103480526, filed on March 24, 2025, No. CN2025105334153, filed on April 26, 2025, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to the field of medicine, in particular to a compound for use as an estrogen receptor degrader and uses thereof. BACKGROUND

[0003] A PROTAC molecule is a bifunctional molecule, one end of which contains a ligand that binds to an E3 ubiquitin ligase, and the other end contains a ligand that binds to a target protein, and the two parts are connected by a linker unit. By pulling closer through the linker unit, the E3 ligase and the target protein are very close, and then the polyubiquitination of the target protein and the degradation of the proteasome are caused. PROTACs adopt a completely different mechanism of action and mechanism from small molecule inhibitors. First, the ligand of the E3 ubiquitin ligase recruits the E3 ubiquitin ligase to the vicinity of the target protein, and by pulling the distance with the target protein, the target protein is ubiquitinated. The labeled target protein is degraded by the proteasome system in the body, thereby achieving the effect of inhibiting the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared with traditional small molecule drugs, due to the change of the binding mechanism, PROTACs only need to be transiently combined with the target protein to complete the ubiquitin transfer process to achieve irreversible degradation of the target protein. Therefore, PROTACs have the following advantages: 1) stronger degradation effect and more persistent drug efficacy; 2) higher selectivity for target proteins; 3) can overcome the drug resistance of traditional small molecule inhibitors due to target protein variation (Cell Chem. Biol. 2018, 25, 67-77).

[0004] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor involved in the up- and down-regulation of gene expression. The natural hormones for the estrogen receptor are estradiol (E2) and closely related metabolites. Binding of estradiol to the estrogen receptor causes dimerization of the receptor, which in turn binds to estrogen response elements (EREs) on DNA. The ER-DNA complex recruits other transcription factors responsible for the transcription of DNA downstream of the ERE into mRNA, which is ultimately translated into protein. Alternatively, the interaction of ER with DNA can be indirect through the intermediacy of other transcription factors, the most obvious of which are fos and jun. Because the expression of a large number of genes is regulated by the estrogen receptor, and because the estrogen receptor is expressed in many cell types.

[0005] Thus, modulation of the estrogen receptor by binding to natural hormones or synthetic ER ligands can have profound effects on the physiology and pathophysiology of an organism. There is a clinical need for more novel classes of drugs that degrade the estrogen receptor. SUMMARY

[0006] The present disclosure provides a novel class of estrogen receptor protein degrading targeted chimer PROTACs compounds molecules. These molecules show significant activity in treating estrogen receptor mediated or dependent diseases as estrogen receptor degraders.

[0007] In one aspect of the present disclosure, a compound represented by Formula (II) is provided:

[0008] CLM―L―PTM (II),

[0009] or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof,

[0010] wherein:

[0011] CLM is a cereblon E3 ubiquitin ligase binding moiety;

[0012] L is a bond covalently linking CLM and PTM or -(B L ) q -;

[0013] PTM is a binding moiety targeting estrogen receptor protein comprising a structure represented by Formula (III):

[0014] wherein R1and R2are each independently selected from N or CR mm ;

[0015] R3is selected from H, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, and C1-C6alkoxy are optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, and C1-C6alkylNHacyl;

[0016] R4is selected from N and CR m4 ;

[0017] R5is selected from N and CR m5 ;

[0018] R6is selected from N and CR m6 ;

[0019] R7is selected from N and CR m7 ;

[0020] R m8 is selected from -N(R a )2and -OR a ;

[0021] R m9 Selected from -C(R) a )3、-N(R a )2、-OR a and R a ;or

[0022] R m8 With R1 or R m9 Forming a ring structure; when R1 and R m8 When R1 forms a ring structure with the atoms it is connected to, R1 is C, and R1 and R m8 It forms a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or 4-10 membered heterocyclic group is unsubstituted or 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, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents of the 5-10 heteroaryl group; when R m8 and R m9 When forming a ring with the atoms it is attached to,

[0023] R m8 and R m9 Together with the carbon atoms they are attached to, they form The wavy line represents the site of fusion with the benzene ring;

[0024] R a R mm R m4 R m5 R m6 R m7 R m10 and R m11 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylNHacyl;

[0025] B L Each occurrence may be the same or different, and each is independently selected from CR. L1 R L2 O, S, SO, SO2, NR L3SO2NR L3 SO2NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), 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, and heteroarylene, wherein said cycloalkylene, heterocyclylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups;

[0026] R L1 , R L2 , R L3 , and R L4 are each independently at each occurrence selected from H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, O-C 3-8 cycloalkyl, O-C 3-11 heterocyclyl, C(O)-C 3-8 cycloalkyl, C(O)-C 3-11 heterocyclyl, O-aryl, O-heteroaryl, S-C 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 heterocyclyl, N(C 3-8 heterocyclyl)2, N(C 3-8 heterocyclyl)(C 1-8alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), P(O)(O-C 1-8 alkyl)2, C≡C-C 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, C(O)-C 1-8 alkyl, C(O)O-C 1-8 alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 alkyl, SO2N(C 1-8 alkyl)2, SONH-C 1-8 alkyl, SON(C 1-8 alkyl)2, C(O)NH-C 1-8 alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 heterocyclyl, C(O)N(C 1-8 alkyl)2, N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, NHC(O)NH(C 1-8 alkyl), NHC(O)N(C 1-8 alkyl)2, NHC(O)NH2, 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), NHSO2N(C 1-8 alkyl)2, and NHSO2NH2, optionally, said C 1-8 alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 heterocyclyl, C 6-10aryl and 5-10 membered heteroaryl are each independently substituted with 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;

[0027] q is an integer greater than 1.

[0028] In some embodiments, the CLM comprises a structure selected from:

[0029] wherein W 1 and W 2 are each independently CR a R b , C(=O), NR a , or SO2, and at least one of W 1 and W 2 is C(=O);

[0030] G and Z are each independently selected from O, S, and Se;

[0031] W 5 , W 6 are each independently C(R m )2, NR m , O, or S;

[0032] W 11 is CR a R b , C(=O), NR a , or SO2,

[0033] R8, R9, R a , R m , R N , and R b are each independently at each occurrence selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyl- oxyacyl, and C1-C6 alkylNHacyl;

[0034] R 22 is selected from a single bond, C(O), O, S, SO2, -NR m -, -NR mCombinations of one or more of C(O)-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene;

[0035] n is 0, 1, 2, or 3;

[0036] R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or

[0037] R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups.10 one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C

[0038] R 52 and R 62 together with the carbon atom to which they are attached form a and R 32 , R 42 , and R 72 are each independently selected from the group consisting of H, a deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl, wherein said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C 10 one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C

[0039] R d , R e , R f , R g , R D , R E , R F , R G , R f1 , R g1 , R F1 and R G1 are each independently, at each occurrence, C(R m )2, NR m , O, C(O), or S;

[0040] W 3 and W 4 are each independently CR m or N;

[0041] R t , R T , R t1 and R T1 are each independently CR m or N, R t , R T , Rt1 and R T1 is connected to the side represents a linking site between CLM and L;

[0042] m1and m2are each independently 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6;

[0043] m3is 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4is 1, 2, 3, 4, 5, 6, 7, or 8 at each occurrence, and m3+ m4≤ 8;

[0044] m31is 0, 1, 2, 3, 4, 5, 6, or 7, m41is 1, 2, 3, 4, 5, 6, 7, or 8, and m31+ m41≤ 8;

[0045] m51is 0, 1, 2, 3, 4, 5, 6, or 7, m61is 1, 2, 3, 4, 5, 6, 7, or 8, and m51+ m61≤ 8;

[0046] m5and m6are each independently 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+ m6≤ 7; and

[0047] m7and m8are each independently 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+ m8≤ 7.

[0048] In some embodiments, R1is CR mm ; R m8 is -N(R a )2; R m9 is selected from -C(R a )3, -N(R a )2, -OR a , and R a ; or

[0049] R1and R m8 form, with the atom to which they are attached, a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl containing 1-3 heteroatoms each independently selected from N, O, and S, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R m8with the atom to which it is attached forms a saturated or unsaturated 5-7 membered heterocyclyl containing 1 or 2 N heteroatoms, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R m8 with the atom to which it is attached forms a saturated or unsaturated 5-7 membered heterocyclyl containing 1 or 2 N heteroatoms, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R with the atom to which it is attached forms a saturated or unsaturated 5-7 membered heterocyclyl containing 1 or 2 N heteroatoms, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R substituted with 1, 2, or 3 substituents optionally selected from the group consisting of F, Cl, Br, I, methyl, ethyl, isopropyl, hydroxyl, nitro, cyano, and amino; or

[0050] R m8 and R m9 with the atom to which it is attached forms a saturated or unsaturated 5-7 membered heterocyclyl containing 1 or 2 N heteroatoms, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R with the atom to which it is attached forms a saturated or unsaturated 5-7 membered heterocyclyl containing 1 or 2 N heteroatoms, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R substituted with 1, 2, or 3 substituents optionally selected from the group consisting of F, Cl, Br, I, methyl, ethyl, isopropyl, hydroxyl, nitro, cyano, and amino; or

[0051] preferably, R1and R m8 with the atom to which it is attached forms a saturated or unsaturated 5-7 membered heterocyclyl containing 1 or 2 N heteroatoms, which saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R1and R m9 selected from the group consisting of -C(R a )3, -N(R a )2, -OR a , and R a ;

[0052] preferably, R a , R mm , R m4 , R m5 , R m6 , R m7 , R m10 , and R m11 each occurrence is independently selected from the group consisting of 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, and amino; preferably, R a , R mm , R m4 , R m5 , R m6 , R m7 , R m9 , R m10 , R m11 , R m12 , and R m13each occurrence is independently selected from the group consisting of H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, cyano, and amino.

[0053] In yet another aspect of the present disclosure, there is provided a compound represented by Formula (II-1):

[0054] CLM―L―PTM (II-1),

[0055] or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof,

[0056] wherein:

[0057] CLM is a cereblon E3 ubiquitin ligase binding moiety;

[0058] L is a bond or -(B L ) q covalently linking CLM and the PTM;

[0059] PTM comprises a structure represented by Formula (III-1):

[0060] wherein R2 is selected from N or CR mm

[0061] R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyl- oxyacyl, and C1-C6 alkylNHacyl;

[0062] R4 is selected from N and CRm4;

[0063] R5 is selected from N and CRm5;

[0064] R6 is selected from N and CRm6;

[0065] R7 is selected from N and CRm7;

[0066] R mm , R m4 , R m5 , R m6 ​R m7 R m9 R m10 R m11 R m12 and R m13 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl;

[0067] B L Each occurrence may be the same or different, and each is independently selected from CR. L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), 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 , cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. L1 and / or R L2 Group substitution;

[0068] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, 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 groups, N(C) 3-8 Heterocyclic group)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, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C)1-8 alkyl)C(O)N(C 1-8 alkyl)2, NHC(O)NH(C 1-8 alkyl), NHC(O)N(C 1-8 alkyl)2, NHC(O)NH2, 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), NHSO2N(C 1-8 alkyl)2, and NHSO2NH2, optionally, said C 1-8 alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently substituted with 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;

[0069] q is an integer greater than or equal to 1 ;

[0070] Preferably, the CLM comprises a structure selected from:

[0071] W 1 and W 2 are each independently CR a R b , C(=O), NR a , or SO2, and at least one of W 1 and W 2 is C(=O);

[0072] G and Z are each independently selected from O, S, and Se;

[0073] W 5 , W 6 are each independently C(R m )2, NR m , O, or S at each occurrence;

[0074] W 11 is CR a R b , C(=O), NR a , or SO2,

[0075] R8, R9, Ra R m R N R b each occurrence is independently selected from the group consisting of H, carboxyl, deuterium, halogen, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, hydroxyl, Ci-C6hydroxyalkyl, nitro, cyano, amino, Ci-C6alkylamino, Ci-C6alkylacyl, Ci-C6alkyloxyacyl, and Ci-C6alkylNHacyl;

[0076] R 22 is selected from the group consisting of a single bond, C(O), O, S, SO2, -NR m -, -NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0077] n is 0, 1, 2, or 3;

[0078] R 32 and R 42 together with the carbon atom to which they are attached form and R 52 R 62 and R 72 each occurrence is independently selected from the group consisting of H, deuterium, halogen, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, hydroxyl, Ci-C6hydroxyalkyl, nitro, cyano, amino, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl, wherein said Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6heteroalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl; or

[0079] R 42 and R 52 together with the carbon atom to which they are attached form and R 32 R 62 and R 72Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or

[0080] R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups;

[0081] R d R e R f R g R D R E R F R G R f1 R g1 RF1 and R G1 each occurrence is independently C(R m )2, NR m , O, C(O), or S;

[0082] W 3 and W 4 are each independently CR m or N;

[0083] R t , R T , R t1 , and R T1 are each independently CR m or N, R t , R T , R t1 , and R T1 are each independently CR mm or N, R m4 , R m5 , R m6 , and R m7 are each independently CR m9 or N, R m10 , R m11 , R m12 , and R m13 represent the site of attachment between CLMand L; represents the site of attachment between CLMand L;

[0084] m1and m2are each independently 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6;

[0085] m3is 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4is 1, 2, 3, 4, 5, 6, 7, or 8 at each occurrence, and m3+ m4≤ 8;

[0086] m31is 0, 1, 2, 3, 4, 5, 6, or 7, m41is 1, 2, 3, 4, 5, 6, 7, or 8, and m31+ m41≤ 8;

[0087] m51is 0, 1, 2, 3, 4, 5, 6, or 7, m61is 1, 2, 3, 4, 5, 6, 7, or 8, and m51+ m61≤ 8;

[0088] m5and m6are each independently 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+ m6≤ 7; and

[0089] m7and m8are each independently 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+ m8≤ 7.

[0090] In some embodiments, R mm , R m4 , R m5 , R m6 , R m7 , R m9 , R m10 , R m11 , R m12 , and R m13each occurrence is independently selected from the group consisting of H, deuterium atom, F, CI, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R mm , R m1 , R m2 , R m3 , R m4 , R m5 , R m6 , R m7 , R m9 , R m10 , R m11 , R m12 , and R m13 each occurrence is independently selected from the group consisting of H, F, CI, Br, I, Ci-C3alkyl, Ci-C3alkoxy, hydroxyl, cyano, and amino.

[0091] In some embodiments, R2is selected from the group consisting of N, CH, C-F, and C-CH3, preferably CH; and / or

[0092] R3is R m1 , R m2 , and R m3 each occurrence is independently selected from the group consisting of H, carboxyl, deuterium atom, halogen, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, hydroxyl, Ci-C6hydroxyalkyl, nitro, cyano, amino, Ci-C6alkylamino, Ci-C6alkylacyl, Ci-C6alkyloxyacyl, and Ci-C6alkylNHacyl; preferably, R m1 , R m2 , and R m3 each occurrence is independently selected from the group consisting of H, deuterium atom, F, CI, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, amino; preferably, R m1 , R m2 , and R m3 each occurrence is independently selected from the group consisting of H, F, CI, Br, I, Ci-C3alkyl, Ci-C3alkoxy, hydroxyl, cyano, and amino; preferably, R3is selected from the group consisting of fluoroethyl, difluoroethyl, and trifluoroethyl, preferably R3is difluoroethyl; preferably, R3is -CH2-CHF2; and / or

[0093] R4is selected from N, CH, C-F, C-Cl, C-Br, C(Ci-C6alkyl), and C(Ci-C6alkoxy), preferably N, CH, C-F, C-Cl, C-Br, or C-OCH3, more preferably C-F; and / or

[0094] R5is N or CH, preferably CH; and / or

[0095] R6is selected from N, CH, C-F, C-Cl, C-Br, C(Ci-C6alkyl), and C(Ci-C6alkoxy), preferably N, CH, C-F, C-Cl, C-Br, or C-OCH3, more preferably C-F; and / or

[0096] R7is N or CH, preferably CH; and / or

[0097] R m9 selected from hydrogen, halogen, and Ci-C6alkyl, preferably hydrogen, fluorine, or methyl, more preferably hydrogen; and / or

[0098] R m10 selected from hydrogen and Ci-C6alkyl, preferably hydrogen; and / or

[0099] R m11 selected from hydrogen and Ci-C6alkyl, preferably hydrogen or methyl, more preferably methyl.

[0100] In some embodiments, selected from more preferably

[0101] In some embodiments, selected from unsubstituted or substituted with one or more substituents selected from deuterium atom, F, Cl, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, and amino

[0102] In some embodiments, selected from unsubstituted or substituted with one or more substituents selected from deuterium atom, F, Cl, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, and amino

[0103] In some embodiments, the PTM is selected from:

[0104] Preferably, the PTM is selected from

[0105] In some embodiments, B L each occurrence is selected from CR L1 R L2 , O, S, SO, SO2, NR L3 , C(O), CºC, 3-16 membered cycloalkylene, 3-16 membered heterocyclylene, 6-10 membered arylene, and 5-10 membered heteroarylene, wherein the 3-16 membered cycloalkylene, 3-16 membered heterocyclylene, 6-10 membered arylene, and 5-10 membered heteroarylene is optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups; and / or

[0106] R L1 , R L2 , R L3 , and R L4 each occurrence is selected from H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, O-C 3-8 cycloalkyl, O-C 3-11 heterocyclyl, C(O)-C 3-8 cycloalkyl, C(O)-C 3-11 heterocyclyl, O-aryl, O-heteroaryl, S-C 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 heterocyclyl, N(C 3-8 heterocyclyl)2, N(C 3-8 heterocyclyl)(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)(O-C 1-8 alkyl)(C 1-8 alkyl), P(O)(O-C 1-8 alkyl)2, CºC-C 1-8alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 3-8 alkyl, C≡CH, CH=CH-(C 3-11 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 1-8 alkyl, C≡CH, CH=CH-(C 3-11 alkyl, C≡CH, CH=CH-(C 3-8 alkyl, C≡CH, CH=CH-(C 3-11 alkyl, C≡CH, CH=CH-(C 6-10 alkyl, C≡CH, CH=CH-(C 1-6 alkyl, C≡CH, CH=CH-(C

[0107] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and / or 1 , W 2each occurrence is independently CR a R b or C(=O); preferably, W 1 is C(=O), W 2 is CH, or W 1 is CH, W 2 is C(=O); and / or

[0108] G is O; Z is O; and / or

[0109] W 5 , W 6 each occurrence is independently C(R m )2; preferably, W 5 is CH, W 6 is CH; and / or

[0110] W 11 is C(=O); and / or

[0111] R8, R9, R a , R m , R N , and R b are each independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino;

[0112] R 22 is selected from a single bond, C(O), NH, O, C(O)NH, NHC(O), N(C1-C3alkyl), N(C1-C3alkyl)C(O), C(O)N(C1-C3alkyl), and C1-C3alkylene; preferably, R 22 is selected from a single bond, C(O), NH, C(O)NH, NHC(O), N(CH3), N(CH3)C(O), and C(O)N(CH3); and / or

[0113] n is 1; and / or

[0114] R 32 and R 42 together with the carbon atom to which they are attached form and R 52 , R 62 , and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, amino, C3-C8cycloalkyl, C4-C 10Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, 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 Each heteroaryl group is independently 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 52 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or

[0115] R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, 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, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, 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 Each heteroaryl group is independently 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 32 R62 and R 72 each independently is selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy;

[0116] R 52 and R 62 together with the carbon atom to which they are attached form a and R 32 , R 42 and R 72 each independently is selected from the group consisting of 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 heterocyclyl, C6-C 10 aryl, and C5-C 10 heteroaryl, wherein said C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 heterocyclyl, C6-C 10 aryl, and C5-C 10 heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of 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 heterocyclyl, C6-C 10 aryl, and C5-C 10 heteroaryl; preferably, R 32 , R 42 and R 72 each independently is selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; and / or

[0117] W 3 is N, W 4 is CH or W 3 is CH, W 4 is N.

[0118] In some embodiments, the CLM comprises a structure selected from the group consisting of:

[0119] wherein W 1 , W 2 , W 3 , W 4, W 5 , W 6 , W 11 , R8, R9, R N , R m , R F , R G , R T , R f , R g , R t , R T1 , R F1 , R G1 , R 32 , R 42 , R 52 , R 62 , R 72 , m3, m4, m31, m41, m5 and m6 are each defined as in any of the preceding embodiments;

[0120] R 1D , R 1E , R 1d , R 1e each occurrence is independently selected from C(R m )2, NR m , O and C(O), R m are defined as in any of the preceding embodiments;

[0121] m1, m9 and m10 are each independently at each occurrence an integer of 0, 1, 2, 3, 4, or 5, and m1+m9+m10≤5;

[0122] m7, m11 and m12 are each independently at each occurrence an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6.

[0123] In some embodiments, W 1 and W 2 are each independently CR a R b , and at least one of W 1 and W 2 is C(=O);

[0124] W 3 and W 4 are each independently CR m or N, and one of W 3 and W 4 is N;

[0125] W 5 , W 6 are each independently at each occurrence C(R m )2;

[0126] R 1D , R 1E , R 1d , and R 1e , each occurrence is independently selected from C(R m )2, NR m , O, and C(O);

[0127] R F , R G , R f , R g , R F1 , and R G1 each occurrence is independently selected from C(R m )2;

[0128] R T , R t , and R T1 each occurrence is independently N;

[0129] R8, R9, R 32 , R 42 , R 52 , R 62 , R 72 , R a , R b , R N , and R m each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, and cyano;

[0130] m1, m9, and m10 each occurrence is independently an integer of 0, 1, 2, 3, 4, or 5, and m1+m9+m10≤5; preferably m1, m9, and m10 each occurrence is independently an integer of 0, 1, or 2, and m1+m9+m10≤2, preferably m1+m9+m10=1, m1+m9+m10=2 or m1+m9+m10=0;

[0131] m7, m11, and m12 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6; preferably m7, m11, and m12 each occurrence is independently an integer of 0, 1, 2, or 3, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1;

[0132] m3, m4 each occurrence is independently an integer of 0, 1, 2, 3, or 4; m3, m4 are not simultaneously 0; m3+m4≤5; preferably m3+m4=4, m3+m4=3 or m3+m4=2;

[0133] each occurrence of m5, m6 is independently an integer of 0, 1, 2, 3, or 4; preferably, m5+m6 = 3, m5+m6 = 2 or m5+m6 = 1;

[0134] each occurrence of m31, m41 is independently an integer of 0, 1, 2, 3, or 4; m31, m41 are not simultaneously 0; m31+m41≤5; preferably, m31+m41 = 4, m31+m41 = 3 or m31+m41 = 2; and

[0135] W 11 is C(=O).

[0136] In some embodiments, the CLM comprises a structure selected from the group consisting of Formula (IV-1A), Formula (IV-1B), and Formula (IV-1C), wherein:

[0137] W 1 is C(=O), W 2 is CH2, or W 1 is CH2, W 2 is C(=O); preferably, W 1 is C(=O), W 2 is CH2.

[0138] W 5 , and W 6 each occurrence is independently CH2, C(C1-C6alkyl)2, or C(C1-C6alkyl)H; preferably, W 5 is CH2, W 6 is CH2.

[0139] R8, and R9 are each independently selected from the group consisting of H, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, and hydroxyl; preferably, R8 is H, R9 is H;

[0140] R 32 , R 42 , R 52 , and R 62 each occurrence is independently selected from the group consisting of H, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, and cyano, more preferably H, F, Cl, Br, methyl, methoxy, or cyano; more preferably, R 32 is F, Cl, or Br, R 42 , R 52 , and R 62 each occurrence is independently H.

[0141] R F , and R Geach occurrence is independently selected from CH2, NH, O, and C(O); preferably CH2; m3 is 2; m4 is 2;

[0142] R 1D , and R 1E each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

[0143] In some embodiments, the CLM is selected from:

[0144] Preferably, the CLM is selected from

[0145] In some embodiments, B L is selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -C(O)-, -NH-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3) 2 -, -N(CH3)-, -N(CH2CH3)-, wherein, is a point of attachment.

[0146] In some embodiments, L is selected from the following structures:

[0147] covalent bond, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -C(O)-(CH2) s -, -(CH2)p -O-(CH2) s -、-(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、

[0148] wherein j is each occurrence independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0149] k, s, p and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0150] is a point of attachment to CLM or PTM;

[0151] L is preferably selected from the group consisting of a covalent bond, -(CH2)2- OCH2CH2, -(CH2)2-(OCH2CH2)2, -(CH2)2-(OCH2CH2)3, -(CH2)2-(OCH2CH2)4, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-(CH2)9-, -NH-(CH2) 10 -、-NH-(CH2) 11 -、-NH-(CH2) 12 -、-NH-(CH2) 13 -、-NH-(CH2) 14 -、-NH-(CH2) 15-NH-CH2-,-NH-(CH2)2-,-NH-(CH2)3-,-NH-(CH2)4-,-NH-(CH2)5-,-NH-(CH2)6-,-NH-(CH2)7-,-NH-(CH2)8-,-C(O)-NH-CH2-,-C(O)-NH-(CH2)2-,-C(O)-NH-(CH2)3-,-C(O)-NH-(CH2)4-,-(CH2)4-C(O)-NH-(CH2)4-,-(CH2)2-C(O)-NH-(CH2)3-,-(CH2)5-C(O)-NH-(CH2)8-,-C(O)-NH-(CH2) 2)5-,-C(O)-NH-(CH2)6-,-C(O)-NH-(CH2)7-,-C(O)-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-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-,-C(O)-NH-(CH2-CH 2-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-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-C(O)-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-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-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)3-NH-, -NH-CH2-CH2-O-CH2-CH2-C(O)-, -C(O)-CH2-CH2-O-CH2-CH2-NH-, -NH-(CH2)4-C(O)-, -NH-(CH2)5-C(O)-, -NH-(CH2)6-C(O)-, -C(O)-(CH2)4-NH-, -C(O)-(CH2)5-NH-, -C(O)-(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-C(O)-, -CH2-CH2-O-(CH2)3-C(O)-, -CH2-CH2-O-(CH2)4-C(O)-, -C(O)-(CH2)2-O-CH2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-,-(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O)-(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-,

[0152] 14. A compound of formula (IA),

[0153] or an isomer, isotopic form, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof,

[0154] in which X1is N or CH; X2is N or CH; X3is N or CH;

[0155] q1is 0 or 1 ; q2is 0, 1 or 2; p1is 0 or 1 ; p2is 0 or 1 ; p3is 0 or 1 ; p4is 0 or 1 ;

[0156] R3is selected from the group consisting of fluoroethyl, difluoroethyl and trifluoroethyl;

[0157] R m9 is selected from the group consisting of hydrogen, halogen and Ci-C6alkyl;

[0158] R m10 is selected from the group consisting of hydrogen and Ci-C6alkyl;

[0159] R m11 is selected from the group consisting of hydrogen, methyl, ethyl and isopropyl;

[0160] R4is selected from the group consisting of N, CH, C-F, C-Cl, C-Br, C(Ci-C6alkyl) and C(Ci-C6alkoxy);

[0161] R5is N or CH;

[0162] R6is selected from the group consisting of N, CH, C-F, C-Cl, C-Br, C(Ci-C6alkyl) and C(Ci-C6alkoxy),

[0163] R7is N or CH;

[0164] CLM comprises a structure selected from the group consisting of formula (IV-1a), formula (IV-1b) and formula (IV-1c):

[0165] in which W 1 is C(=O), W 2 is CH2or W 1 is CH2, W 2 is C(=O); preferably, W 1 is C(=O), W 2 is CH2;

[0166] R 32 , R 42 , R 52 and R 62 are each independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, Ci-C3alkyl, Ci-C3alkoxy and cyano, more preferably H, F, Cl, Br, methyl, methoxy or cyano; more preferably, R 32 is F, Cl or Br, R 42 , R 52 and R 62 are each independently at each occurrence H;

[0167] R F , R G each occurrence is independently selected from CH2, NH, O and C(O); preferably CH2; m3 is 2; m4 is 2;

[0168] R 1D , R 1E each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

[0169] In some embodiments, the compound is selected from:

[0170] Preferably, the compound is selected from the compounds of Table A.

[0171] In yet another aspect of the present disclosure, there is provided a compound that binds to an estrogen receptor protein comprising a structure represented by Formula (I’):

[0172] or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:

[0173] wherein R ER0’ is a leaving group;

[0174] R1, R2, R3, R4, R5, R6, R7, R m8 , R m9 , R m10 and R m11 are each defined as in any of the preceding embodiments.

[0175] In some embodiments, R ER0’ is selected from -(CR ER0a RER0b ) n1 R ER0c , methanesulfonate (Ms), trifluoromethanesulfonate (Tf), p-toluenesulfonyl chloride (TsCl), p-toluensulfonate (Ts), -C(O)OR ER0d , and -OC(O)R ER0d ;

[0176] R ER0a , R ER0b , R ER0c , and R ER0d are each independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH, said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with 1 or more substituents independently selected from a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino;

[0177] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0178] Preferably, R ER0’ is selected from Cl, Br, I, Ms, Tf, TsCl, Ts, C(O)OCH3, C(O)OCH3, CH2NO2, CH2ON=NH, and CH2NH2;

[0179] Preferably, is selected from More preferably,

[0180] Preferably, is selected from:

[0181] In yet another aspect of the present disclosure, there is provided a compound that binds to an estrogen receptor protein comprising a structure represented by Formula (I-1’):

[0182] or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof;

[0183] wherein R ER0’as a leaving group;

[0184] R2, R3, R4, R5, R6, R7, R m8 , R m9 , R m10 , and R m11 are each defined as in any of the preceding embodiments.

[0185] In some embodiments, R ER0’ is selected from -(CR ER0a R ER0b ) n1 R ER0c , mesylate (Ms), triflate (Tf), tosylchloride (TsCl), tosylate (Ts), -C(O)OR ER0d , and -OC(O)R ER0d ;

[0186] R ER0a , R ER0b , R ER0c , and R ER0d are each independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH, said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with 1 or more substituents independently selected from a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino;

[0187] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0188] In some embodiments, R ER0’ is selected from F, Cl, Br, I, Ms, Tf, TsCl, Ts, C(O)OCH3, C(O)OCH3, CH2NO2, CH2ON=NH, and CH2NH2;

[0189] Preferably, is more preferably is

[0190] Preferably, is selected from:

[0191] In yet another aspect of the present disclosure, there is provided a compound that binds to an estrogen receptor protein, the compound being a compound of Formula I, or an isomer, an isotopic derivative, a polymorph, a prodrug, or a pharmaceutically acceptable salt or solvate thereof:

[0192] wherein R ER0 is selected from -(CR ER0a R ER0b ) n1 R ER0c , mesylate (Ms), triflate (Tf), TsCl, Ts, -C(O)OR ER0d , and -OC(O)R ER0d ;

[0193] R ER0a , R ER0b , R ER0c , and R ER0d are each independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH, said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with 1 or more substituents independently selected from a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino;

[0194] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0195] R ER1 , and R ER2 are each independently selected from N and CR ERm ;

[0196] R ER3H, F, CI, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, and C1-C6alkoxy are optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, and C1-C6alkylaminoacyl; preferably, R ER3 is

[0197] R ER4 is selected from N and CR ERm4 ;

[0198] R ER5 is selected from N and CR ERm5 ;

[0199] R ER6 is selected from N and CR ERm6 ;

[0200] R ER7 is selected from N and CR ERm7 ;

[0201] R ERm8 is selected from -N(R ERa )2, and -OR ERa ;

[0202] R ERm9 is selected from -C(R ERa )3, -N(R ERa )2, -OR ERa , and R ERa ; or

[0203] R ERm8 is capable of forming a ring structure with R ER1 or R ERm9 ; when R ER1 and R ERm8 form a ring structure with the atom to which each is attached, R ER1 is C,

[0204] R ER1 and R ERm8Each of the atoms to which it is attached forms a 4-10 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the 4-10 membered heterocyclic group is unsubstituted or 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, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R ER1 and R ERm8 The bonded atom forms a 5-7 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the 5-7 membered heterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R ER1 and R ERm8 It forms a saturated or unsaturated 5-7 membered heterocyclic group containing one or two N heteroatoms with the attached carbon atom, wherein the 5-7 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano and amino;

[0205] Or, when R ERm8 and R ERm9 When R forms a ring with the atoms it is attached to, ERm8 and R ERm9 Together with the atoms they are attached to, they form Here, the zigzag lines represent sites where the benzene ring fused; preferably, R ER1 and R ERm8 It forms a ring structure with the atoms it is connected to; R ERm9 Selected from -C(R) ERa )3、-N(R ERa )2、-OR ERa and R ERa ;

[0206] and

[0207] R ERa R ERb R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 RERm6 , R ERm7、 R ERm10 and R ERm11 each occurrence is independently selected from the group consisting of H, carboxyl, deuterium, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, and C1-C6alkylaminoacyl; preferably, R ERa , R ERb , R ERm , R ERm1 , R ERm2 , R ERm3 , R ERm4 , R ERm5 , R ERm6 , R ERm7、 R ERm10 and R ERm11 each occurrence is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino.

[0208] In yet another aspect of the present disclosure, there is provided a compound that binds to an estrogen receptor protein, the compound being a compound of Formula I-1, or an isomer, isotopic derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof:

[0209] wherein R ER0 is selected from the group consisting of -(CR ER0a R ER0b ) n1 R ER0c , mesylate (Ms), triflate (Tf), tosylchloride (TsCl), tosylate (Ts), -C(O)OR ER0d , and -OC(O)R ER0d ;

[0210] R ER0a , R ER0b , R ER0c and R ER0deach independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxy, nitro, cyano, amino, and -ON=NH, said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with 1 or more substituents independently selected from a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxy, carboxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino;

[0211] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0212] R ER2 is selected from N and CR ERm ;

[0213] R ER3 is selected from H, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxy, nitro, cyano, and amino; said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, and C1-C6alkoxy optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from carboxy, a deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, and C1-C6alkylaminoacyl; preferably, R ER3 is

[0214] R ER4 is selected from N and CR ERm4 ;

[0215] R ER5 is selected from N and CR ERm5 ;

[0216] R ER6 is selected from N and CR ERm6 ;

[0217] R ER7 is selected from N and CR ERm7 ;

[0218] R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm9 R ERm10、 R ERm11 R ERm12 and R ERm13 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm9 R ERm10、 R ERm11 R ERm12 and R ERm13 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm9 R ERm10、 R ERm11 R ERm12 and R ERm13 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, and amino.

[0219] In some implementation schemes, substituted with one or more substituents selected from the group consisting of a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino

[0220] In some embodiments, the above-mentioned compound is selected from the group consisting of:

[0221] In another aspect of the present disclosure, a compound represented by Formula (IV) is provided:

[0222] CLM―L―A L2 (IV)

[0223] or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,

[0224] wherein CLM, L are defined as in any one of the preceding embodiments;

[0225] A L2 is independently selected from the group consisting of H, a deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl, wherein each of said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C 10 heterocyclyl, aryl, and heteroaryl;

[0226] Preferably, A L2 is selected from the group consisting of

[0227] In another aspect of the present disclosure, a compound represented by Formula (IV) is provided, the compound having the following structure

[0228] CLM―La (Formula IV)

[0229] or an isomer, an isotopic derivative, a polymorph, a prodrug, or a pharmaceutically acceptable salt or a solvate thereof,

[0230] wherein:

[0231] La is -(B L ) q -A L2 ;

[0232] A L2 is independently selected from H, a deuterium atom, halogen, C1-C6alkyl, heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C3-C8cycloalkyl, C4-C10cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each of said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C4-C10cycloalkenyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C10cycloalkenyl, heterocyclyl, aryl, and heteroaryl; 10 haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C10cycloalkenyl, heterocyclyl, aryl, and heteroaryl; 10 haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C10cycloalkenyl, heterocyclyl, aryl, and heteroaryl; 10 haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, C4-C10cycloalkenyl, heterocyclyl, aryl, and heteroaryl;

[0233] said B L , q, CLM are as defined in any of the preceding embodiments.

[0234] In some embodiments, the compound is selected from the following structures:

[0235] In yet another aspect of the present disclosure, there is provided a use of the compound or isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof of any of the preceding aspects in the manufacture of a medicament for degrading an estrogen receptor protein.

[0236] In yet another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound according to any one of the preceding aspects.

[0237] In yet another aspect of the present disclosure, there is provided a use of a compound according to any one of the preceding aspects, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the preceding, in the manufacture of a medicament for treating or preventing a disease; wherein the disease is a disease treated by degrading estrogen receptor protein or a disease associated with accumulation and / or aggregation of estrogen receptor protein.

[0238] In some embodiments, the disease is cancer, preferably the cancer is breast cancer, breast ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myelogenous leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

[0239] In yet another aspect of the present disclosure, there is provided a use of a compound according to any one of the preceding aspects, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the preceding, in the manufacture of a medicament for treating or preventing a disease; wherein the disease is a disease treated by degrading estrogen receptor protein or a disease associated with accumulation and / or aggregation of estrogen receptor protein.

[0240] In some embodiments, the disease is cancer, preferably the cancer is breast cancer, breast ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myelogenous leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

[0241] In yet another aspect of the present disclosure, there is provided a method of treating or preventing a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the preceding aspects, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the preceding; wherein the disease is a disease treated by degrading estrogen receptor protein or a disease associated with accumulation and / or aggregation of estrogen receptor protein.

[0242] In some embodiments, the disease is cancer, preferably the cancer is breast cancer, breast ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myelogenous leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

[0243] In another aspect, this disclosure provides the use of a compound of Formula IV in the preparation of a medicament for treating diseases or conditions by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating diseases or conditions mediated by estrogen receptor protein and IKZF2, said compound having the following chemical structure:

[0244] CLM-L-PTM (Formula IV);

[0245] Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0246] L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -;

[0247] CLM is selected from the following structures:

[0248] W 1 and W 2 Whether they are the same or different, each is independently a CR. a R b Or C(O), and W 1 and W 2 At least one of them is C(O);

[0249] R 1D R 1E R F and R G Each occurrence is independently C(R) m 2. NR m C(O), O or S;

[0250] R T For N or CR 2h ;

[0251] R 32 R42, R 62 R m and R 2hEach of the following groups is independently selected from H, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl 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 heterocyclic, C6-C 10 The aryl and 5-10-membered heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, 4-10-membered heterocyclic groups, and C6-C6 heterocyclic groups. 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R 32 R42, R 62 R 2h Each time Rm appears, it is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 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 is each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxy, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, halogenated C3-C8cycloalkyl, halogenated 4-10 membered heterocyclyl, halogenated C6-C10aryl, and halogenated 5-10 membered heteroaryl; 10 one or more substituents on the aryl and 5-10 membered heteroaryl are each independently selected from F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxy, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, halogenated C3-C8cycloalkyl, halogenated 4-10 membered heterocyclyl, halogenated C6-C10aryl, and halogenated 5-10 membered heteroaryl; 32 , R42, R 62 , R 2h , and R m are each independently at each occurrence selected from H, deuterium atom, F, Cl, Br, I, C1-C6alkyl, deuterated C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, and hydroxy; further preferably, R 32 , R 42 , R 62 , R 2h , and R m are each independently at each occurrence selected from H, deuterium atom, F, Cl, Br, I, C1-C3alkyl, deuterated C1-C3alkyl, C1-C3alkoxy, haloC1-C3alkyl, haloC1-C3alkoxy, and hydroxy; further preferably, R 32 , R 42 , R 62 , R 2h , and R m are each independently at each occurrence selected from H, F, Cl, Br, I, C1-C3alkyl, hydroxy, and C1-C3alkoxy; further preferably, R 32 , R 42 , R 62 , R 2h , and R m are each independently at each occurrence selected from H, F, Cl, Br, I, C1-C3alkyl, and C1-C3alkoxy;

[0252] m7, m11, and m12 are each independently at each occurrence an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6;

[0253] m3and m4are each independently at each occurrence an integer of 0, 1, 2, 3, or 4; m3and m4are not simultaneously 0; m3+m4≤5;

[0254] R8 is selected from H, halogens, deuterium atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, hydroxyl groups, cycloalkyl groups, C1-C6 haloalkyl groups, and hydroxyalkyl groups; preferably, R8 is selected from H, halogens, deuterium atoms, C1-C3 alkyl groups, and hydroxyl groups; more preferably, R8 is selected from H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl groups, and hydroxyl groups;

[0255] R9, R a and R b Each is independently selected from H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy;

[0256] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), 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 Monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups, wherein the monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. 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 L3C(O), C≡C, 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from N, O and S, 5-15 membered bridged cyclic group containing 0-5 heteroatoms independently selected from N, O and S, and 5-15 membered spirocyclic group containing 0-5 heteroatoms independently selected from N, O and S, wherein the 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic alkylene, 5-15 membered bridged cyclic group and 5-15 membered spirocyclic group are optionally separated by 0, 1, 2 or 3 R L1 and / or R L2 Group substitution;

[0257] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, C 1-8 Alkoxy, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic groups, 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 groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl groups, -OH groups, -NH2 groups, -SH groups, S(O)2P(O) (OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl group, -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 1-8alkyl)2, Si(OH)3, Si(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl, C(O)-O-C 1-8 alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 alkyl, S(O)2N(C 1-8 alkyl)2, S(O)NH-C 1-8 alkyl, S(O)N(C 1-8 alkyl)2, C(O)NH-C 1-8 alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 heterocyclyl, C(O)N(C 1-8 alkyl)2, N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, NHC(O)NH(C 1-8 alkyl), NHC(O)N(C 1-8 alkyl)2, NHC(O)NH2, N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), N(C 1-8 alkyl)S(O)2N(C 1-8 alkyl)2, NHS(O)2NH(C 1-8 alkyl), NHS(O)2N(C 1-8 alkyl)2and NHS(O)2NH2, optionally, the C 1-8 alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 heterocyclyl and C 3-8 heterocyclyl, each independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl and alkylamino;

[0258] q is an integer greater than or equal to 1 ; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and

[0259] PTM is a binding estrogen receptor protein moiety selected from the following structural formulae:

[0260] R1and R2are each independently selected from N and CR m ;

[0261] R3is independently selected at each occurrence from H, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, and C1-C6alkoxy are optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, and C1-C6alkylaminoacyl; preferably, R3is

[0262] R4is each independently selected at each occurrence from N and CRm4;

[0263] R5is each independently selected at each occurrence from N and CRm5;

[0264] R6is each independently selected at each occurrence from N and CRm6;

[0265] R7is each independently selected at each occurrence from N and CRm7;

[0266] R m8 is selected from -N(R a )2and -OR a ; R m9 is selected from -C(R a )3, -N(R a )2, -OR a , and R a ; or

[0267] R m8 forms a ring structure with R1; when R1and R m8 form a ring structure with the atom to which each is attached, R1is C, R1and R m8 form a saturated or unsaturated C4-C 10 cycloalkylene group or a 4-10 membered heterocyclylene group containing 1-3 heteroatoms each independently selected from N, O, and S, the saturated or unsaturated C4-C 10Cycloalkylene or 4-10 membered heterocyclo is unsubstituted or optionally substituted with one or more substituents 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, 4-10 membered heterocyclo, C6-C10 aryl, 5-10 membered heteroaryl, a saturated or unsaturated C5-C7 cycloalkylene, and a 5-7 membered heterocycloalkylene containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, R1and R 10 Cycloalkylene or 4-10 membered heterocyclo is unsubstituted or optionally substituted with one or more substituents 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, 4-10 membered heterocyclo, C6-C10 aryl, 5-10 membered heteroaryl, a saturated or unsaturated C5-C7 cycloalkylene, and a 5-7 membered heterocycloalkylene containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, R1and R m8 Cycloalkylene or 4-10 membered heterocyclo is unsubstituted or optionally substituted with one or more substituents 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, 4-10 membered heterocyclo, C6-C10 aryl, 5-10 membered heteroaryl, a saturated or unsaturated C5-C7 cycloalkylene, and a 5-7 membered heterocycloalkylene containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, R1and R m8 Cycloalkylene or 4-10 membered heterocyclo is unsubstituted or optionally substituted with one or more substituents 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, 4-10 membered heterocyclo, C6-C10 aryl, 5-10 membered heteroaryl, a saturated or unsaturated C5-C7 cycloalkylene, and a 5-7 membered heterocycloalkylene containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, R1and R

[0268] R a , R m , R m1 , R m2 , R m3 , R m4 , R m5 , R m6 , R m7 , R 10 , and R 11 each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyl- oxyacyl, and C1-C6 alkylaminoacyl; preferably, R a , R m , R m1 , R m2 , R m3 , R m4 , R m5 , R m6, R m7 , R 10 , R 11 each occurrence is independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, and amino.

[0269] In yet another aspect of the present disclosure, a compound is provided, the compound having the structure of Formula I:

[0270] CLM―La(Formula I)

[0271] or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof,

[0272] wherein:

[0273] CLM is selected from the group consisting of the following structures:

[0274] W 1 and W 2 are the same or different, each being independently CR a R b or C(=O), and at least one of W 1 and W 2 is C(=O);

[0275] W 5 , W 6 each occurrence is independently C(R m )2;

[0276] R 1D , R 1E , R F , and R G each occurrence is independently C(R m )2, NR m , C(=O), O, or S;

[0277] R T is N or CR 2h ;

[0278] R 32 , R 42 , R 62 , R m , and R 2heach occurrence is independently selected from H, a deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is 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; preferably, R 32 , R 42 , R 62 , R 2h , and R m each occurrence is independently selected from H, a deuterium atom, halogen, C1-C6 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 heterocyclyl, C6-C 10 aryl, and C5-C 10 heteroaryl, wherein each occurrence of C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 heterocyclyl, C6-C 10 aryl, and C5-C 10 heteroaryl is independently optionally substituted with one or more substituents 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 heterocyclyl, C6-C 10 aryl, and C5-C 10 heteroaryl; preferably, R 32 , R 42 , R 62 , R 2h , and 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, hydroxy, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 heterocyclyl, C6-C 10 aryl, and C5-C 10Heteroaryl groups, 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 Each heteroaryl group is independently 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; more preferably, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and hydroxyl groups; more preferably, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy and hydroxyl groups; more preferably, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, hydroxyl and C 1-3 Alkyl group; more preferably, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, and C.1-3 alkyl;

[0279] m7, m11 and m12 are each independently at each occurrence an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6;

[0280] m3, m4 are each independently at each occurrence an integer of 0, 1, 2, 3, or 4; m3, m4 are not simultaneously 0; m3+m4≤5;

[0281] R8is selected from the group consisting of H, halogen, deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxyl, cycloalkyl, C1-C6haloalkyl, and hydroxyalkyl; preferably, R8is selected from the group consisting of H, halogen, deuterium atom, C1-C3alkyl, and hydroxyl; more preferably, R8is selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C1-C3alkyl and hydroxyl;

[0282] R9, R a , and R b are each independently selected from the group consisting of H, halogen, C1-C3alkyl, C3-C6cycloalkyl, and C1-C6alkoxy;

[0283] La is -(B L ) q -A L2 ;

[0284] B L are each the same or different at each occurrence and are each independently selected from the group consisting of: CR L1 R L2 , O, S, S(O), S(O)2, NR L3 , S(O)2NR L3 , S(O)NR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 S(O)2NR L4 , C(O), 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 L4monocycloalkylene, monoheterocyclylene, bridged cyclylene, and spiro cyclylene, wherein the monocycloalkylene and monoheterocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; preferably, B L is independently selected at each occurrence from: CR L1 R L2 , O, S, SO, SO2, NR L3 , CO, C≡C, 3-8 membered monocycloalkylene, 3-8 membered monoheterocyclylene containing 1-3 heteroatoms independently selected from N, O, and S, 5-15 membered bridged cyclylene containing 0-5 heteroatoms independently selected from N, O, and S, and 5-15 membered spiro cyclylene containing 0-5 heteroatoms independently selected from N, O, and S, wherein the 3-8 membered monocycloalkylene, 3-8 membered monoheterocyclylene, 5-15 membered bridged cyclylene, and 5-15 membered spiro cyclylene are optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups;

[0285] R L1 , R L2 , R L3 , and R L4 is independently selected at each occurrence from H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 3-11 heterocyclyl, O-C 3-8 cycloalkyl, O-C 3-11 heterocyclyl, CO-C 3-8 cycloalkyl, CO-C 3-11 heterocyclyl, S-C 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 heterocyclyl, N(C 3-8 heterocyclyl)2, N(C 3-8 heterocyclyl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), P(O)(O-C1-8 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, SO x NH-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 groups, 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), NHSO2N(C 1-8 Alkyl)2, and NHSO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl and C 3-11 Each heterocyclic group is independently replaced by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl and alkylamino;

[0286] 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; and

[0287] A L2 is independently selected from the group consisting of H, a deuterium atom, a halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, and C4-C 10 heterocyclyl, wherein said C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, and C4-C 10 heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of 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, and C4-C 10 heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of 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, and C4-C

[0288] and when -(B L ) q -A L2 is a carbon chain structure without a cyclic structure, q is an integer of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0289] and when -(B L ) q -A L2 contains a monocyclic structure, and the number of cyclic structures contained is 1, the monocyclic structure is C3-C8 heterocycloalkyl containing 1-3 N atoms;

[0290] and when -(B L ) q -A L2 is not H, -CH3, and -C(O)-CH3.

[0291] In some embodiments, W 1 and W 2 are each independently CR a R b , and at least one of W 1 and W 2 is C(=O); and / or

[0292] W 5 and W 6 are each independently C(R m )2; and / or

[0293] R 1D and R 1E each occurrence is independently selected from C(R m )2, NR m , O, and CO; and / or

[0294] R F and R G each occurrence is independently selected from C(R m )2; and / or

[0295] R T is N; and / or

[0296] Z is CH or N; and / or

[0297] R8, R9, R 32 , R 42 , R 62 , R a , R b , and R m each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl; and / or

[0298] m7, m11, and m12 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6; preferably m7, m11, and m12 each occurrence is independently an integer of 0, 1, 2, or 3, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1; and / or

[0299] m3 and m4 each occurrence is independently an integer of 0, 1, 2, 3, or 4; m3 and m4 are not simultaneously 0; and m3+m4=4, m3+m4=3, or m3+m4=2.

[0300] In some embodiments, the CLM is selected from:

[0301] In some embodiments, B L is selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-, -C≡C-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, -N(CH3)-, -N(CH2CH3)-,

[0302] is a point of attachment.

[0303] In some embodiments, -(B L ) q - is selected from the group consisting of:

[0304] 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 -,

[0305] wherein each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0306] k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0307] is a point of attachment to CLM or PTM;

[0308] In some embodiments, -(B L ) q- is selected from a covalent bond, -(CH2)2-OCH2CH2-, -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, -(CH2)2-(OCH2CH2)4, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-(CH2)9-, -NH-(CH2) 10 - -(CH2)2-, -NH-(CH2) 11 - -(CH2)2-, -NH-(CH2) 12 - -(CH2)2-, -NH-(CH2) 13 - -(CH2)2-, -NH-(CH2) 14 - -(CH2)2-, -NH-(CH2) 15-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH-C(O)-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-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-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)3-NH-, -NH-CH2-CH2-O-CH2-CH2-C(O)-, -C(O)-CH2-CH2-O-CH2-CH2-NH-, -NH-(CH2)4-C(O)-, -NH-(CH2)5-C(O)-, -NH-(CH2)6-C(O)-, -C(O)-(CH2)4-NH-, -C(O)-(CH2)5-NH-, -C(O)-(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-C(O)-, -CH2-CH2-O-(CH2)3-C(O)-, -CH2-CH2-O-(CH2)4-C(O)-, -C(O)-(CH2)2-O-CH2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-,-CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O-)(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-,

[0309] -CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O-)(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-, L ) q -CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O-)(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 -NH-(CH2)2-OCH2CH2-, -NH-(CH2)2-(OCH2CH2)2-, -NH-(CH2)2-(OCH2CH2)4-, -NH-(CH2)4-C(O)-NH-(CH2)7-, -NH-(CH2)3-C(O)-NH-(CH2)3-, -NH-(CH2)2-C(O)-NH-CH2-,

[0310] In some embodiments, the PTM is selected from the following structural formula:

[0311] R1, and R2are each independently selected from N and CR m ,

[0312] R3is selected from H, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, and C1-C6alkoxy are optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium atom, halogen, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, and C1-C6alkylaminoacyl; preferably, R3is

[0313] R4is each occurrence independently selected from N or CRm4;

[0314] R5is each occurrence independently selected from N or CRm5;

[0315] R6is each occurrence independently selected from N or CRm6;

[0316] R7is each occurrence independently selected from N or CRm7;

[0317] R m8 is selected from -N(R a )2and -OR a ;

[0318] Rm9 selected from -C(R a )3, -N(R a )2, -OR a , and R a ; or

[0319] R m8 and R1or R m9 form a ring structure; when R1and R m8 form a ring structure with the atoms to which they are attached, R1is C, R1and R m8 form a saturated or unsaturated 4-10 membered cycloalkyl or 4-10 membered heterocycle containing 1-3 heteroatoms each independently selected from N, O, and S, which is unsubstituted or substituted with one or more substituents optionally selected from F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, cyano, amino, nitro, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl; preferably, R1and R 10 form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl containing 1, or 2 N heteroatoms, which is unsubstituted or substituted with one or more substituents optionally selected from H, deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; or m8 form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl containing 1, or 2 N heteroatoms, which is unsubstituted or substituted with one or more substituents optionally selected from H, deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; or m8 form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclyl containing 1, or 2 N heteroatoms, which is unsubstituted or substituted with one or more substituents optionally selected from H, deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, nitro, cyano, and amino; or

[0320] R m8 and R m9the carbon atom to which they are attached is substituted with one or more substituents each independently selected from the group consisting of oxo, F, CI, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, amino, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, 5-10 membered heteroaryl, haloalkyl, haloalkoxy, hydroxyalkyl, cyanoalkyl, and oxo; preferably, R 10 one or more substituents on the aryl and 5-10 membered heteroaryl are independently selected from the group consisting of oxo, F, CI, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, amino, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, 5-10 membered heteroaryl, haloalkyl, haloalkoxy, hydroxyalkyl, cyanoalkyl, and oxo; preferably, R m8 and R m9 the carbon atom to which they are attached is substituted with one or more substituents each independently selected from the group consisting of oxo, F, CI, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, amino, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, 5-10 membered heteroaryl, haloalkyl, haloalkoxy, hydroxyalkyl, cyanoalkyl, and oxo; preferably, R m8 and R m9 the carbon atom to which they are attached is substituted with one or more substituents each independently selected from the group consisting of oxo, F, CI, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, nitro, cyano, amino, C3-C8cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, 5-10 membered heteroaryl, haloalkyl, haloalkoxy, hydroxyalkyl, cyanoalkyl, and oxo; preferably, R

[0321] Q is, at each occurrence, independently selected from CR 11 and N;

[0322] Q 1 is, at each occurrence, O, S, or NR 11 ;

[0323] R a , R m , R m1 , R m2 , R m3 , R m4 , R m5 , R m6 , R m7 , R 10 , R 11 , R p1 , R p2 and R p3each occurrence is independently selected from H, carboxyl, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyl- oxyacyl, C1-C6 alkylaminoacyl; preferably, R a , R m , R m1 , R m2 , R m3 , R m4 , R m5 , R m6 , R m7 , R 10 , R 11 , R p1 , R p2 and R p3 each occurrence is independently selected from H, 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; and

[0324] m13, m14, m15 are each independently selected from 0, 1, 2, 3, 4, 5. In some embodiments, the PTM is selected from:

[0325] In some embodiments, the compound has a structure selected from:

[0326] Preferably, the compound is selected from:

[0327] In yet another aspect of the present disclosure, there is provided a method of treating a disease or condition in a subject in need thereof, or treating or preventing a disease or condition mediated by estrogen receptor protein and IKZF2 in a subject in need thereof, by simultaneously degrading estrogen receptor protein and IKZF2 protein, comprising administering to the subject a compound of Formula IV as previously described.

[0328] In yet another aspect of the present disclosure, there is provided a compound of Formula IV for use in treating or preventing a disease or condition in a subject in need thereof, or treating or preventing a disease or condition mediated by estrogen receptor protein and IKZF2 in a subject in need thereof, by simultaneously degrading estrogen receptor protein and IKZF2 protein.

[0329] In some embodiments, wherein the disorder is a tumor or cancer, preferably the tumor or cancer is breast cancer, breast ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myelogenous leukemia, acute myelogenous leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, or cervical cancer. DETAILED DESCRIPTION

[0330] Definitions and Detailed Descriptions

[0331] In the present application, unless otherwise indicated, the scientific and technical terms used herein have the meanings that would be commonly understood by a person of ordinary skill in the art. Also, the relevant terms and laboratory procedures used herein are those that are generally used in the corresponding field. Also, in order to better understand the present application, the definitions and explanations of the relevant terms are provided below.

[0332] In the description herein, the description of "some embodiments", "some implementations" or "some implementations" describes a subset of all possible embodiments, but it can be understood that "some embodiments" can be the same subset or different subsets of all possible embodiments, and can be combined with each other without conflict.

[0333] As used herein and unless otherwise indicated, the terms "comprising", "including", "having", "containing", including grammatical equivalents thereof, are generally understood either open-ended or non-limiting, for example, not excluding additional unlisted elements or steps.

[0334] In the specification and claims reported herein, the phrase "and / or" is interpreted to mean "either of the elements or both of the elements", that is, the elements can exist jointly in some cases or the elements can exist separately in other cases.

[0335] When a numerical range is listed, each value and sub-range within the range is intended to be included. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0336] The term "alkyl" as contemplated herein refers to saturated aliphatic hydrocarbon groups which are straight chain or branched chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently optionally selected from one or more of H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0337] The term "heteroalkyl" refers to one or more -CH2- groups replaced by heteroatoms selected from N, O, and S, or one or more -CH- groups replaced by N atoms; wherein the alkyl groups are as defined above; the heteroalkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, and the substituents are preferably independently optionally selected from one or more of H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups.

[0338] The term "cycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon substituents, which can be monocycloalkyl, bicycloalkyl, bridged cycloalkyl, or spirocycloalkyl, etc.; the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably comprises 3 to 12 carbon atoms, more preferably comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably comprises 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. The cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, and the substituents are preferably independently optionally selected from one or more of H atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups.

[0339] "Spirocycloalkyl" refers to polycyclic cyclic hydrocarbon groups formed between two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom). Spirocycloalkyl groups are classified as mono-, bi-, and polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings. Preferred are 6- to 14-membered (C 6-14 ) spirocycloalkyl groups, more preferred are 7- to 11-membered (C 7-11 ) spirocycloalkyl groups. Specific examples of spirocycloalkyl groups include, but are not limited to:

[0340] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. The alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from one or more of H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups.

[0341] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent group is preferably one or more groups independently selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0342] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent group is preferably one or more groups independently selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0343] The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent, which can be a monocyclic heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spirocyclic heterocyclyl, and the like; which contains 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m(where m is an integer from 0 to 2), with the remainder of the ring atoms being carbon, but the ring moiety does not include -O-O-, -O-S-, or -S-S-. The heterocyclyl group preferably 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 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and further preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0344] The term "spirocyclic heterocyclyl" refers to a polycyclic heterocyclyl group formed by sharing one carbon atom (referred to as a spiro atom) between two or more saturated or partially unsaturated monocyclic rings, of which one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) mheteroatoms, the remaining ring atoms being carbon. When the heteroatom is a nitrogen atom, the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, R being hydrogen or another substituent as herein defined). Each monocyclic ring can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Spiroheterocyclyl groups are classified as mono-, bi- or polyspiroheterocyclyl groups, depending on the number of rings which share a spiro atom. Preferred are "5 to 20 membered spiroheterocyclyl groups" having 5 to 20 ring atoms, one of the monocyclic rings being a 3 to 8 membered monocyclic heterocyclyl ring, the other monocyclic ring being a 3 to 8 membered monocyclic heterocyclyl ring or a 3 to 8 membered monocyclic cycloalkyl ring. Specific examples of spiroheterocyclyl groups include, but are not limited to:

[0345] These spiroheterocyclyl groups can be attached to the remainder of the molecule through any one of the suitable ring atoms, preferably the N atom.

[0346] Heterocyclyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently and optionally selected from one or more of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group.

[0347] The term "aryl" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic rings share pairs of adjacent carbon atoms) group with a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Aryl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently and optionally selected from one or more of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group.

[0348] The term "heteroaryl" means a heteroaromatic system comprising 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. Heteroaryl groups are preferably 5- to 10-membered (e.g. 5-, 6-, 7-, 8-, 9- or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. Heteroaryl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently and optionally selected from one or more of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group.

[0349] The term "haloalkyl" means an alkyl group, as defined above, substituted with one or more halogens.

[0350] The term "hydroxyalkyl" means an alkyl group, as defined above, substituted with one or more hydroxyl groups.

[0351] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0352] The term "amino" means -NH2.

[0353] The term "cyano" means -CN.

[0354] The term "nitro" means -NO2.

[0355] The term "leaving group" means an atom or a group (which can or can not be charged) that departs from an atom or molecule that is considered to be the residual or major portion of a molecule involved in a particular reaction, such as a nucleophilic substitution reaction. Representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

[0356] The term "ubiquitin ligase" means a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes ubiquitin to be attached to a lysine on a target protein and subsequently targets the specific protein substrate for degradation by a proteasome. Thus, the E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, is the cause of the transfer of ubiquitin to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, so that a second ubiquitin is attached to the first, a third ubiquitin is attached to the second, and so on. Polyubiquitination marks the protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but can instead be altered in their cellular location or function, for example, via binding to other proteins that have domains capable of binding ubiquitin. To make things more complicated, different lysines on ubiquitin can be targeted by E3s to make chains. The most common lysine is Lys48 on ubiquitin chains. This is the lysine that is used to make polyubiquitin, which is recognized by the proteasome.

[0357] The term "target protein" refers to proteins and peptides having 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 a cell's integrated function, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme modulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, biological process regulation, development, cell differentiation, response to stimulus, behavioral protein, cell adhesion protein, 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 structure and biological origin activity, translation regulator activity. The proteins include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, and numerous others, including humans, microorganisms, viruses, fungi, and parasites as targets for drug therapy, other animals including domesticated animals, microorganisms and other antimicrobial agents for which targets are used to determine antibiotics, plants, even viruses, and numerous others.

[0358] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group can or can not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0359] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of one another replaced with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, which can or cannot be possible, can be determined by a person skilled in the art without undue effort (experimentally or theoretically).

[0360] The term "one or more" means 1 or more than 1, for example 2, 3, 4, or 5, under reasonable conditions.

[0361] Unless otherwise indicated, the use of indicates the absolute configuration of a stereogenic center. The use of or denotes the relative configuration of a stereocenter; a bond including the possibility of configurations, as chemically allowed. in which refers to a chemical bond junction.

[0362] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is safe and effective for use in mammals, and possesses the desirable biological activity.

[0363] Specific embodiments

[0364] The following examples are directed to the intermediate compounds and final products identified in the specification and synthetic schemes. The following examples are used to describe the preparation of the compounds of the present application in detail, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of compounds falling within the scope of the present application as described. At times, the reactions may not be applicable to every compound within the scope of the present application as described. A person skilled in the art will readily identify compounds to which this occurs. In these instances, the reactions described can be successfully performed by conventional modifications known to those skilled in the art.

[0365] The starting materials, chemical reagents, and solvents used in the present application are commercially available, purchased from AnguChem, Shanghai Bide Pharmaceutical, Beijing Ino Kai, Jiangsu Aikang, China National Pharmaceutical Group, Beijing Bailingwei, Yunnan New Blue Sky, etc.

[0366] The compounds synthesized in the present application are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS) for their structures.

[0367] The determination of nuclear magnetic resonance (NMR) is carried out by Bruke AVANCE-400 / 600 nuclear magnetic instrument, and the deuterated solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0368] The determination of mass spectrometry (MS) is carried out by Waters Acquity Plus device.

[0369] High performance liquid preparation is carried out by Waters 2489 device.

[0370] Medium pressure flash preparative chromatograph is COMBIFLASH NEXTGEN 300+.

[0371] Thin layer chromatography silica gel plate uses Silica gel 60 thin layer chromatography silica gel plate (aluminum plate, containing fluorescence).

[0372] Silica gel thin layer chromatography used silica gel (100-200 mesh, 200-300 mesh) purchased from E. Merck.

[0373] Reaction progress detection in the examples used thin layer chromatography (TLC), the system of developing agent used to monitor the reaction and eluent used to purify the compounds using column chromatography included: petroleum ether / ethyl acetate system, dichloromethane / methanol system.

[0374] PROTAC synthesis general formula ER-T-1

[0375] Wherein: R1 is selected from F or H, etc., R2 is selected from Cl or H or F or methoxy, etc., X is selected from N or C or C-F, etc.

[0376] The preparation process of an exemplary compound ER-P-1 is as follows:

[0377] First step: compound ER-P-1-3

[0378] Compound ER-P-1-1 (12.0 g, 60.90 mmol, 1.0 eq) was dissolved in tetrahydrofuran (120 mL), n-BuMgCl (57 mL, 91.35 mmol, 1.5 eq) and n-BuLi (73 ml, 182.70 mmol, 3.0 eq) were added to the reaction system at 0°C, and the reaction was carried out at this temperature for 2 hours. ER-P-1-2 (20 g, 85.26 mmol, 1.4 eq) was added to the reaction system, and the reaction was carried out for 2 hours. The reaction system was quenched with saturated aqueous ammonium chloride solution, the pH was adjusted to 5-6 with 2M hydrochloric acid, and ethyl acetate was extracted, concentrated under reduced pressure, and the obtained crude product was concentrated by beating (petroleum ether: ethyl acetate = 5:1) to obtain yellow solid compound ER-P-1-3 (8.9 g, 53.1%).

[0379] 1 H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 4.54 (s, 1H), 4.02 (s, 1H), 2.99 (s, 1H), 2.82-2.78 (m, 1H), 1.43 (s, 9H), 1.14 (d, J = 6.6 Hz, 3H).

[0380] LC-MS (ESI): [M+H] + = 276.47.

[0381] Second step: compound ER-P-1-5

[0382] Compound ER-P-1-3 (8.9 g, 32.32 mmol, 1.0 eq) was dissolved in dichloromethane (100 mL), and hydrochloric acid in dioxane (45 mL) was added after cooling to 0 °C. After the dropwise addition was completed, it was returned to room temperature and reacted for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product obtained by concentrating the organic phase was directly used in the next reaction. Compound crude product (7.5 g, 42.80 mmol, 1.0 eq), ER-P-1-4 (11 g, 51.36 mmol, 1.2 eq), and DIEA (35 mL, 171.2 mmol, 4 eq) were dissolved in dioxane (50 mL), and reacted at 80 °C under nitrogen protection for 2 hours. After the reaction system was cooled to room temperature, it was concentrated under reduced pressure, petroleum ether: ethyl acetate = 2:1 (75 mL) was added, and a yellow solid compound ER-P-1-5 (8.1 g, 79.1%) was obtained by filtration.

[0383] 1 H NMR (600 MHz, CDCl3) δ 10.81 (s, 1H), 8.07 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.99-5.67 (m, 1H), 3.12-2.93 (m, 3H), 2.93-2.85 (m, 1H), 2.85-2.66 (m, 1H), 1.14 (d, J = 16.8 Hz, 3H).

[0384] LC-MS (ESI): [M+H] + = 240.36.

[0385] Third step: synthesis of compound ER-P-1-7

[0386] Compound ER-P-1-5 (1 g, 4.18 mmol, 1.0 eq) was dissolved in toluene (10 mL), and trifluoroacetic acid (1.5 mL) and ER-P-1-6 (2.7 g, 12.54 mmol, 3.0 eq) were added dropwise to the system. It was reacted at 115 °C for 72 hours. Water was added to quench the reaction system, and it was extracted with ethyl acetate. It was washed with saturated brine, and the combined organic phase was dried with anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain a yellow oil compound ER-P-1-7 (105 mg, 5.7%).

[0387] 1H NMR(600MHz,Chloroform-d)δ7.92(s,1H),7.28(s,1H),7.19(s,1H),7.11–7.06(m,2H),5.66-5.46(m,1H),5.42(s ,1H),3.57–3.46(m,2H),3.11-3.05(m,1H),2.81(dd,J=15.2,3.8Hz,1H),2.78–2.69(m,1H),1.08(d,J=6.4Hz,3H).

[0388] LC-MS(ESI)[M+H] + =442.19.

[0389] Step 4: Synthesis of compound ER-P-1-8

[0390] Compound ER-P-1-7 (400 mg, 0.9 mmol, 1.0 eq) was dissolved in dioxane (10 mL), and 17 (350 mg, 1.36 mmol, 1.5 eq), Pd2(dba)3 (82 mg, 0.09 mmol, 0.1 eq), Ruphos (84 mg, 0.18 mmol, 0.2 eq), and sodium tert-butoxide (260 mg, 2.71 mmol, 3.0 eq) were added. The system was reacted at 110 °C for 2 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography to give a yellow oily compound ER-P-1-8 (200 mg, 35.7%).

[0391] 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),7.86(s,1H),7.25(s,1H),7.14(s,1H),6.54(d,J=13.0Hz, 2H),5.92–5.59(m,1H),5.21(s,1H),4.04(d,J=7.2Hz,1H),3.65(s,1H),3.55-3.50(m,3H),3.45 -3.41(m,1H),3.23(s,6H),3.09–2.89(m,3H),2.79(dd,J=16.0,4.7Hz,1H),2.72–2.56(m,1H),1 .84–1.67(m,4H),1.57-1.55(m,1H),1.49–1.30(m,8H),1.26-1.24(m,1H),0.99(d,J=6.5Hz,3H).

[0392] LC-MS(ESI)[M+H] + =619.48.

[0393] Fifth step: synthesis of compound ER-P-1

[0394] Compound ER-P-1-9 (800 mg, 1.29 mmol, 1.0 eq) was dissolved in formic acid (5 mL). The reaction was carried out at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the obtained crude product was directly used for the next step. The crude product (180 mg, 0.31 mmol, 1.0 eq) was dissolved in DMSO (2 mL), and compound 10 (see below for preparation, 74 mg, 0.19 mmol, 0.6 eq), sodium triacetoxyborohydride (133 mg, 0.63 mmol, 2.0 eq) were added to the system. The reaction was carried out at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and the obtained crude product was purified by reverse column chromatography, and then white solid compound ER-P-1 (32.3 mg, 10.8%) was obtained by Prep-HPLC.

[0395] 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 11.01 (s, 1H), 7.87 (s, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.56 (d, J = 13.1 Hz, 2H), 5.95 - 5.60 (m, 1H), 5.23 (s, 1H), 5.08 (dd, J = 13.2, 4.9 Hz, 1H), 4.71 - 4.62 (m, 2H), 4.37 (d, J = 17.6 Hz, 1H), 4.28 - 4.15 (m, 1H), 3.77 - 3.67 (m, 3H), 3.46 - 3.42 (m, 2H), 3.38 - 3.21 (m, 3H), 3.11 - 2.96 (m, 6H), 2.94 - 2.86 (m, 1H), 2.80 (dd, J = 15.9, 4.6 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.46 - 2.31 (m, 2H), 2.21 (t, J = 13.7 Hz, 2H), 2.04 - 1.94 (m, 3H), 1.90 - 1.80 (m, 3H), 1.78 - 1.69 (m, 2H), 1.56 - 1.43 (m, 6H), 1.38 (t, J = 11.2 Hz, 2H), 1.00 (d, J = 6.4 Hz, 3H).

[0396] LC-MS (ESI): [M+H] + = 946.60.

[0397] Synthetic route of exemplary CRBN fragment

[0398] Step 1: Synthesis of compound 2

[0399] Compound 1 (110 g, 206.87 mmol, 1.0 eq) was dissolved in methanol (500 mL), sulfuric acid (55 mL) was added to the reaction system at 0 °C. The reaction was carried out at 65 °C for 3 hours. Concentration under reduced pressure, the concentrated crude was washed with water after filtration to obtain white solid compound 2 (95 g, 81.12%).

[0400] 1 H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 8.3, 2.0 Hz, 1H), 3.84 (s, 3H).

[0401] LCMS (ESI): [M+H] + = 228.89.

[0402] Step 2: Synthesis of compound 3

[0403] Compound 2 (60 g, 259.69 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (500 mL), urotropine (121.35 g, 865.63 mmol, 4.0 eq) was added. After the addition was completed, it was raised to 125 °C and reacted for 16 hours. The reaction system was cooled to room temperature, quenched with 2M hydrochloric acid, and filtered to obtain yellow solid compound 3 (27 g, 40.13%).

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 3.88 (s, 3H).

[0405] LC-MS (ESI): [M+H] + = 257.07.

[0406] Step 3: Synthesis of compound 5

[0407] Compound 3 (25 g, 96.50 mmol, 1.0 eq), compound 4 (24.19 g, 101.33 mmol, 1.05 eq), sodium cyanoborohydride (12.13 g, 193.01 mmol, 2.0 eq), acetic acid (8.3 mL, 144.76 mmol, 1.5 eq) and DIEA (17.7 mL, 101.33 mmol, 1.05 eq) were dissolved in methanol (450 mL) at -20 °C and the reaction was carried out at 20 °C for 3 h under nitrogen protection. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate. The crude product obtained after concentration of the organic phase was purified by column chromatography to obtain compound 5 (30 g, 75.22%) as a yellow oil.

[0408] 1 H NMR (600 MHz, Chloroform-d) δ 7.61 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 5.46 (s, 1H), 4.92 (dd, J = 8.9, 6.3 Hz, 1H), 4.59 (d, J = 17.6 Hz, 1H), 4.48 (d, J = 17.6 Hz, 1H), 2.45 - 2.24 (m, 3H), 2.22 - 2.14 (m, 1H), 1.45 (s, 9H).

[0409] LC-MS (ESI): [M+H-Boc] + = 312.08.

[0410] Fourth step: synthesis of compound 7

[0411] Compound 5 (15 g, 44.23 mmol, 1.0 eq) and compound 6 (10.38 g, 48.65 mmol, 1.1 eq) were dissolved in tetrahydrofuran (150 mL), and triphenylphosphine (23.0 g, 88.46 mmol, 2.00 eq) and diethyl azodicarboxylate (15.41 g, 88.46 mmol, 2.0 eq) were added to the system at 0 °C. The system was allowed to warm to room temperature and the reaction was carried out for 8 h. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate. The crude product obtained after concentration of the organic phase was purified by column chromatography to obtain compound 7 (20 g, 54.62%) as a yellow oil.

[0412] 1H NMR (600 MHz, Chloroform-d) δ 7.71 - 7.67 (m, 1H), 7.45 (dd, J = 8.0, 1.1 Hz, 1H), 6.42 - 6.38 (m, 1H), 5.87 (s, 1H), 5.55 (s, 1H), 4.92 (dd, J = 8.6, 6.3 Hz, 1H), 4.65 (d, J = 17.3 Hz, 1H), 4.56 - 4.49 (m, 3H), 3.99 (s, 2H), 3.61 (s, 2H), 2.42 - 2.25 (m, 5H), 2.17 (dt, J = 12.5, 8.1 Hz, 1H), 1.50 (d, J = 1.1 Hz, 9H), 1.43 (d, J = 1.1 Hz, 9H).

[0413] LC-MS (ESI) [M+H-Boc] + = 508.29.

[0414] Fifth step: synthesis of compound 8

[0415] Compound compound 7 (30 g, 72.41 mmol, 1.0 eq) was dissolved in toluene (120 mL), to which azobisisobutyronitrile (3.57 g, 21.72 mmol, 0.3 eq), tributyltin (105.38 g, 362.06 mmol, 5.0 eq) was added and the system was reacted at 110 °C for 16 hours. After the reaction system was cooled to room temperature, the reaction system was quenched with saturated aqueous cesium fluoride solution and extracted with ethyl acetate. Saturated brine was washed, and the combined organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product obtained was purified by column chromatography to obtain white solid compound 8 (16 g, 70.05%).

[0416] 1 H NMR (600 MHz, Chloroform-d) δ 7.45 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.29 (s, 1H), 5.32 (s, 1H), 4.90 (dd, J = 9.0, 6.4 Hz, 1H), 4.55 (s, 2H), 4.49 (d, J = 17.0 Hz, 1H), 4.41 (d, J = 17.1 Hz, 1H), 2.90 (s, 2H), 2.45 - 2.13 (m, 6H), 1.90 (s, 2H), 1.76 (d, J = 13.5 Hz, 2H), 1.51 (s, 9H), 1.44 (s, 9H).

[0417] LC-MS (ESI) [M+H-tBu] + = 474.39.

[0418] Sixth step: synthesis of compound 9

[0419] Compound 8 (10 g, 18.88 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL), dichloro hydrazine (1.86 g, 9.44 mmol, 0.5 eq) was added at 0 °C. The reaction was carried out at room temperature for 12 h. The organic phase was concentrated and the crude product was purified by column chromatography to obtain compound 9 (24.4 g, 57.28%) as a white solid.

[0420] 1 H NMR (600 MHz, DMSO-d6) δ 7.45 (s, 1H), 4.70 - 4.66 (m, 1H), 4.62 (t, J = 6.4 Hz, 2H), 4.46 - 4.32 (m, 2H), 3.99 - 3.87 (m, 2H), 3.17 (d, J = 3.6 Hz, 1H), 2.85 (s, 2H), 2.20 - 2.12 (m, 4H), 1.82 (td, J = 12.9, 4.5 Hz, 2H), 1.71 - 1.63 (m, 2H), 1.42 (s, 6H), 1.32 (s, 6H), 1.24 (s, 9H).

[0421] LC-MS (ESI) [M+H] + = 564.45.

[0422] Seventh step: synthesis of compound 6

[0423] Compound 11 (52 g, 243.81 mmol, 1.0 eq) was dissolved in toluene (500 mL), aluminum isopropoxide (64.74 mg, 316.96 mmol, 1.3 eq) was added to the system. The reaction was carried out at 110 °C for 16 h. After the reaction system was cooled to room temperature, the reaction system was quenched with water and extracted with ethyl acetate. Saturated brine was washed, and the combined organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by column chromatography to obtain compound 6 (26.5 g, 50.96%) as a yellow oil.

[0424] 1 H NMR (600 MHz, CDCl3) δ 5.67 (s, 1H), 4.07 (s, 2H), 3.98 - 3.92 (m, 2H), 3.54 (dd, J = 8.2, 4.0 Hz, 2H), 2.15 (d, J = 6.8 Hz, 2H), 1.49 (s, 9H).

[0425] LC-MS (ESI): [M-tBu+H] + = 158.20

[0426] Eighth step: synthesis of compound 10

[0427] Compound benzenesulfonic acid (5.05 g, 31.91 mmol, 2.0 eq) was dissolved in acetonitrile (90 mL) and heated to 100 °C, and compound 9 (9 g, 15.96 mmol, 1.0 eq) was added to the system. The reaction was carried out at 80 °C for 12 h. After the reaction system was cooled to room temperature, filtration was performed to obtain white solid compound 10 (7.3 g, 83.49%).

[0428] 1 H NMR (600 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.55 (s, 1H), 5.07 (d, J = 13.3, 5.1 Hz, 1H), 4.74 - 4.58 (m, 2H), 4.37 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.5 Hz, 1H), 3.36 (d, J = 13.0 Hz, 2H), 3.03 (q, J = 12.3 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.60 (d, J = 15.7, 3.1 Hz, 1H), 2.41 (d, J = 13.3, 4.5 Hz, 1H), 2.07 (s, 3H), 2.03 - 1.86 (m, 3H).

[0429] LC-MS (ESI) [M+H] + = 390.39.

[0430] Synthetic route of exemplary Linker

[0431] First step: synthesis of compound 12

[0432] Compound 11 (50 g), imidazole (51.6 g) were dissolved in DMF (500 ml) at room temperature, the system was cooled to 0 °C, and then trimethylchlorosilane (41.2 g) was added dropwise to the system. After the dropwise addition was completed, the system was warmed to room temperature and stirred overnight. After the reaction was completed, it was dissolved in ethyl acetate, washed with water three times, the aqueous phase was extracted with ethyl acetate three times, the ethyl acetate was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography with a mobile phase of EA / PA = 20% to obtain compound 12 (59 g, 97%) as a colorless oil.

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 3.85 (p, J = 4.2 Hz, 1H), 3.58 (s, 3H), 2.42 - 2.29 (m, 1H), 1.87 - 1.73 (m, 2H), 1.60 - 1.45 (m, 6H).

[0434] Second step: synthesis of compound 13

[0435] Compound 12 (11 g), 1-Cbz-piperidin-4-one (9.9 g) was dissolved in super dry dichloromethane, and the air was replaced by nitrogen for 3 times. The system was cooled to -78 °C under nitrogen protection, and then trimethylsilyl trifluoromethanesulfonate (1.1 g) was slowly added dropwise. After the addition was completed, the reaction was stirred at -78 °C for 1 h. Then a solution of triethylsilane (5.8 g) in dichloromethane (10 ml) was slowly added dropwise. After the addition was completed, the system was moved to room temperature, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated, and the sample was stirred and purified by column chromatography with a mobile phase system of EA / PE = 30% to give compound 13 (13.7 g, 73%) as a yellow oil.

[0436] 1 H NMR (400 MHz, DMSO-d6) δ 7.40-7.25 (m, 5H), 5.07 (s, 2H), 3.75-3.65 (m, 2H), 3.61-3.47 (m, 5H), 3.13 (s, 2H), 2.42-2.32 (m, 2H), 1.83-1.28 (m, 12H).

[0437] LC-MS (ESI) [M+H] + = 376.40

[0438] Third step: synthesis of compound 14

[0439] Compound 13 (6.8 g) was dissolved in tetrahydrofuran (10 ml) at room temperature, and the air was replaced by nitrogen for 3 times. Lithium aluminum hydride (0.82 g) was slowly added under ice bath, and the reaction was carried out under ice bath for 3 h. The reaction was detected by TLC, and after the reaction was completed, water was added dropwise under ice bath for quenching, and then filtered. The filtrate was evaporated to dryness and the sample was stirred and purified by column chromatography with a mobile phase system of EA / PE = 47% to give compound 14 (4.5 g, 71%) as a colorless oil.

[0440] 1 H NMR (600 MHz, DMSO-d6) δ 7.41-7.30 (m, 5H), 5.07 (s, 2H), 4.36 (t, J = 5.3 Hz, 1H), 3.73-3.66 (m, 2H), 3.64-3.60 (m, 1H), 3.55-3.50 (m, 1H), 3.22 (t, J = 5.8 Hz, 2H), 3.18-3.06 (m, 2H), 1.77-1.71 (m, 2H), 1.70-1.63 (m, 2H), 1.47-1.20 (m, 9H).

[0441] LC-MS (ESI) [M+H] + = 348.35

[0442] Step 4: Synthesis of compound 15

[0443] Oxalyl chloride (3.3 g) was dissolved in dichloromethane (300 ml), and the system was purged with nitrogen three times, then cooled to -80 °C, and then a solution of DMSO (2.7 g) in dichloromethane (10 ml) was slowly added dropwise. After the dropwise addition was completed, the system was stirred at this temperature for 15 min, and then a solution of compound 14 (6 g) in dichloromethane (10 ml) was slowly added dropwise, and the reaction was stirred at -80 °C for 20 min. Then a solution of triethylamine (7.0 g) in dichloromethane (5 ml) was slowly added dropwise, and after the dropwise addition was completed, the system was slowly warmed to room temperature, and the reaction was stirred at room temperature for 20 min. Then water (5 ml) was added dropwise to quench the system. The reaction system was washed with water three times, and the dichloromethane solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography with a mobile phase system of EA / PE = 30% to give compound 15 (4 g, 67%) as an anhydrous oil.

[0444] 1 H NMR (600 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.40-7.30 (m, 5H), 5.06 (s, 2H), 3.73-3.63 (m, 2H), 3.59-3.51 (m, 2H), 3.20-3.05 (m, 2H), 2.37-2.31 (m, 1H), 1.77-1.67 (m, 4H), 1.62-1.53 (m, 4H), 1.53-1.45 (m, 2H), 1.36-1.28 (m, 2H).

[0445] LC-MS (ESI) [M+H] + = 346.39

[0446] Step 5: Synthesis of compound 16

[0447] Compound 15 (1.6 g) was dissolved in methanol (7 ml) at room temperature, and then p-toluenesulfonic acid (80 mg) and trimethyl orthoformate (4.9 g) were added at once. The system was warmed to 35 °C and stirred for 3 h. After the reaction was completed as detected by TLC, the system was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution until pH = 8, and then dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by column chromatography with a mobile phase system of EA / PE = 10% to give compound 16 (1.4 g, 78%) as a colorless oil.

[0448] 1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.27 (m, 5H), 5.07 (s, 2H), 4.04 (d, J = 7.2 Hz, 1H), 3.73 - 3.66 (m, 2H), 3.65 - 3.61 (m, 1H), 3.55 - 3.49 (m, 1H), 3.23 (s, 6H), 3.19 - 3.05 (m, 2H), 1.78 - 1.67 (m, 4H), 1.61-1.53 (m, 1H), 1.45 - 1.27 (m, 8H).

[0449] LC-MS (ESI) [M+H] + = no correct mass signal

[0450] Step 6: Synthesis of compound 17

[0451] Compound 16 (1.1 g) was dissolved in methanol (6 ml) at room temperature, and palladium on carbon (220 mg, 55% in water) was added. The system was purged with hydrogen gas for 3 times, and the reaction was carried out under hydrogen atmosphere for 12 hours. After TLC detection showed that the reaction was completed, the palladium on carbon was filtered, and the filtrate was concentrated to give compound 17 (0.7 g, 96%) as a colorless oil.

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 4.03 (d, J = 7.2 Hz, 1H), 3.64 - 3.54 (m, 1H), 3.45 - 3.28 (m, 2H), 3.23 (s, 6H), 2.98 - 2.83 (m, 2H), 2.56 - 2.41 (m, 2H), 1.80 - 1.62 (m, 4H), 1.61 - 1.49 (m, 1H), 1.48 - 1.18 (m, 8H).

[0453] LC-MS (ESI) [M+H] + = 258.47

[0454] Table A:

[0455] Test Example 1 Inhibitory effect on cell proliferation in T-47D cells

[0456] T-47D (ATCC) cells were cultured in PRMI-1640 medium (30-2001, ATCC) containing 10% FBS (10099141C, Gibco), 0.0069 mg / mL insulin at 37℃, 5% CO2 until they entered the logarithmic growth phase. T-47D cells were seeded in 96-well plates at a density of 3,000 cells per well, and at the same time, 10.00, 1.00, 0.10, 0.01, 0.001, 0.0001, 0.00001, 0.000001, 0.0000001 μM of the PROTAC compounds 1-11 provided in the embodiments of the present application and the positive control ARV-471 (source: Innoke) were prepared to treat the cells, and the cells were incubated in a 37℃, 5% CO2 cell incubator for 6 days. According to the manufacturer's instructions, the CCK-8 kit (Beyotime, Product number: C0040) was used to detect cell viability. According to the inhibition rate, the IC 50 values of each compound after 6 days of action were calculated using GraphPad Prism software, and the results are shown in Table 1.

[0457] Table 1 Inhibition IC 50 values of the PROTAC compounds provided by the present application and the positive control on T-47D cell proliferation

[0458] Conclusion: The PROTAC compounds provided by the present application can effectively inhibit the proliferation of T-47D cells, and the inhibition activity IC 50 values of the PROTAC compounds provided by the present application are lower than 50 nM, and further lower than 10 nM.

[0459] Test Example 2 Inhibition of cell proliferation in MCF-7 cells

[0460] The complete culture medium required for MCF-7 cells (source: ATCC) is DMEM (gibco, Product number: 11995-065) basic culture medium containing 10% fetal bovine serum. MCF-7 cells were seeded in 96-well plates at a density of 800 cells per well, and at the same time, 100.00, 20.00, 4.00, 0.80, 0.16, 0.032, 0.0064, 0.0013, 0.00027 μM of the PROTAC compounds 1-11 provided in the embodiments of the present application and the positive control ARV-471 (source: Innoke) were prepared to treat the cells, and the cells were incubated in a 37℃, 5% CO2 cell incubator for 9 days. According to the manufacturer's instructions, the CCK-8 kit (Beyotime, Product number: C0040) was used to detect cell viability. According to the inhibition rate, the IC 50 values of each PROTAC compound after 9 days of action were calculated using GraphPad Prism software, and the results are shown in Table 2.

[0461] Table 2 Inhibition IC of MCF-7 cell proliferation by the PROTAC compound provided by the application and positive control 50 value

[0462] Conclusion: The PROTAC compound provided by the application can effectively inhibit the proliferation of MCF-7 cells, and the inhibition activity IC 50 value is lower than 50nM, and further lower than 10nM.

[0463] Test Example 3 Degradation of ERa in MCF-7 cells

[0464] MCF-7 (ATCC) cells were cultured in DMEM medium (11995-065, Gibco) containing 10% FBS (10099141C, Gibco) at 37°C, 5% CO2 until they entered the logarithmic growth phase. MCF-7 cells were seeded in a 6-well plate at a density of 3x10 5 After the cells adhered, 1μL of compound dimethyl sulfoxide solution (final concentration 0.15-1000nM) was added and incubated in a 37°C, 5% CO2 incubator for 4h. After 4h, the culture medium was discarded, each well was washed once with 1mL of pre-cooled 1x DPBS, and the cells were lysed with 50μL of RIPA lysis buffer (P0013B, Biyun Tian) and 1x protease inhibitor cocktail (P1005, Biyun Tian). After standing on ice for 20min, centrifugation was performed at 14000g, 4°C for 30min, and the supernatant was carefully taken and subjected to immunoblotting to detect the protein level of ERa.

[0465] Western blotting: The total protein concentration in the collected cell lysate supernatant was determined by BCA Protein Concentration Determination Kit (enhanced) (P0009, Biyun Tian). According to the total protein concentration determined by BCA, the total protein concentration was adjusted to 1 μg / μL with RIPA lysis buffer and 5×SDS-PAGE protein loading buffer (MB01015, Jin Sui), denatured at 95°C for 5 min, and after denaturation, the condensed water on the wall of the centrifugal tube was enriched by centrifugation as the loading sample. 20 μL of the loading sample (20 μg of total protein) was added to the sample well of the 12% precast gel (M00669, Jin Sui), and electrophoresis was performed at 100 V for 20 min and then at 150 V for 40 min. After electrophoresis, the proteins in the SDS-PAGE gel were transferred to a PVDF membrane at a constant voltage of 100 V for 60 min. After the transfer, the PVDF membrane corresponding to the ERa protein and the internal reference protein was cut and placed in 1×QμickBlock blocking solution (P0252, Biyun Tian) for 30 min at room temperature on a shaker. After blocking, ERa primary antibody (1:1000, 8644S, CST) was added and incubated overnight at 4°C on a shaker. After incubation, the PVDF membrane was washed three times with 1×TBST buffer for 5 min each time; Rabbit IgG (H+L) secondary antibody (1:7500, SA5-35571, Invitrogen) was added and incubated at room temperature for 1 h, and then washed three times with 1×TBST buffer for 5 min each time; finally, scanning and imaging were performed using a dual-color infrared laser imaging system (Odyssey DLx, LI-COR). The protein map was analyzed by Image Stμdio Lite analysis software for gray value analysis. The gray correction value of each sample was calculated using the formula: gray correction value = target protein gray value / corresponding internal reference gray value. The gray correction values of the compound group and DMSO were compared, and the degradation rate of the compound was calculated. Compound 10 was directly tested for DC 50 values.

[0466] Table 3 Degradation rate (%) of the PROTAC compounds provided by the application and the positive control sample on ERa in MCF-7 cells

[0467] Conclusion: The PROTAC compounds provided by the application have obvious degradation effect on ERa in MCF-7 cells.

[0468] Test Example 4 Degradation effect on ERa in T-47D cells

[0469] T-47D (ATCC) cells were cultured in PRMI-1640 medium (30-2001, ATCC) containing 10% FBS (10099141C, Gibco) at 37°C, 5% CO2 until they entered the logarithmic growth phase. The T-47D cells were diluted to 3x105 Cells were seeded at a density of 2x104 / well in 6-well plates and incubated at 37°C in 5% CO2 for 24 h. After the cells adhered, 1 μL of compound dimethyl sulfoxide solution (final concentration 0.15-1000 nM) was added and the cells were incubated at 37°C in 5% CO2 for 4 h. After 4 h, the culture medium was discarded, each well was washed once with 1 mL of pre-cooled 1x DPBS, and the cells were lysed with 50 μL of RIPA lysis buffer (P0013B, Biyun Tian) and 1x protease inhibitor cocktail (P1005, Biyun Tian). After incubation on ice for 20 min, the lysate was centrifuged at 14000 g at 4°C for 30 min, and the supernatant was carefully taken and subjected to immunoblotting to detect the protein level of ERa.

[0470] Table 4 Degradation rate (%) of the PROTAC compounds provided by the application and the positive control on ERa in T-47D cells

[0471] Conclusion: The PROTAC compounds provided by the application have obvious degradation effect on ERa in T-47D cells.

[0472] Test Example 5 Degradation of IKZF2 in T-47D cells by the PROTAC compounds of the application

[0473] T-47D (HTB-133, ATCC) cells were cultured in RPMI 1640 medium (30-2001, ATCC) containing 10% FBS (SH30406.05, Hyclone) at 37°C in 5% CO2 until they entered the logarithmic growth phase. 6-well cell culture plates were seeded with 2 mL of T-47D cells per well, and the cell density was 2x10 5 After 24 h of incubation at 37°C in 5% CO2 after the addition of 1 uL of compound dimethyl sulfoxide solution (final concentration 0.15-1000 nM), the culture medium was discarded, each well was washed twice with PBS, 40 μL of RIPA lysis buffer (P0013B, Biyun Tian) and 1x protease inhibitor cocktail (P1005, Biyun Tian) were added to resuspend and lyse the cells, and after incubation on ice for 15 min, the lysate was collected in a 1.5 mL centrifuge tube, centrifuged at 12000 rpm at 4°C for 30 min, and the supernatant was carefully taken and subjected to immunoblotting to detect the protein level of IKZF2.

[0474] Table 5 Degradation of IKZF2 in T-47D cells by the PROTAC compounds of the application and the positive control DC 50

[0475] Conclusion: The PROTAC compound of the application has obvious degradation effect on IKZF2 in T-47D cells.

[0476] Test Example 6, Pharmacokinetic (PK) properties

[0477] Mouse general PK test

[0478] Reagent: Acetonitrile (fischer A998-4). Instrument: Shimadzu LC40HPLC System for liquid phase, AB SCIEX X500B QTOF Platform for mass spectrometry. ICR: Female mice, 20-24 g, purchased from Vantian Li Hua.

[0479] The dosing regimen is shown in the following table.

[0480] The experimental procedure is as follows:

[0481] 1. After gavage administration without fasting of mice, blood was taken from the retro-orbital plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h (ER-P-1 / ER-P-2 / ER-P-7 to 48 h) and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h (ER-P-1 / ER-P-3 / ER-P-7 to 48 h) after intravenous administration, respectively. The whole blood was collected into an anticoagulant tube containing EDTA. The gavage and intravenous vehicle were DMSO:solutol:H2O = 1:1:8.

[0482] 2. The supernatant was obtained by centrifugation within 1 hour after whole blood collection, 4000 rpm, 10 min at 4°C. The supernatant plasma sample was stored in a -80°C freezer for standby.

[0483] 3. The sample plasma and blank plasma were taken out before analysis and thawed on ice or in a 4°C refrigerator.

[0484] 4. Preparation of standard curve samples: The test compound was diluted with DMSO to the required concentration, 5 μL of the compound solution was added to 45 μL of mouse blank plasma, 200 μL of internal standard acetonitrile (IS, 50 nM labetalol and 500 nM terfenadine) was added to precipitate the protein, 3200 rpm centrifugation for 40 min, and 8-10 concentration gradients were set for the standard curve.

[0485] 5. The quality control samples were prepared according to the preparation method of the standard curve, and the lower limit of quantification and high, low four quality control samples were set, and each concentration of quality control sample was in triplicate.

[0486] 6. 50 μL of sample plasma at different times was taken, and 200 μL of internal standard acetonitrile was added to precipitate the protein.

[0487] 7. After centrifugation of the calibration samples, quality control samples and plasma samples at different time points, 100 L supernatant was diluted with water at a ratio of 1:1, and then subjected to LC-MS / MS analysis. The blood drug concentrations at different times were calculated using Excel. The PK parameters in the following table were calculated using the Phoenix WinNonlin tool, and the specific experimental results are shown in Table 6.

[0488] Table 6 Mouse pharmacokinetic parameters of exemplary compounds of the present disclosure Note: "-" means not applicable; i.v. is intravenous administration; p.o. is oral administration; Clobs is systemic clearance, Vss_obs is the observed steady-state volume of distribution, C0 is the extrapolated zero-time blood drug concentration, Tmax is the time to peak, Cmax is the peak concentration, AUClast is the area under the concentration-time curve from zero time to the last quantifiable concentration, AUCINF_obs is the area under the curve from time zero to infinity, F(0-last) is the bioavailability.

[0489] As can be seen from the results in Table 6, the exemplary compounds of the present disclosure have superior pharmacokinetic properties.

[0490] Test Example 7, in vivo efficacy test

[0491] 1. T-47D DWT Xenograft model

[0492] 6-week-old B-NDG female mice (Bao Saigu Biotechnology Co., Ltd.) were implanted subcutaneously on the right side of the neck with 1.7 mg of 90-day sustained-release 17β-estradiol sustained-release tablets (Innovative Research of America). Three days later, each mouse was subcutaneously injected with 200 μL of T-47D cells (containing 50% ABW matrix glue, cat#: 082724) in the posterior axillary region, and the number of injected cells was 1 x 107 cells per mouse. The tumor growth was observed regularly, and when the tumor grew to an average volume of about 200 mm3, the drug administration was started. The drug was administered once a day for 28 consecutive days (qd x 28), and the administration dose was according to Table 19. Each animal was administered orally, and the administration vehicle was DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy experiment, the tumor volume and body weight were measured three times a week, and the TGI was calculated. After the 28th day of administration, whole blood was taken from the orbit at 1, 2, 4, 6, 8, 24 h, and the efficacy endpoint PK was tested, and the tumor was taken to test the drug concentration in the tumor.

[0493] Table 7 T-47D DWT Tumor growth inhibition and target protein degradation results in model mice

[0494] 2. T-47DD538G Xenograft model

[0495] 6-week-old B-NDG female mice (Bioscribe) were implanted subcutaneously on the right side of the neck with 1.7 mg of 90-day sustained release 17β-estradiol sustained release tablets (Innovative Research of America). Three days later, each mouse was injected subcutaneously in the rear armpit with 200 μL of T-47D D538G cells (containing 50% ABW Matrigel, cat#: 082724), with the number of cells injected being 1 x 107 cells per mouse. Tumor growth was observed regularly, and when the tumors grew to an average volume of about 200 mm3, the drug administration began. The drug was administered once a day for 28 consecutive days (qd x 28), with the oral gavage administration volume for each animal being 10 mL / kg, and the administration vehicle being DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy experiment, the tumor volume and body weight were measured three times a week, and the TGI was calculated. After the 28th day of administration, whole blood was taken from the orbit at 1, 2, 4, 6, 8, and 24 h, respectively, to test the efficacy endpoint PK, and the tumors were taken to test the drug concentration in the tumors.

[0496] The tumor growth inhibition (TGI) of each group was calculated as follows:

[0497] TGI% = [1-(Ti-T0) / (Ci-C0)]x100, where Ti is the average tumor volume of the treatment group on the ith day, T0 is the average tumor volume of the treatment group at grouping, Ci is the average tumor volume of the Vehicle group on the ith day, and C0 is the average tumor volume of the Vehicle group at grouping, with the unit of tumor volume being mm3.

[0498] The tumor volume T = (long diameter x short diameter2) / 2, and all measurements are in millimeters.

[0499] Table 8 T-47D D538G Tumor growth inhibition results in model mice

[0500] The results show that the exemplary compounds of the present application significantly inhibit tumor growth in tumor-bearing mice.

[0501] The present application has been described by way of the above examples, but it should be understood that the above examples are for illustrative and descriptive purposes only, and are not intended to limit the present application to the scope of the described examples. Furthermore, those skilled in the art can understand that the present application is not limited to the above examples, and that more various modifications and changes can be made according to the teachings of the present application, and these modifications and changes all fall within the scope of the present application claimed. The scope of protection of the present application is defined by the attached claims and their equivalent scope.

Claims

1. The compound represented by formula (II): CLM―L―PTM (II), Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, in: CLM is the ubiquitin-binding site of the cerebellar protein E3; L is the bond that covalently connects the CLM and PTM, or -(B L ) q -; PTM is the binding site that targets the estrogen receptor protein, and it comprises the structure shown in formula (III): In the formula, R1 and R2 are each independently selected from N or CR. mm ; R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; R4 is selected from N and CR. m4 ; R5 is selected from N and CR. m5 ; R6 is selected from N and CR m6 ; R7 is selected from N and CR m7 ; R m8 Selected from -N(R) a )2 and -OR a ; R m9 Selected from -C(R a )3, -N(R a )2, -OR a , and R a ; or R m8 With R1 or R m9 Forming a ring structure; when R1 and R m8 When R1 forms a ring structure with the atoms it is connected to, R1 is C, and R1 and R m8 It forms a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or 4-10 membered heterocyclic group is unsubstituted or 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, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents of the 5-10 heteroaryl group; when R m8 and R m9 When R forms a ring with the atoms it is attached to, m8 and R m9 Together with the carbon atoms they are attached to, they form The wavy line represents the site of fusion with the benzene ring; R a R mm R m4 R m5 R m6 R m7 R m10 and R m11 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylNHacyl; B L Each occurrence may be the same or different, and each is independently selected from CR. L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), 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 , cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and 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 groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, 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 groups, N(C) 3-8 Heterocyclic group)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, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, 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), NHSO2N(C 1-8 Alkyl)2, and NHSO2NH2, 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 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; q is an integer greater than 1; Preferably, the CLM comprises a structure selected from the following: Among them, W 1 and W 2 Each independently for CR a R b C (=O), NR a Or SO2, and W 1 and W 2 At least one of them is C (=O); G and Z are each independently selected from O, S, and Se; W 5 W 6 Each occurrence is independently C(R) m 2. NR m , O or S; W 11 For CR a R b C (=O), NR a Or SO2, R8, R9, R a R m R N and R b Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylNHacyl; R 22 Selected from single bonds, C(O), O, S, SO2, -NR m -、-NR m Combinations of one or more of C(O)-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2, or 3; R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; R d R e R f R g R D R E R F R G R f1 R g1 R F1 and R G1 Each occurrence is independently C(R) m 2. NR m O, C(O) or S; W 3 and W 4 Each independently for CR m Or N; R t R T R t1 and R T1 Each independently for CR m Or N, R t R T R t1 and R T1 Side connection Represents the connection site between CLM and L; m1 and m2 are each independently 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; m3 appears in the form of 0, 1, 2, 3, 4, 5, 6 or 7 each time, and m4 appears in the form of 1, 2, 3, 4, 5, 6, 7 or 8 each time, and m3 + m4 ≤ 8; m31 is 0, 1, 2, 3, 4, 5, 6 or 7, m41 is 1, 2, 3, 4, 5, 6, 7 or 8, and m31+m41≤8; m51 is 0, 1, 2, 3, 4, 5, 6 or 7, m61 is 1, 2, 3, 4, 5, 6, 7 or 8, and m51+m61≤8; m5 and m6 each appear independently as 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7; and Each occurrence of m7 and m8 is independently 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7.

2. The compound of claim 1, wherein R1 is CR mm ;R m8 -N(R) a )2;R m9 Selected from -C(R) a )3、-N(R a )2、-OR a and R a ;or R1 and R m8 The bonded atom forms a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or 5-7 membered heterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino; preferably, R1 and R m8 The bonded atom forms a saturated or unsaturated 5-7 membered heterocyclic group containing one or two N heteroatoms, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino; preferably, R1 and R m8 Together with the atoms they are attached to form The It is substituted by one, two, or three substituents selected from F, Cl, Br, I, methyl, ethyl, isopropyl, hydroxy, nitro, cyano, and amino; or R m8 and R m9 Together with the carbon atoms they are attached to, they form The It is substituted by one, two or three substituents selected from F, Cl, Br, I, methyl, ethyl, isopropyl, hydroxy, nitro, cyano and amino; Preferably, R1 and R m8 It forms a ring structure with the atoms it is connected to; R m9 Selected from -C(R) a )3、-N(R a )2、-OR a and R a ; Preferably, R a R mm R m4 R m5 R m6 R m7 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R a R mm R m4 R m5 R m6 R m7 R m9 R m10 R m11 R m12 and R m13 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, and amino.

3. The compound represented by formula (Ⅱ-1): CLM―L―PTM (Ⅱ-1), Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, in: CLM is the ubiquitin-binding site of the cerebellar protein E3; L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -; PTM comprises the structure shown in equation (Ⅲ-1): In the formula, R2 is selected from N or CR mm , ; R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; R4 is selected from N and CRm4; R5 is selected from N and CRm5; R6 is selected from N and CRm6; R7 is selected from N and CRm7; R mm R m4 R m5 R m6 R m7 R m9 R m10 R m11 R m12 and R m13 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; B L Each occurrence may be the same or different, and each is independently selected from CR. L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), 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 , cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and 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 groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, 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 groups, N(C) 3-8 Heterocyclic group)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, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, 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), NHSO2N(C 1-8 Alkyl)2, and NHSO2NH2, 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 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; q is an integer greater than or equal to 1; Preferably, the CLM comprises a structure selected from the following: W 1 and W 2 Each independently for CR a R b C (=O), NR a Or SO2, and W 1 and W 2 At least one of them is C (=O); G and Z are each independently selected from O, S, and Se; W 5 W 6 Each occurrence is independently C(R) m 2. NR m , O or S; W 11 For CR a R b C (=O), NR a Or SO2, R8, R9, R a R m R N and R b Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylNHacyl; R 22 Selected from single bonds, C(O), O, S, SO2, -NR m -、-NR m Combinations of one or more of C(O)-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2, or 3; R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; R d R e R f R g R D R E R F R G R f1 R g1 R F1 and R G1 Each occurrence is independently C(R) m 2. NR m O, C(O) or S; W 3 and W 4 Each independently for CR m Or N; R t R T R t1 and R T1 Each independently for CR m Or N, R t R T R t1 and R T1 Side connection Represents the connection site between CLM and L; m1 and m2 are each independently 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; m3 appears in the form of 0, 1, 2, 3, 4, 5, 6 or 7 each time, and m4 appears in the form of 1, 2, 3, 4, 5, 6, 7 or 8 each time, and m3 + m4 ≤ 8; m31 is 0, 1, 2, 3, 4, 5, 6 or 7, m41 is 1, 2, 3, 4, 5, 6, 7 or 8, and m31+m41≤8; m51 is 0, 1, 2, 3, 4, 5, 6 or 7, m61 is 1, 2, 3, 4, 5, 6, 7 or 8, and m51+m61≤8; m5 and m6 each appear independently as 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7; and Each occurrence of m7 and m8 is independently 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7.

4. The compound of claim 3, wherein, R mm R m4 R m5 R m6 R m7 R m9 R m10 R m11 R m12 and R m13 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m9 R m10 R m11 R m12 and R m13 Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, and amino.

5. The compound according to any one of claims 1-4, wherein, R2 is selected from N, CH, CF, and C-CH3, preferably CH; and / or R3 is R m1 R m2 and R m3 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; preferably, R m1 R m2 and R m3 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R m1 R m2 and R m3 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, cyano, and amino; preferably, R3 is selected from fluoroethyl, difluoroethyl, and trifluoroethyl, preferably, R3 is difluoroethyl; preferably, R3 is -CH2-CHF2; and / or R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl), and C (C1-C6 alkoxy), preferably N, CH, CF, C-Cl, C-Br, or C-OCH3, more preferably CF; and / or R5 is N or CH, preferably CH; and / or R6 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl), and C (C1-C6 alkoxy), preferably N, CH, CF, C-Cl, C-Br, or C-OCH3, more preferably CF; and / or R7 is N or CH, preferably CH; and / or R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups, preferably hydrogen, fluorine, or methyl, more preferably hydrogen; and / or R m10 Selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen; and / or R m11 It is selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen or methyl, more preferably methyl.

6. The compound of claim 1, wherein, Selected from More preferably 7. The compound according to any one of claims 1-6, wherein, Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. Preferably, Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

8. The compound according to any one of claims 1-7, wherein, The PTM is selected from: Preferably, the PTM is selected from...

9. The compound according to any one of claims 1-8, wherein, B L Each occurrence is independently selected from CR L1 R L2 O, S, SO, SO2, NR L3 C(O), C≡C, 3-16 cyclic alkylene, 3-16 heterocyclic alkylene, 6-10 arylalkylene, and 5-10 heterocyclic arylalkylene, wherein the 3-16 cyclic alkylene, 3-16 heterocyclic alkylene, 6-10 arylalkylene, and 5-10 heterocyclic arylalkylene are optionally surrounded by 0, 1, 2, or 3 R's. L1 and / or R L2 Group substitution; and / or R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and 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 groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, 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 groups, N(C) 3-8 Heterocyclic group)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, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, 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), NHSO2N(C 1-8 alkyl)2, and NHSO2NH2, wherein 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 heteroaryl group are each independently and selectively chosen from F, Cl, Br, I, C. 1-6 Substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups; and / or q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and / or W 1 W 2 Each occurrence is independently designated as CR. a R b Or C (=O); preferably, W 1 For C (=O), W 2 For CH, or W 1 For CH, W 2 For C (=O); and / or G is O; Z is O; and / or W 5 and W 6 Each occurrence is independently C(R) m )2; Preferably, W 5 CH2, W 6 CH2; and / or W 11 For C (=O); and / or R8, R9, R a R m R N and R b Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; and / or R 22 Selected from single bonds, C(O), NH, O, C(O)NH, NHC(O), N(C1-C3 alkyl), N(C1-C3 alkyl)C(O), C(O)N(C1-C3 alkyl) and C1-C3 alkylene; preferably, R 22 Selected from single bonds, C(O), NH, C(O)NH, NHC(O), N(CH3), N(CH3)C(O) and C(O)N(CH3); and / or n is 1; and / or R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, 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, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, 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 Each heteroaryl group is independently 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 52 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, 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, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, 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 Each heteroaryl group is independently 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 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, 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, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, 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 Each heteroaryl group is independently 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 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; and / or W 3 For N, W 4 For CH or W 3 For CH, W 4 Let N be the number of elements in the array.

10. The compound according to any one of claims 1-8, wherein, The CLM includes structures selected from the following: Among them, W 1 W 2 W 3 W 4 W 5 W 6 W 11 R8, R9, R N R m R F R G R T R f R g R t R T1 R F1 R G1 R 32 R 42 R 52 R 62 R 72 Each of m3, m4, m31, m41, m5, and m6 is defined as described in claims 1, 2, or 6; R 1D R 1E R 1d R 1e Each occurrence is independently selected from C(R) m 2. NR m O and C(O), R m The definition is the same as that in claims 1, 2, or 6; Each time m1, m9 and m10 appear, they are each an independent integer of 0, 1, 2, 3, 4 or 5, and m1 + m9 + m10 ≤ 5; Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; Preferably, W 1 and W 2 Each independently for CR a R b And W 1 and W 2 At least one of them is C (=O); W 3 and W 4 Each independently for CR m Or N, and W 3 and W 4 One of them is N; W 5 and W 6 Each occurrence is independently C(R) m )2; R 1D R 1E R 1d and R 1e Each occurrence is independently selected from C(R) m 2. NR m O and C(O); R F R G R f R g R F1 and R G1 Each occurrence is independently selected from C(R) m )2; R T R t and R T1 Each occurrence is independently represented by N; R8, R9, R 32 R 42 R 52 R 62 R 72 R a R b R N and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl and cyano groups; Each time m1, m9, and m10 appear, they are each an independent integer of 0, 1, 2, 3, 4, or 5, and m1 + m9 + m10 ≤ 5; preferably, each time m1, m9, and m10 appear, they are each an independent integer of 0, 1, or 2, and m1 + m9 + m10 ≤ 2, preferably m1 + m9 + m10 = 1, m1 + m9 + m10 = 2, or m1 + m9 + m10 = 0; Each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably, each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1; Each occurrence of m3 and m4 is an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5; preferably, m3 + m4 = 4, m3 + m4 = 3, or m3 + m4 = 2. Each occurrence of m5 and m6 is an independent integer of 0, 1, 2, 3, or 4; preferably, m5+m6=3, m5+m6=2, or m5+m6=1. Each occurrence of m31 and m41 is an independent integer of 0, 1, 2, 3, or 4; m31 and m41 are not both 0; m31 + m41 ≤ 5; preferably, m31 + m41 = 4, m31 + m41 = 3, or m31 + m41 = 2; and W 11 It is C (=O); Preferably, the CLM comprises a structure selected from formulas (IV-1A), (IV-1B), and (IV-1C), wherein: W 1 For C (=O), W 2 For CH2, or W 1 CH2, W 2 For C (=O); preferably, W 1 For C (=O), W 2 It is CH2; W 5 and W 6 Each occurrence is independently CH2, C(C1-C6 alkyl)2, or C(C1-C6 alkyl)H; preferably, W 5 CH2, W 6 It is CH2; R8 and R9 are each independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy and hydroxyl groups each time they appear; preferably, R8 is H and R9 is H. R 32 R 42 R 52 and R 62 Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and cyano, more preferably H, F, Cl, Br, methyl, methoxy, or cyano; more preferably, R 32 For F, Cl or Br, R 42 R 52 and R 62 Each occurrence is independently represented by H; R F and R G Each occurrence is independently selected from CH2, NH, O, and C(O); CH2 is preferred; m3 is 2; m4 is 2; R 1D and R 1E Each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

11. The compound of claim 10, wherein, The CLM is selected from: Preferably, the CLM is selected from...

12. The compound according to any one of claims 1-11, wherein, B L It is selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -C(O)-, -NH-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3) 2 -、-N(CH3)-、-N(CH2CH3)-、 in, This is the connection point.

13. The compound of claim 12, 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 -C(O)-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、 Each time j appears, it is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; For connection points of CLM or PTM; L is preferably selected from covalent bonds, -(CH2)2-OCH2CH2, -(CH2)2-(OCH2CH2)2, -(CH2)2-(OCH2CH2)3, -(CH2)2-(OCH2CH2)4, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-(CH2)9-, and -NH-(CH2). 10 -、-NH-(CH2) 11 -、-NH-(CH2) 12 -、-NH-(CH2) 13 -、-NH-(CH2) 14 -、-NH-(CH2) 15 -NH-CH2-,-NH-(CH2)2-,-NH-(CH2)3-,-NH-(CH2)4-,-NH-(CH2)5-,-NH-(CH2)6-,-NH-(CH2)7-,-NH-(CH2)8-,-C(O)-NH-CH2-,-C(O)-NH-(CH2)2-,-C(O)-NH-(CH2)3-,-C(O)-NH-(CH2)4-,-(CH2)4-C(O)-NH-(CH2)4-,-(CH2)2-C(O)-NH-(CH2)3-,-(CH2)5-C(O)-NH-(CH2)8-,-C(O)-NH-(CH2) 2)5-,-C(O)-NH-(CH2)6-,-C(O)-NH-(CH2)7-,-C(O)-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-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-,-C(O)-NH-(CH2-CH 2-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-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-C(O)-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-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-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)3-NH-,-NH-CH2-CH2-O-CH2-CH2-C(O)-,-C(O)-CH2-CH2-O-CH2-CH2-NH-,-NH-(CH2) 4-C(O)-,-NH-(CH2)5-C(O)-,-NH-(CH2)6-C(O)-,-C(O)-(CH2)4-NH-,-C(O)-(CH2)5-NH-,-C(O)-(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-C H2-CH2)-NH-,-(CH2)6-(O-CH2-CH2)-NH-,-CH2-CH2-O-(CH2)2-C(O)-,-CH2-CH2-O-(CH2)3-C(O)-,-CH2-CH2-O-(CH2)4-C(O)-,-C(O)-(CH2)2-O-CH 2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6--(CH2)2-C(O)-,-(CH2)3-C(O)-,-(CH2)4-C(O)-,-(CH2)5-C(O)-,-(CH2)6-C(O)-,-C(O)-(CH2)2-C(O)-,-C(O)-(CH2)3-C(O)-,-C(O)-(CH2)4-C(O)-,-C(O)-(CH2)5-C(O)-,-C(O)-(CH2)6-C(O)-,-CH2-C(O)-CH2-,-CH2- C(O)-(CH2)2-,-CH2-C(O)-(CH2)3-,-CH2-C(O)-(CH2)4-,-(CH2)2-C(O)-CH2-,-(CH2)2-C(O)-(CH2)2-,-(CH2)2-C(O)-(CH2)3-,-(CH2)2-C(O)-(CH2)4-,-(CH2)3-C(O)-CH2-,-(CH2)3-C(O)-(CH2)2-,-(CH2)3-C(O)-(CH2) 2)3-、-(CH2)3-C(O)-(CH2)4-、-(CH2)4-C(O)-CH2-、-(CH2)4-C(O)-(CH2)2-、-(CH2)4-C(O)-(CH2)3-、-(CH2)4-C(O)-(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-, 14. The compound represented by formula (IA), Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, In the formula, X1 is N or CH; X2 is N or CH; X3 is N or CH; q1 is 0 or 1; q2 is 0, 1 or 2; p1 is 0 or 1; p2 is 0 or 1; p3 is 0 or 1; p4 is 0 or 1; R3 is selected from fluoroethyl, difluoroethyl, and trifluoroethyl; preferably, R3 is selected from -CH2-CHF2; R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups; R m10 Selected from hydrogen and C1-C6 alkyl groups; R m11 Selected from hydrogen, methyl, ethyl, and isopropyl; R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy); R5 is either N or CH; R6 is selected from N, CH, CF, C-Cl, C-Br, C(C1-C6 alkyl), and C(C1-C6 alkoxy). R7 is either N or CH; CLM includes structures selected from those shown in Equations (IV-1a), (IV-1b), and (IV-1c): in, W 1 For C (=O), W 2 For CH2, or W 1 CH2, W 2 For C (=O); preferably, W 1 For C (=O), W 2 It is CH2; R 32 R 42 R 52 and R 62 Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and cyano, more preferably H, F, Cl, Br, methyl, methoxy, or cyano; more preferably, R 32 Each time it appears, it is F, Cl, or Br, R 42 R 52 and R 62 Each occurrence is independently represented by H; R F and R G Each occurrence is independently selected from CH2, NH, O, and C(O); CH2 is preferred; m3 is 2; m4 is 2; R 1D and R 1E Each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

15. The compound of claim 1, wherein, The compounds are selected from: Preferably, the compound is selected from the compounds in Table A.

16. Compounds containing the structure shown in formula (I') that bind estrogen receptor proteins: Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates: in, R ER0’ It is a leaving group; R1, R2, R3, R4, R5, R6, R7, R m8 R m9 R m10 and R m11 Each of the following is a definition of any one of claims 1, 2, and 5; Preferably, R ER0’ Selected from -(CR) ER0a R ER0b ) n1 R ER0c Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethanesulfonate group (Ts), -C(O)OR ER0d and -OC(O)R ER0d ; R ER0a R ER0b R ER0c and R ER0d Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH. The C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino. n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Preferably, R ER0’ Selected from Cl, Br, I, Ms, Tf, TsCl, Ts, C(O)OCH3, C(O)OCH3, CH2NO2, CH2ON=NH and CH2NH2; Preferably, Selected from More preferably Preferably, Selected from:

17. Compounds containing the structure shown in formula (I-1') that bind estrogen receptor proteins: Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates; in, R ER0’ It is a leaving group; R2, R3, R4, R5, R6, R7, R m8 R m9 R m10 and R m11 Each custom is identical to any one of claims 3, 4 and 5; Preferably, R ER0’ Selected from -(CR) ER0a R ER0b ) n1 R ER0c Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethanesulfonate group (Ts), -C(O)OR ER0d and -OC(O)R ER0d ; R ER0a R ER0b R ER0c and R ER0d Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH. The C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino. n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Preferably, R ER0’ Selected from F, Cl, Br, I, Ms, Tf, TsCl, Ts, C(O)OCH3, C(O)OCH3, CH2NO2, CH2ON=NH and CH2NH2; Preferably, for More preferably Preferably, Selected from:

18. A compound that binds to an estrogen receptor protein, said compound being a compound of Formula I, or an isomer, isotopic derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof: in, R ER0 Selected from -(CR) ER0a R ER0b ) n1 R ER0c Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethanesulfonate group (Ts), -C(O)OR ER0d and -OC(O)R ER0d ; R ER0a R ER0b R ER0c and R ER0d Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH. The C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino. n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R ER1 and R ER2 Each is independently selected from N and CR ERm ; R ER3 The group is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally surrounded by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, etc. Substituents of the following groups: C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ER3 for R ER4 Selected from N and CR ERm4 ; R ER5 Selected from N and CR ERm5 ; R ER6 Selected from N and CR ERm6 ; R ER7 Selected from N and CR ERm7 ; R ERm8 Selected from -N(R) ERa )2, and -OR ERa ; R ERm9 Selected from -C(R) ERa )3、-N(R ERa )2、-OR ERa and R ERa ;or R ERm8 Able to work with R ER1 or R ERm9 Forming a ring structure; when R ER1 and R ERm8 When R forms a ring structure with the atoms it is connected to, ER1 For C, R ER1 and R ERm8 Each of the atoms to which it is attached forms a 4-10 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the 4-10 membered heterocyclic group is unsubstituted or 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, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R ER1 and R ERm8 The bonded atom forms a 5-7 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the 5-7 membered heterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R ER1 and R ERm8 It forms a saturated or unsaturated 5-7 membered heterocyclic group containing one or two N heteroatoms with the attached carbon atom, wherein the 5-7 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano and amino; Or, when R ERm8 and R ERm9 When R forms a ring with the atoms it is attached to, ERm8 and R ERm9 Together with the atoms they are attached to, they form Here, the zigzag lines represent sites where the benzene ring fused; preferably, R ER1 and R ERm8 It forms a ring structure with the atoms it is connected to; R ERm9 Selected from -C(R) ERa )3、-N(R ERa )2、-OR ERa and R ERa ; and R ERa R ERb R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm10 and R ERm11 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERa R ERb R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm10 and R ERm11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

19. A compound that binds to an estrogen receptor protein, said compound being a compound of formula I-1, or an isomer, isotopic derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof: in, R ER0 Selected from -(CR) ER0a R ER0b ) n1 R ER0c Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethanesulfonate group (Ts), -C(O)OR ER0d and -OC(O)R ER0d ; R ER0a R ER0b R ER0c and R ER0d Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH. The C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino. n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R ER2 Selected from N and CR ERm ; R ER3 The group is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally surrounded by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, etc. Substituents of the following groups: C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ER3 for R ER4 Selected from N and CR ERm4 ; R ER5 Selected from N and CR ERm5 ; R ER6 Selected from N and CR ERm6 ; R ER7 Selected from N and CR ERm7 ; R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm9 R ERm10、 R ERm11 R ERm12 and R ERm13 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm9 R ERm10、 R ERm11 R ERm12 and R ERm13 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ERm9 R ERm10、 R ERm11 R ERm12 and R ERm13 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, and amino.

20. The compound according to any one of claims 16-19, wherein, Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

21. The compound according to any one of claims 16-20, wherein the compound is selected from:

22. The compound represented by formula (Ⅳ): CLM―L―A L2 (Ⅳ) Or its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates. In the formula, CLM and L are defined as in any of claims 1, 3 and 9-13; A L2 Independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; Preferably, A L2 Selected from 23. The compound of claim 22, wherein the compound is selected from the following structures:

24. Use of any compound or isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate of any one of claims 16-21 in the preparation of a medicament for degrading estrogen receptor proteins.

25. A pharmaceutical composition comprising a compound according to any one of claims 1-15.

26. Use of the compound of any one of claims 1-15 or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the pharmaceutical composition of claim 25 in the preparation of a medicament for treating or preventing a disease; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins.

27. The use as described in claim 26, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

28. The compound of any one of claims 1-15 or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the pharmaceutical composition of claim 25, for the treatment or prevention of a disease; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins.

29. A compound or isomer thereof, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate, or pharmaceutical composition for the use described in claim 28, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

30. A method of treating or preventing a disease, comprising administering to a subject in need a therapeutically effective amount of the compound or isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof, or the pharmaceutical composition of claim 25; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins.

31. The method of claim 30, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

32. Use of a compound of Formula IV in the preparation of a medicament for treating a disease or condition by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating a disease or condition mediated by estrogen receptor protein and IKZF2, said compound having the following chemical structure: CLM-L-PTM (Formula IV); Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -; CLM is selected from the following structure: W 1 and W 2 Whether they are the same or different, each is independently a CR. a R b Or C(O), and W 1 and W 2 At least one of them is C(O); R 1D R 1E R F and R G Each occurrence is independently C(R) m 2. NR m C(O), O or S; R T For N or CR 2h ; R 32 R 42 R 62 R m and R 2h Each of the following groups is independently selected from H, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl 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 heterocyclic, C6-C 10 The aryl and 5-10-membered heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, 4-10-membered heterocyclic groups, and C6-C6 heterocyclic groups. 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 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 Each heteroaryl group is independently 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, 4-10 membered heterocyclic, C6-C 10 The aryl group is substituted with one or more substituents of 5-10 heteroaryl groups; more preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and hydroxyl; more preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, deuterated C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, and hydroxyl; more preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, hydroxyl, and C1-C3 alkoxy; more preferably, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy groups; Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; m3 and m4 each appear independently as integers of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5; R8 is selected from H, halogens, deuterium atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, hydroxyl groups, cycloalkyl groups, C1-C6 haloalkyl groups, and hydroxyalkyl groups; preferably, R8 is selected from H, halogens, deuterium atoms, C1-C3 alkyl groups, and hydroxyl groups; more preferably, R8 is selected from H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl groups, and hydroxyl groups; R9, R a and R b Each is independently selected from H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), 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 Monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups, wherein the monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. 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 C(O), C≡C, 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from N, O and S, 5-15 membered bridged cyclic group containing 0-5 heteroatoms independently selected from N, O and S, and 5-15 membered spirocyclic group containing 0-5 heteroatoms independently selected from N, O and S, wherein the 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic alkylene, 5-15 membered bridged cyclic group and 5-15 membered spirocyclic group are optionally separated by 0, 1, 2 or 3 R L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, C 1-8 Alkoxy, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-1 1 heterocyclic group, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic groups, 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 groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl groups, -OH groups, -NH2 groups, -SH groups, S(O)2P(O) (OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl group, -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, C(O)-C 1-8 Alkyl, C(O)-OC 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2 and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic groups and C 3-8 Each heterocyclic group is independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl and alkylamino; 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; and PTM is the estrogen receptor protein portion, selected from the following structural formulas: R1 and R2 are each independently selected from N and CR. m ; Each time R3 appears, it is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally replaced by 1, 2, 3, 4, or 5 groups, each independently selected from carboxyl, deuterium, and other groups. Substituents of atoms, halogens, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R3 is... Each occurrence of R4 is independently selected from N and CRm4; Each occurrence of R5 is independently selected from N and CRm5; Each occurrence of R6 is independently selected from N and CRm6; Each occurrence of R7 is independently selected from N and CRm7; R m8 selected from -N(R a )2 and -OR a ; R m9 selected from -C(R a )3, -N(R a )2, -OR a and R a ; or R m8 Forming a ring structure with R1; when R1 and R m8 When R1 forms a ring structure with the atoms it is connected to, R1 is C, and R1 and R m8 It forms saturated or unsaturated C4-C bonds with the carbon atoms it is attached to. 10 The subcyclic hydrocarbon group or a 4-10 membered subheterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated C4-C 10 The cyclic hydrocarbon group or 4-10 membered heterocycle is unsubstituted or 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, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R1 and R2 are substituents selected from 5-10 heteroaryl groups. m8 The bonded atom forms a saturated or unsaturated C5-C7 subcyclic hydrocarbon group or a 5-7 membered subheterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated C5-C7 subcyclic hydrocarbon group and the 5-7 membered subheterocyclic group are unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino. Preferably, R1 and R... m8 The atom to which it is attached forms a saturated or unsaturated C5-C7 subcyclic hydrocarbon group or a 5-7 membered subheterocyclic group containing one or two N atoms, wherein the saturated or unsaturated C5-C7 subcyclic hydrocarbon group or the 5-7 membered subheterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano and amino; R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 and R 11 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 R 11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, and amino.

33. The use as described in claim 32, wherein W 1 and W 2 Each independently for CR a R b And W 1 and W 2 At least one of them is C (=O); and / or W 5 and W 6 Each occurrence is independently C(R) m )2; and / or R 1D and R 1E Each occurrence is independently selected from C(R) m 2. NR m O and CO; and / or R F and R G Each occurrence is independently selected from C(R) m )2; and / or R T For N; and / or Z is CH or N; and / or R8, R9, R 32 R 42 R 62 R a R b and R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl; and / or Each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably, each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1; and / or Each time m3 and m4 appear, they are each an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; and m3+m4=4, m3+m4=3, or m3+m4=2.

34. The use as described in claim 32 or 33, wherein, The CLM is selected from:

35. The use as described in any one of claims 32-34, wherein, B L Selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-, -C≡C-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, -N(CH3)-, -N(CH2CH3)-, This is the connection point.

36. The use as described in claim 35, wherein -(B L ) q -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, Each time j appears, it is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and For connection points with CLM or PTM; Preferably, -(B L ) q - Selected from covalent bonds, -(CH2)2-OCH2CH2-, -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, -(CH2)2-(OCH2CH2)4, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-(CH2)9-, -NH-(CH2) 10 -、-NH-(CH2) 11 -、-NH-(CH2) 12 -、-NH-(CH2) 13 -、-NH-(CH2) 14 -、-NH-(CH2) 15 -NH-CH2-,-NH-(CH2)2-,-NH-(CH2)3-,-NH-(CH2)4-,-NH-(CH2)5-,-NH-(CH2)6-,-NH-(CH2)7-,-NH-(CH2)8-,-C(O)-NH-CH2-,-C(O)-NH-(CH2)2-,-C(O)-NH-(CH2)3-,-C(O)-NH-(CH2)4-,-(CH2)4-C(O)-NH-(CH2)4-,-(CH2)2-C(O)-NH-(CH2)3-,-(CH2)5-C(O)-NH-(CH2)8-,-C(O)-NH-(CH2) 2)5-,-C(O)-NH-(CH2)6-,-C(O)-NH-(CH2)7-,-C(O)-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-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-,-C(O)-NH-(CH2-CH 2-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-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-C(O)-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-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-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)3-NH-,-NH-CH2-CH2-O-CH2-CH2-C(O)-,-C(O)-CH2-CH2-O-CH2-CH2-NH-,-NH-(CH2) 4-C(O)-,-NH-(CH2)5-C(O)-,-NH-(CH2)6-C(O)-,-C(O)-(CH2)4-NH-,-C(O)-(CH2)5-NH-,-C(O)-(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-C H2-CH2)-NH-,-(CH2)6-(O-CH2-CH2)-NH-,-CH2-CH2-O-(CH2)2-C(O)-,-CH2-CH2-O-(CH2)3-C(O)-,-CH2-CH2-O-(CH2)4-C(O)-,-C(O)-(CH2)2-O-CH 2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6--(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -CO-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2-C (O)-(CH2)2-,-CH2-C(O)-(CH2)3-,-CH2-C(O)-(CH2)4-,-(CH2)2-C(O)-CH2-,-(CH2)2-C(O)-(CH2)2-,-(CH2)2-C(O)-(CH2)3-,-(CH2)2-C(O)-(CH2)4-,-(CH2)3-C(O)-CH2-,-(CH2)3-C(O)-(CH2)2-,-(CH2)3-C(O)-(CH2)2- )3-、-(CH2)3-C(O)-(CH2)4-、-(CH2)4-C(O)-CH2-、-(CH2)4-C(O)-(CH2)2-、-(CH2)4-C(O)-(CH2)3-、-(CH2)4-C(O-)(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-、 More preferably, -(B L ) q - Selected from covalent bonds, -(CH2)5-, -(CH2)8-, -NH-(CH2)5-, -NH-(CH2)8-, -NH-(CH2) 13 -, -NH-(CH2)2-OCH2CH2-, -NH-(CH2)2-(OCH2CH2)2-, -NH-(CH2)2-(OCH2CH2)4-, -NH-( CH2)4-C(O)-NH-(CH2)7-, -NH-(CH2)3-C(O)-NH-(CH2)3-, -NH-(CH2)2-C(O)-NH-CH2-, 37. The use as described in claim 36, wherein, The PTM is selected from:

38. The use as described in any one of claims 32-37, wherein, The structure of the compound is selected from: Preferably, the compound is selected from:

39. A method for treating a disease or condition in a subject of need by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating or preventing a disease or condition mediated by estrogen receptor protein and IKZF2 in a subject of need, comprising administering to the subject the compound described in claims 32-38.

40. A compound according to claims 32-38, used for treating or preventing a disease or condition in a subject of need by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating or preventing a disease or condition mediated by estrogen receptor protein and IKZF2 in a subject of need.

41. Use of the method or compound as claimed in claim 39 or 40, wherein the disease is a tumor or cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, or cervical cancer.

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