Multidrug linker and antibody-drug conjugate

Abstract

A multidrug linker, an antibody-drug conjugate comprising the multidrug linker, a preparation method for the antibody-drug conjugate, and uses of the multidrug linker and the antibody-drug conjugate in disease treatment. A specific structure can effectively reduce the aggregation of a multi-payload drug-antibody conjugate, thereby facilitating process scale-up. In addition, payload drugs can achieve a significant synergistic effect, thereby achieving a synergistic anti-tumor effect, effectively overcoming the resistance to drugs, and improving the therapeutic window of drugs.

Description

Multidrug linkers and antibody-drug conjugates Technical Field

[0001] The present invention relates to a multidrug (e.g., dual-drug) linker for an antibody-drug conjugate (ADC), an ADC based on the multidrug linker, and a preparation method and use thereof. Background Art

[0002] Traditional antibody-drug conjugates are all single-loaded drug conjugates, that is, the same toxin linker is connected to a single antibody molecule, and different ADCs only differ in the number and site of drug loading. Single-loaded drug antibody conjugates achieve targeted therapy of tumor cells by combining a single drug molecule with an antibody molecule. However, due to the heterogeneity and drug resistance of tumor cells, the effectiveness of single-loaded drug antibody conjugates in treatment has certain limitations. In the past decade, tumor immunotherapy and antibody-drug conjugates have achieved remarkable success in tumor treatment. However, high response rates are only reflected in some specific tumors or specific tumors with high antigen expression, such as the success of HER2 / 3 ADC in breast cancer, while the clinical application response in gastrointestinal solid tumors is moderate or even poor. These solid tumors show significant heterogeneity between tumor cells and the surrounding microenvironment (TME). In other words, the tumor is not just a mass of transformed cells, but also has a fibrotic microenvironment. Some solid tumor types, particularly those associated with extensive fibrotic tumor stroma, such as pancreatic ductal adenocarcinoma (PDAC), renal cell carcinoma (RCC), lung cancer, and colorectal cancer, respond poorly to immunotherapy. The entire fibrosis reaction directly and indirectly affects the therapeutic response to chemotherapy and immunotherapy. Dual-drug antibody-drug conjugates can, on the one hand, improve the overall efficacy, and on the other hand, transform the tumor from "cold" to "hot," further enhancing the efficacy of combination with immunotherapy drugs.

[0003] Dual toxins can reduce drug resistance because they can overcome intracellular or extracellular obstacles that single toxins may encounter, such as downregulation of target expression, upregulation of drug pump expression, and activation of DNA repair mechanisms. ADCs can leverage the high specificity and affinity of antibodies to precisely deliver two synergistic chemotherapy drugs into tumor cells, thereby achieving a highly effective killing effect. Therefore, researchers have begun exploring methods to combine two or more drug molecules to form dual-loaded or multi-loaded drug-antibody conjugates, thereby achieving synergistic effects of multiple drugs and improving therapeutic efficacy. The drug molecule combinations that have been disclosed so far are mainly combinations of different toxins, including combinations with the same mechanism or different mechanisms, such as: MMAE / MMAF combination (Nat Commun 2021; 12:3528; Angew Chem Int Ed Engl 2017; 56:733-7; Bioconjugate Chem. 2023, 34, 4, 748–755); DM1 / MMAE combination (Nature Protocols 2017; 12:1702-21; Pharmaceutics 2023; 15:2020); PNU-159682 / MMAF combination (Antib Ther 2019; 2:71-8); MMAE / α-Amanitin combination (Int J Mol Sci 2018; 19:2098); MMAE / PBD combination (Bioorg Med Chem Lett 2018; 28:3617-21). Early efficacy experiments have demonstrated that dual-toxin ADC molecules can significantly improve drug efficacy while increasing the killing activity of ADC drugs against drug-resistant tumor cells.In addition, there are existing reports related to dual-toxin ADC drugs in terms of coupling methods and processes, including: using MMAF in series with different drugs to obtain dual-toxin-loaded antibody-drug conjugate molecules (PCT / CN2021 / 107079) and using one or more cysteine ​​residues or cysteine ​​derivative residues as drug connection carriers to simultaneously couple one or more drugs to a limited number of connection sites on the antibody (PCT / CN2019 / 112663); connecting traditional VC-PAB-MMAE, GGFG-DXd, Eribulin and other drugs in parallel through bidentate linkers (PCT / CN2022 / 080942); constructing multiple drug-antibody drug conjugates by "orthogonal" deprotection and drug loading in site-specific substances (PCT / US2017 / 066504); introducing two protected cysteine ​​groups [Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr)+Cys(Cys(SiPr) (Acm)], combined with different deprotection reactions to construct dual-loaded ADCs (Angew Chem Int Ed Engl 2017; 56:733-7). However, the process requires the use of highly toxic catalytic reagents such as Hg(OAc)2, which increases drug safety risks and also has potential adverse effects on protein structure and stability.

[0004] The above-mentioned prior art mainly realizes the antibody coupling of different toxins through “linear linkers” and “branched linkers”. Since the water solubility of the existing linker-toxin compositions is relatively poor, the current dual loads are only applied to antibody-drug conjugates of some high-activity toxins with low drug loading requirements (low DAR values). However, the biggest problem currently limiting the clinical application of ADC drugs is the safety window, and MMAF, PBD, and PNU-159682 molecules, as classic ADC-loaded toxins, have large dose-limiting toxicity, and the related ADC molecules have all failed in clinical development (Risk Minimization of Antibody-Drug Conjugates in Oncology: A Review. Drug Saf 2021; 44: 733-42). The basic strategy of the above-mentioned prior art is to randomly combine highly active drugs to further expand the “toxicity spectrum” of ADC drugs, so that the same ADC drug has greater and wider toxicity while obtaining higher activity. Furthermore, from a technical perspective, the aforementioned prior art only considers the simple combination of existing linkers, combining toxin molecules and chemotherapy drugs with traditional linkers through simple "series" or "parallel" connections to obtain dual-toxin-loaded antibody-drug conjugates. However, the chemotherapy drug-linker combination also has the problem of high hydrophobicity. Therefore, when the dual-drug linker combination is coupled to the antibody macromolecule, the stability of the antibody molecule is greatly reduced, further leading to problems such as shortened drug half-life in vivo, poor PK properties, and immune response. In addition, early research focused on toxin combinations such as auristatins, which are highly hydrophilic and active, and are relatively easy to achieve dual-drug antibody-drug conjugates. However, topoisomerase inhibitors, targeted DNA damage response (DDR) inhibitors, and most tumor-targeted drugs that have been widely studied in recent years generally have relatively low activity and very high hydrophobicity. Therefore, these compositions, as antibody-drug conjugate payload molecules, first require high DAR values ​​and appropriate drug ratios to achieve better efficacy and safety, which are difficult to achieve with the existing technology.

[0005] Therefore, there is an urgent need in this field to provide more suitable new antibody-drug conjugates that can carry multiple types of drugs with synergistic mechanisms, achieve efficient, simple, and practical chemical preparation and conjugation, and / or improve the pharmaceutical properties, metabolic properties, efficacy and / or safety of existing antibody-drug conjugates, such as improving the molecular stability of multi-drug-loaded ADCs, improving the in vivo PK properties of drugs, and increasing the therapeutic window.

[0006] Summary of the Invention

[0007] One aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula I:

[0008] in,

[0009] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0010] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0011] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0012] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0013] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0014] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0015] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0016] When a=0, B1 is a direct key and T1 is not a direct key;

[0017] When b=0, B1 is not a direct key.

[0018] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula Ia:

[0019] in:

[0020] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0021] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0022] B1 is a branching group;

[0023] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0024] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0025] D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different;

[0026] a is 1, 2 or 3.

[0027] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula Ib:

[0028] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0029] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0030] B2 is a branching group;

[0031] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0032] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0033] D1 and D3 are the first and third drug units, respectively, and are the same or different;

[0034] b is 1, 2, or 3.

[0035] In other embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure represented by Formula I:

[0036] in,

[0037] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0038] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0039] B1 and B2 are independently branching groups;

[0040] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0041] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0042] D1, D2, and D3 are the first, second, and third drug units, respectively, and are the same or different; and

[0043] a and b are independently 1, 2 or 3.

[0044] In a preferred embodiment, the present invention provides a compound selected from formula A1 to A188, or a tautomer, meso racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0045] Another aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula II:

[0046] in,

[0047] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0048] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0049] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0050] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0051] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0052] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0053] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0054] When a=0, B1 is a direct key and T1 is not a direct key;

[0055] When b=0, B1 is not a direct key.

[0056] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIa:

[0057] in:

[0058] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0059] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0060] B1 is a branching group;

[0061] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0062] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0063] D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different;

[0064] a is 1, 2 or 3.

[0065] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIb:

[0066] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0067] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0068] B2 is a branching group;

[0069] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0070] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0071] D1 and D3 are the first and third drug units, respectively, and are the same or different;

[0072] b is 1, 2, or 3.

[0073] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula II:

[0074] in,

[0075] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0076] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0077] B1 and B2 are independently branching groups;

[0078] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0079] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0080] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0081] a and b are independently 1, 2 or 3.

[0082] In a preferred embodiment, the present invention provides a compound selected from formula B1 to B190, or a tautomer, meso racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0083] Another aspect of the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the structural formula of the linker is shown in Formula IV below:

[0084] in,

[0085] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0086] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0087] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0088] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0089] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0090] Connection points 2, 3, and 4 are connected to the drug unit;

[0091] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0092] When a=0, B1 is a direct key and T1 is not a direct key;

[0093] When b=0, B1 is not a direct key.

[0094] In some embodiments, the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IVa:

[0095] in:

[0096] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0097] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0098] B1 is a branching group;

[0099] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0100] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0101] Connection points 2 and 3 connect to the drug unit;

[0102] a is 1, 2 or 3.

[0103] In some embodiments, the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IVb:

[0104] in:

[0105] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0106] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0107] B2 is a branching group;

[0108] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0109] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0110] Connection points 2 and 3 connect to the drug unit;

[0111] b is 1, 2, or 3.

[0112] In some embodiments, the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the structural formula of the linker is shown in Formula IV below:

[0113] in,

[0114] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0115] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0116] B1 and B2 are independently branching groups;

[0117] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0118] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0119] Connection points 2, 3, and 4 are connected to the drug unit;

[0120] a and b are independently 1, 2 or 3.

[0121] In some embodiments, the present invention provides a linker as shown in D1 to D37, or a tautomer, meso-racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0122] Another aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula III:

[0123] Wherein, Ab is an antibody molecule, and m is an integer or decimal from 1 to 8;

[0124] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0125] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0126] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0127] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0128] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0129] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0130] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0131] When a=0, B1 is a direct key and T1 is not a direct key;

[0132] When b=0, B1 is not a direct key.

[0133] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIIa:

[0134] in:

[0135] Wherein, Ab is an antibody molecule, and m is an integer or decimal from 1 to 8;

[0136] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0137] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0138] B1 is a branching group;

[0139] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0140] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0141] D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different;

[0142] a is 1, 2 or 3.

[0143] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIIb:

[0144] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0145] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0146] B2 is a branching group;

[0147] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0148] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0149] D1 and D3 are the first and third drug units, respectively, and are the same or different;

[0150] b is 1, 2, or 3.

[0151] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure represented by Formula III:

[0152] Wherein, Ab is an antibody molecule, and m is an integer or decimal from 1 to 8;

[0153] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0154] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0155] B1 and B2 are independently branching groups;

[0156] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0157] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0158] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0159] a and b are independently 1, 2 or 3.

[0160] In a preferred embodiment, the present invention provides a compound selected from formula C1 to C190, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0161] Other aspects of the present invention will be readily apparent from the following detailed description of specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0162] Figure 1 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP1;

[0163] Figure 2 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP1;

[0164] Figure 3 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP2;

[0165] Figure 4 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP2;

[0166] Figure 5 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP3;

[0167] Figure 6 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP3;

[0168] Figure 7 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP4;

[0169] Figure 8 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP4;

[0170] Figure 9 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP5;

[0171] Figure 10 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP5;

[0172] Figure 11 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP6;

[0173] Figure 12 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP6;

[0174] Figure 13 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP7;

[0175] Figure 14 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP7;

[0176] Figure 15 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP8;

[0177] Figure 16 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP8;

[0178] Figure 17 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP9;

[0179] Figure 18 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP9;

[0180] Figure 19 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP10;

[0181] Figure 20 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP10;

[0182] Figure 21 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP11;

[0183] Figure 22 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP11;

[0184] Figure 23 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP12;

[0185] Figure 24 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP12;

[0186] Figure 25 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP13;

[0187] Figure 26 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP13;

[0188] Figure 27 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP17;

[0189] Figure 28 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MDP17;

[0190] Figure 29 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MD1;

[0191] Figure 30 shows the hydrophobic chromatography (HIC-HPLC) profile of the antibody conjugate T-MD1;

[0192] FIG31 shows a curve showing the volume change of human breast cancer HCC1954 over time after administration of the antibody conjugates MTX-1000, T-MDP2, T-MDP3, and MTX-1000 prepared in accordance with the disclosed embodiments in combination with the small molecule Rucaparib;

[0193] FIG32 shows the tumor growth inhibition curve of colon cancer COLO205 cells after administration of the antibody conjugates T-T1000e (MTX-1000), T-MDP2, T-MDP17, and the combination of T-T1000e and T-MCD1 (T-Rucaparib ADC) prepared in the Examples of the present disclosure;

[0194] FIG33 shows the tumor growth curve of colon cancer COLO205 inhibited by administration of the antibody conjugates T-MDP3, T-MDP7, T-MDP10, T-MDP11, T-MDP12 and huIgG-MDP2 prepared in the examples of the present disclosure;

[0195] FIG34 shows the tumor growth curves of colon cancer COLO205 in the groups administered with the antibody conjugates RS7-MDP2, T-MDP15, T-MDP16, and T-MDP27 prepared in the examples of the present disclosure;

[0196] Figure 35 shows the tumor growth curves of human colorectal adenocarcinoma SW837 cells that were inhibited by administration of the antibody conjugates U3-1407, P-MDP2, P-MDP3, P-MDP12, P-MDP15, P-MDP22, P-MDP27, and P-T1000e prepared in accordance with the disclosed embodiments;

[0197] FIG36 shows the tumor growth curves of human breast cancer MDA-MB-436 in the groups administered with the antibody conjugates DS5573a-MCD1, DS5573a-MDP2, and DS5573a-MDP6 prepared according to the examples of the present disclosure;

[0198] Figure 37 shows the growth curve of human pancreatic cancer BXPC-3 tumors inhibited by administration of the antibody conjugate Tisotumab-TM5-2 prepared in the Examples of the present disclosure;

[0199] Figure 38 shows that the DAR value of the antibody conjugate T-MDP2 detected by LCMS is 8.05;

[0200] Figure 39 shows that the DAR value of the antibody conjugate T-MDP12 detected by LCMS is 7.90;

[0201] Figure 40 shows a schematic diagram of the reaction steps for antibody coupling according to some embodiments of the present invention;

[0202] Figure 41 shows a schematic diagram of step A of engineering antibody thiomab according to some embodiments of the present invention;

[0203] Figure 42 shows a schematic diagram of step B of engineering the antibody thiomab according to some embodiments of the present invention;

[0204] Figure 43 shows the in vivo anti-tumor activity of antibody-drug conjugates RS7-A132, RS7-A46, and RS7-A149 against the human pancreatic cancer cell line BXPC-3;

[0205] FIG44 shows the in vivo anti-tumor activity of the antibody-drug conjugate against human breast cancer T-47D;

[0206] Figure 45 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate T-MDP54;

[0207] Figure 46 shows the mass spectrum of the antibody conjugate T-MDP54;

[0208] Figure 47 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate RS7-MDP12;

[0209] Figure 48 shows the mass spectrum of the antibody conjugate RS7-MDP12;

[0210] Figure 49 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate RS7-MDP44;

[0211] Figure 50 shows the mass spectrum of the antibody conjugate RS7-MDP44;

[0212] Figure 51 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate RS7-MDP47;

[0213] Figure 52 shows the mass spectrum of the antibody conjugate RS7-MDP47;

[0214] Figure 53 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate thioRS7-T1000e (DAR2)-TM5-21 (DAR8);

[0215] Figure 54 shows the mass spectrum of the antibody conjugate thioRS7-T1000e(DAR2)-TM5-21(DAR8);

[0216] Figure 55 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate thioRS7-T1000e (DAR2)-TM5-22 (DAR8);

[0217] Figure 56 shows the mass spectrum of the antibody conjugate thioRS7-T1000e(DAR2)-TM5-22(DAR8);

[0218] Figure 57 shows the size exclusion chromatography (SEC-HPLC) profile of the antibody conjugate thioRS7-MDP2 (DAR2)-TM5-21 (DAR8);

[0219] Figure 58 shows the mass spectrum of the antibody conjugate thioRS7-MDP2(DAR2)-TM5-21(DAR8);

[0220] Figure 59 shows the changes in aggregates of some antibody conjugates after three freeze-thaw experiments;

[0221] Figure 60 shows the changes in aggregates of some antibody conjugates after accelerated stability testing. DETAILED DESCRIPTION

[0222] definition

[0223] In the present invention, the term "alkyl" generally refers to a residue derived from an alkane by removing a hydrogen atom. An alkyl group can be substituted or non-substituted, substituted or non-substituted. The term "alkyl" generally refers to a saturated straight or branched aliphatic hydrocarbon group having a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing a hydrogen atom, and can be a straight or branched group containing 1 to 20 carbon atoms, for example, a chain alkyl containing 1 to 12 carbon atoms, for example, 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, etc. The alkyl group may be substituted or unsubstituted, substituted or unsubstituted, for example, when substituted, the substituent may be substituted at any available point of attachment, and the substituent may be independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, for example, hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 Aliphatic group.

[0224] In the present invention, the term "alkylene" generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of an alkane group. It can be a straight-chain or branched group containing 1 to 20 carbon atoms. For example, the term "methylene" can refer to a residue derived from a group containing 1 carbon atom by removing two hydrogen atoms. The methylene group can be substituted or unsubstituted, substituted or unsubstituted; for example, an alkylene group containing 1 to 12 carbon atoms, for example, an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and 1,5-butylene (-CH2CH2CH2CH2CH2-), and the like. Alkylene may be substituted or unsubstituted, substituted or unsubstituted, for example, when substituted, the substituent may be substituted at any available point of attachment, and the substituent may be independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, for example, hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1- 6 aliphatic groups. The methylene or alkylene groups may be substituted or unsubstituted.

[0225] In the present invention, the term "alkenyl" generally refers to a straight or branched hydrocarbon group containing one or more double bonds. Illustrative examples of alkenyl include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, and hexenyl. C 2-6 Illustrative examples of alkenyl groups include butadienyl, pentadienyl, hexadienyl and hexatrienyl and their branched forms. The position of the unsaturated bond (double bond) can be at any position of the carbon chain. The alkenyl group can be substituted or unsubstituted.

[0226] In the present invention, the term "alkenylene" generally refers to a residue derived from an alkene carbon atom by removing two hydrogen atoms. For example, it can be allylene, vinylene, butenylene, pentenylene and hexenylene. Alkenylene can be substituted or unsubstituted.

[0227] In the present invention, the term "alkynyl" generally refers to an unsaturated straight-chain or branched alkynyl group, such as ethynyl, 1-propynyl, propargyl, butynyl, etc. The alkynyl group may be substituted or unsubstituted.

[0228] In the present invention, the term "alkynylene" generally refers to a residue derived from a carbon atom of an alkyne by removing two hydrogen atoms. For example, it may be ethynylene, propynylene, propargylene, butynylene, etc. Alkynylenes may be substituted or unsubstituted.

[0229] In the present invention, the term "aryl" generally refers to a residue derived from an aromatic ring by removing a hydrogen atom. The term "aromatic ring" may refer to a 6- to 14-membered, all-carbon monocyclic ring or a fused polycyclic ring (i.e., rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, which may be 6- to 10-membered, such as benzene and naphthalene. The aromatic ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. Aryl groups may be substituted or unsubstituted. When substituted, the substituents may be one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. Aryl groups may be substituted or unsubstituted.

[0230] In the present invention, the term "arylene" generally refers to a residue derived from a carbon atom in an aromatic ring by removing two hydrogen atoms. Examples include phenylene and naphthylene. Arylene may be substituted or unsubstituted.

[0231] In the present invention, the term "heteroaryl" generally refers to a residue derived from a carbon atom in a heteroaromatic ring by removing a hydrogen atom. The term "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms can be selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl groups can be 5 to 10-membered, and can be 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. Heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. Heteroaryl can be substituted or unsubstituted.

[0232] In the present invention, the term "heteroarylene" generally refers to a residue derived from a carbon atom of a heteroaromatic ring by removing two hydrogen atoms. For example, it may be furanylene, thienylene, pyridylene, pyrrolylene, pyrimidylene, pyrazinylene, imidazolylene, tetrazolylene, etc. The heteroarylene group may be substituted or unsubstituted.

[0233] In the present invention, the term "alicyclic group" generally refers to a residue derived by removing a hydrogen atom from the same carbon atom or multiple different carbon atoms of an aliphatic ring. The term "cycloalkane" generally refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, wherein the carbocyclic ring contains 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, or may contain 3 to 8 carbon atoms. Non-limiting examples of alicyclic groups include cyclopropane, cyclobutane, cyclopentane, cyclopentenyl, cyclohexane, cyclohexenyl, cyclohexadienyl, cycloheptane, cycloheptatrienyl, cyclooctanyl, and the like; polycyclic carbocyclic rings may include spiro, fused, and bridged carbocyclic rings. Alicyclic groups may be substituted or unsubstituted. In the present invention, the term "carbocyclic group" generally refers to a residue derived by removing a hydrogen atom from a carbon atom of the carbocyclic ring. The term "carbocycle" generally refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring, wherein the carbocycle contains 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, and may contain 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, and the like; polycyclic carbocycles may include spirocyclic, fused, and bridged carbocycles. Carbocyclyl groups may be substituted or unsubstituted. In some cases, alicyclic and carbocyclic rings may be used interchangeably.

[0234] As used herein, the term "partially unsaturated" generally refers to a cyclic structure containing at least one double or triple bond between the ring molecules. The term "partially unsaturated" encompasses cyclic structures with multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined herein. The term "unsaturated" refers to a moiety having one or more degrees of unsaturation.

[0235] In the present invention, the term "alicyclic group" generally refers to a residue derived from a carbon atom of an alicyclic ring by removing two hydrogen atoms. Examples include cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexadienylene, cycloheptanylene, cycloheptatrienylene, and cyclooctanylene. Polycyclic carbocycles may include spiro, fused, and bridged carbocycles. Alicyclic groups may be substituted or unsubstituted.

[0236] In the present invention, the term "alicyclic group" generally refers to a stable, non-aromatic, 3- to 7-membered monocyclic carbocyclic structure, a fused 7- to 10-membered bicyclic heterocyclic structure, or a bridged 6- to 10-membered bicyclic heterocyclic structure. These ring structures may be saturated or partially saturated and, in addition to carbon atoms, may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. For example, these ring structures may contain 1 to 4 heteroatoms as defined above. When used to refer to atoms in an alicyclic heterocyclic structure, the term "nitrogen" may include nitrogen that has undergone substitution reactions. For example, an alicyclic heterocyclic group may include a "heterocycloalkyl" group, which may refer to a stable, non-aromatic, 3- to 7-membered monocyclic carbocyclic structure, a fused 7- to 10-membered bicyclic heterocyclic structure, or a bridged 6- to 10-membered bicyclic heterocyclic structure. In addition to carbon atoms, these ring structures may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. For example, these ring structures may contain 1 to 4 heteroatoms as defined above. Heterocycloalkyl groups may be substituted or unsubstituted. Alicyclic heterocyclic groups may be substituted or unsubstituted.

[0237] In the present invention, the term "aliphatic heterocyclic group" generally refers to a residue derived from a carbon atom of an aliphatic heterocyclic ring by removing two hydrogen atoms. The aliphatic heterocyclic group may be substituted or unsubstituted.

[0238] In the present invention, the term "optional" or "optionally" generally means that the subsequently described event or circumstance can but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group can but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0239] In the present invention, the term "substituted" generally refers to one or more hydrogen atoms in a group, for example up to 5, for example 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0240] In the present invention, as known to those skilled in the art, terms such as "alkyl", "alkenyl", "cycloalkyl", etc. may be preceded by an identifier to indicate the number of atoms present in the group in a particular case, for example, C1-C4 alkyl, C3-C7 cycloalkyloxy, C1-C4 alkylcarbonylamino, etc., and the subscript number after "C" indicates the number of carbon atoms present in the group. For example, C3 alkyl refers to an alkyl group having three carbon atoms (e.g., n-propyl, isopropyl); C 1-10 In the examples, the members of the group may have any number of carbon atoms falling within the range of 1-10.

[0241] One or more hydrogen atoms, for example up to 5, for example 1 to 3, in a group are independently replaced by a corresponding number of substituents. The substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0242] In the present invention, the term "compound" generally refers to a substance having two or more different elements. For example, the compound of the present invention may be an organic compound, for example, a compound having a molecular weight of 500 or less, a compound having a molecular weight of 1000 or less, a compound having a molecular weight of 1000 or more, or a compound having a molecular weight of 10,000 or more, or a compound having a molecular weight of 10,000 or more or 100,000 or more. In the present invention, a compound may also refer to a compound connected by chemical bonds, for example, a compound in which one or more molecules having a molecular weight of 1000 or less are connected to a biomacromolecule by chemical bonds, and the biomacromolecule may be a polysaccharide, protein, nucleic acid, polypeptide, etc. For example, the compound of the present invention may include a compound in which a protein is connected to one or more molecules having a molecular weight of 1000 or less, a compound in which a protein is connected to one or more molecules having a molecular weight of 10,000 or less, or a compound in which a protein is connected to one or more molecules having a molecular weight of 100,000 or less.

[0243] In the present invention, the term "comprising" generally refers to including the features specified but not excluding other elements. The terms "above" and "below" generally refer to including the number specified.

[0244] In the present invention, the term "about" generally refers to a variation within the range of 0.5%-10% above or below the specified value, for example, a variation within the range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified value.

[0245] In the present invention, the compounds of the present invention include tautomers, mesomorphs, racemates, enantiomers, and / or diastereomers of the compounds. In the present invention, the term "diastereomer" generally refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, such as, melting points, boiling points, spectral properties and reactivity. In the present invention, the terms "tautomer" or "tautomeric form" are used interchangeably and generally refer to structural isomers of different energies that can be mutually converted by low energy barriers. For example, proton tautomers (proton tautomers) (also referred to as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valence tautomers) include mutual conversions by the reorganization of some bonding electrons. As used herein, the term "meso" generally refers to a molecule containing asymmetric atoms but possessing symmetry factors resulting in a total optical rotation of zero. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species.

[0246] In the present invention, some atoms of the compounds of the present invention may appear in more than one isotopic form. For example, hydrogen may appear in the form of protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H), carbon can exist in three different isotopes ( 12 C. 13 C and 14 C) naturally occurring. Examples of isotopes that can be incorporated into the compounds of the present invention also include, but are not limited to 15 N. 18 O. 17 O. 18 F. 32 P. 33 P.129 I. 131 I. 123 I. 124 I. 125 I, or similar isotopes. Thus, the compounds of the present invention may be enriched in one or more of these isotopes relative to their natural abundance. As is known to those skilled in the art, such isotopically enriched compounds may be used in a variety of applications. For example, heavy isotopes such as deuterium ( 2 Deuterium (H) substitution may offer certain therapeutic advantages, possibly due to greater metabolic stability. 2 The natural abundance of deuterium (H) is approximately 0.015%. Thus, there is approximately one deuterium atom for every 6,500 hydrogen atoms in nature. Therefore, the deuterium-containing compounds of the present invention have a deuterium abundance greater than 0.015% at one or more positions (as appropriate). Unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds that are identical to the structures of the present invention except for the replacement of hydrogen atoms by deuterium or tritium, or the replacement of carbon atoms by carbon-13 or carbon-14, are within the scope of the present invention.

[0247] In the present invention, the term "analog" generally refers to a compound having the same or similar structure or function as the inhibitor, which can inhibit the activity of the enzyme by at least 50%. The analog can be an isomer, isomer, derivative, metabolite, precursor or split product of the inhibitor, or a compound obtained by adding, deleting, replacing or changing one or more atoms, chemical bonds, functional groups, substituents or stereo configurations in the molecular structure of the inhibitor. The analog can have the same or different pharmacological properties as the inhibitor, such as solubility, stability, bioavailability, half-life, toxicity or side effects.

[0248] In the present invention, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds of the present invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to an organism, facilitating the absorption of the active ingredient and thereby exerting its biological activity. Conventional pharmaceutical compositions can be prepared using techniques commonly used in the art.

[0249] In the present invention, the term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" generally refers to a salt of a compound or ligand-drug conjugate of the present invention, or a salt of a compound described in the present invention. Such salts may be safe and / or effective when used in mammals and may have the desired biological activity. The antibody-antibody drug conjugate compound of the present invention may form a salt with an acid. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, or p-toluenesulfonate.

[0250] In the present invention, the term "conjugate" generally refers to a compound prepared by one or more chemical reactions of the compounds of the present invention, or connected to each other through one or more connecting structures such as a bridge, spacer, or linking moiety.

[0251] In the present invention, the term "pharmaceutically acceptable carrier" generally refers to a carrier for administering therapeutic agents, such as antibodies or polypeptides, genes and other therapeutic agents. The term refers to any drug carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and can be administered without excessive toxicity. For example, a pharmaceutically acceptable carrier can be distinguished from a nucleic acid vector used to contain a target gene in genetic engineering. Suitable carriers can be large, slowly metabolized macromolecules, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polyamino acids, amino acid copolymers, lipid aggregates and inactivated viral particles. Those skilled in the art are familiar with these carriers. Pharmaceutically acceptable carriers in therapeutic compositions may include liquids, such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting agents or emulsifiers, pH buffer substances, etc., may also be present in these carriers.

[0252] In the present invention, the term "group capable of coupling with a thiol group" generally means that the compound A has a thiol group, the compound B has a group capable of coupling with a thiol group, and the compound B reacts with the thiol group of the compound A through the group capable of coupling with the thiol group, thereby achieving the connection between the compound A and the compound B.

[0253] In the present invention, the term "linker" generally refers to a chemical structure, a fragment or a bond thereof that is connected to one group at one end and to another group at the other end. It can also be connected to other linkers and then connected to the drug and / or ligand. The direct or indirect connection to the ligand can refer to the group being directly connected to the ligand through a covalent bond, or it can be connected to the ligand through a linker. For example, the linker can be the structure shown in Q1 of the present invention. For example, a chemical structure fragment or bond containing an acid-labile linker structure (such as a hydrazone), a protease-sensitive (such as a peptidase-sensitive) linker structure, a photolabile linker structure, a dimethyl linker structure, or a disulfide-containing linker structure can be used as a linker.

[0254] In the present invention, the term "linking group" generally refers to a group capable of connecting to another group. For example, a compound having a linking group can be connected to another group through a coupling reaction between the linking group and the other group. For example, a maleimide group can serve as a linking group.

[0255] In the present invention, the term "Drug Unit" generally refers to a chemical moiety that is directly or indirectly conjugated to an antibody or antigen-binding fragment to form an immunoconjugate. For example, a "Drug Unit" includes, but is not limited to, a compound with anti-tumor activity as described herein. For example, a Drug Unit includes a topoisomerase inhibitor.

[0256] In the present invention, the term "compound with anti-tumor activity" generally refers to a compound that has the ability to reduce the proliferation rate, viability, or metastatic activity of tumor cells. For example, anti-tumor activity can be demonstrated by a decrease in the growth rate of abnormal cells or a stabilization or reduction in tumor size during treatment, or by a prolonged survival period resulting from treatment compared to a control without treatment. Anti-tumor activity can be assessed using recognized in vitro or in vivo tumor models, such as xenograft models.

[0257] In some embodiments of the present invention, the bioactive molecule in the conjugate is a compound with specific anti-tumor activity, for example, a radioisotope, such as At 211 , I 131 , I 125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 、P 32 , Pb 212or radioisotopes of Lu; metal complexes, such as metal platinum complexes (such as oxaliplatin) or metal gold complexes; glycopeptide antibiotics, such as bleomycin or bleomycin; topoisomerase inhibitors; drugs that interfere with DNA synthesis, such as methotrexate, 5-fluorouracil, cytarabine, gemcitabine, mercaptopurine, pentostatin, fludarabine, cladribine or nelarabine; drugs that act on structural proteins, such as microtubule inhibitors (such as vinca alkaloids, vincristine, vinblastine, paclitaxels, maytansines, auristatins, Tubulysin B or eribulin); tumor signaling pathway inhibitors, such as serine / threonine kinase inhibitors, tyrosine kinase inhibitors, aspartate kinase inhibitors or histidine kinase inhibitors; proteasome inhibitors; epigenetic target inhibitors; tumor angiogenesis inhibitors; cell cycle protein inhibitors;

[0258] In the present invention, the term "topoisomerase inhibitor" or "drug targeting topoisomerase" generally refers to compounds including topoisomerase I inhibitors and topoisomerase II inhibitors or their derivatives. Examples of topoisomerase I inhibitors include, but are not limited to, camptothecin and its analogs; topoisomerase II inhibitors (such as voreloxin (CAS 175414-77-4) or its derivatives, actinomycin D, adriamycin, doxorubicin, duocarmycin, daunorubicin, mitoxantrone, podophyllotoxin or etoposide, etc.). Topoisomerase can refer to an enzyme that corrects the number of DNA loops by cutting the phosphodiester bonds in one or both strands of DNA and then rewinding and sealing.

[0259] In the present invention, the term "camptothecin analogue" generally refers to a compound that is structurally similar to camptothecin or derived from camptothecin. For example, camptothecin analogues may include exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), belotecan (CAS 213819-48-8), (4-NH2)-exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), and the like.

[0260] In the present invention, the term "PARP inhibitor" stands for poly ADP ribose polymerase (PARP) inhibitor, which is a new type of molecular targeted therapy drug that inhibits poly ADP ribose polymerase (PARP). For example, PARP inhibitors may include olaparib, niraparib, rucaparib (Rubraca), talazoparib (Talzenna), fluzoparib, pamiparib, A-966492, AZD5305, venadaparib, mefuparib (CAS 1449746-00-2), etc.

[0261] In the present invention, the term "ATR" refers to the kinase associated with the ataxia telangiectasia mutated gene Rad3, a key enzyme in the homologous recombination repair pathway of damaged DNA and a member of the PIKK family. For example, ATR inhibitors include Elimusertib / BAY1895344, Berzosertib / VE-822, Ceralasertib / AZD6738, M4344, and RP-3500.

[0262] As used herein, the term "CHK1" refers to cell cycle checkpoint kinase 1 (CHK1), a member of the serine / threonine protein kinase family and a core protein of the cell cycle checkpoint in the DNA damage response. Studies have shown that CHK1 protein kinase promotes tumor cell proliferation, that its deficiency can sensitize tumor cells to radiotherapy or chemotherapy, and that its inhibitors, when combined with other molecularly targeted drugs, have a "synthetic lethal" effect. Examples of CHK1 inhibitors include Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), SAR-020106, LY2880070, and AZD7648.

[0263] In the present invention, the term "ATM" is ataxia telangiectasia mutated, which is a serine / threonine protein. For example, the CHK1 inhibitor can be AZD-1390, M-4076, XRD-0394, etc.

[0264] In the present invention, the term "DNA-PK" refers to the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which belongs to the phosphoinositide 3-kinase-related protein (PI3K-related kinase, PIKK) family and is a serine / threonine protein kinase. For example, DNA-PK inhibitors can include wortmannin, AZD7648, LY294002, NU7026, NU7441, VX-984, M3814, CC-115, etc.

[0265] In the present invention, the term "WEE1" refers to an important member of the serine / threonine protein kinase family, a cell cycle regulatory protein, and a key kinase in the DNA damage repair (DDR) pathway. It participates in cell cycle regulation and plays a key role in the G2 / M checkpoint. For example, WEE1 inhibitors can include ZN-C3, Adavosertib (AZD1775), Debio 0123, etc.

[0266] In the present invention, the term "POLQ" refers to an error-prone translocation polymerase that is also involved in the repair of DNA double-strand breaks and is often upregulated in cancerous conditions. For example, a POLQ inhibitor can be ART4215, RP-6685, etc.

[0267] In the present invention, the term "PKMYT1" refers to a regulator of CDK1 phosphorylation, which has established a synthetic lethal relationship with CCNE1 amplification and is an attractive therapeutic target for treating certain types of DNA damage response cancers. For example, a PKMYT1 inhibitor can be RP-6306, etc.

[0268] In the present invention, the term "Rad51" encodes a 339-amino acid polypeptide with a relative molecular mass of 4.3×10⁴. It has five homologs: XRCC2, XRCC3, RAD51B (RAD51L1), RAD51C (RAD51L2), and RAD51D (RAD551L3). These homologs, along with RAD51, participate in the HR process. Tumors that overexpress RAD51 often exhibit treatment resistance and lower overall patient survival. For example, a Rad51 inhibitor can be CYT-0851.

[0269] For the purposes of this invention, the term "Bcl-2 family proteins" refers to a family of evolutionarily related proteins that can receive and transmit intracellular signals or external environmental stress signals, such as nutrient or hypoxic stress, DNA damage, overactivation of oncogenes, and endoplasmic reticulum stress. The Bcl-2 family of proteins plays a key role in tumorigenesis and metastasis. Bcl-2 family proteins are primarily divided into three categories: the anti-apoptotic subfamily, which contains four functional domains: BH1, BH2, BH3, and BH4, and includes Bcl-2, Bcl-xL, and Mcl-1; the pro-apoptotic subfamily, which contains four functional domains: BH1, BH2, BH3, and BH4, and includes Bax, Bak, and Bok; and the pro-apoptotic BH3-only subfamily, which contains only the BH3 domain and includes Bim, Bid, Puma, Noxa, and Bad. For example, the Bcl-2 inhibitor can be Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), ABT-737 (CAS 852808-04-9), A-1331852 (1430844-80-6), or an analog thereof.

[0270] In the present invention, the term "LSD1," also referred to as KDM1A / AOF2, is the first discovered histone-specific demethylase. LSD1 catalyzes flavin adenine dinucleotide (FAD) and belongs to the monoamine oxidase family. For example, LSD1 inhibitors can include tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG-7289, INCB059872, or TAK-418.

[0271] In the present invention, the term "EZH2 inhibitor" generally refers to the catalytic subunit of histone methyltransferase and PRC2, which catalyzes the monomethylation, dimethylation and trimethylation of lysine 27 of histone H3 (H3K27me3). EZH2 inhibitors can promote the antigen presentation ability of the tumor microenvironment and activate anti-tumor adaptive immune responses. For example, EZH2 inhibitors can be Tazemetostat (Epizyme), GSK2816126 (GlaxoSmithKline), CPI-1205 (Constellation Pharmaceuticals), PF-06821497 (Pfizer), SHR2554 (Hengrui Medicine), XNW5004 (Sinovent), HH2853 (Shanghai Haihe Pharmaceutical), etc.

[0272] In the present invention, the term "PRMT5" refers to arginine methylation, a type of histone methylation, which is one of the most common post-translational modifications in mammals and is primarily regulated by the PRMT gene family. PRMT5 inhibitors can include GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001, and the like.

[0273] In the present invention, the term "TLR7 / 8" refers to an endosomal receptor that recognizes single-stranded RNAs (ssRNAs) with viral characteristics, such as abundant GU dinucleotide motifs. TLR7 or TLR8 agonists can include 1V209 derivatives, Resiquimod, etc.

[0274] In this application, the term "STING" refers to the stimulator of interferon genes (STING), which activates the stimulator of interferon genes and triggers an immune response. Numerous studies have shown that STING is involved in the pathogenesis of various diseases. STING activation can induce effective immune responses against pathogens and cancer; however, aberrant STING activation can trigger autoimmune and inflammatory diseases. STING agonists include the cyclic dinucleotide ADUS100, the anthraquinone DMXAA, the aminobenzimidazoles, and the benzothiophene MSA-2.

[0275] In the present invention, the term "Ras-Raf-MAPK pathway inhibitor" refers to a compound that specifically binds to and inhibits the activity of key protein kinases in the Ras-Raf-MAPK pathway, thereby effectively blocking the signal transduction of the pathway. This inhibitor has high selectivity and affinity, and can accurately target key molecules in the Ras-Raf-MAPK pathway, reduce or eliminate their biological activity, and thus inhibit the proliferation, migration and invasion of tumor cells. Related targets and related inhibitors include: SOS1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS 2230836-55-0) or their analogs; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS 2621928-55-8) or their analogs; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS 2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS 2055597-12-9) or its analogs, etc.

[0276] In the present invention, the term "cell cycle pathway inhibitor" refers to inhibitors of CDK kinases (cyclin-dependent kinase kinases), which specifically bind to and inhibit the activity of different CDK kinases, thereby effectively regulating the cell cycle process. Such inhibitors have high selectivity and specificity, can accurately target CDK kinases, reduce or eliminate their biological activity, and thus affect various stages of the cell cycle, including DNA replication, chromosome segregation, and cell division. The inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs.

[0277] In the present invention, the term GSPT1 refers to a post-transcriptional modifier that can bind to the MYC protein and stabilize its structure, thereby enhancing its transcriptional activity. MYC is a transcription factor that can regulate the expression of multiple genes, such as the cell cycle, metabolism, cell death, etc. However, in many cancers, MYC is overexpressed or amplified, leading to the occurrence and development of tumors. Currently, MYC inhibitors have become an effective treatment for MYC-driven solid tumors, but there are also some problems, such as low selectivity, many side effects, and easy drug resistance. Therefore, degrading GSPT1 is a strategy to inhibit the MYC signaling pathway.

[0278] In the present invention, the term "disease associated with the expression of a target" generally means that the occurrence and / or progression of the disease is associated with the expression level of the target. For example, relative to the expression level of normal cells from the tissue or organ, the expression level of a target in cells from a disease area, such as a specific tissue or organ of a patient, is increased, i.e., highly expressed. Or, for example, relative to the expression level of normal cells from the tissue or organ, the expression level of a target in cells from a disease area, such as a specific tissue or organ of a patient, is decreased, i.e., underexpressed. Or, for example, cells from a disease area, such as a specific tissue or organ of a patient, express a target, i.e., are positive. Or, for example, cells from a disease area, such as a specific tissue or organ of a patient, do not express a target, i.e., are negative. For example, the characteristics of target expression can be determined by standard assays known in the art.

[0279] As used herein, the term "effective amount" generally refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect. The precise effective amount for a given subject depends on the subject's size and health, the nature and severity of the condition, and the therapeutic agent and / or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and is within the judgment of the clinician.

[0280] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0281] As used herein, the term "compound of the present invention" refers to any compound provided by the present invention. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of the present invention.

[0282] When a trade name is used herein, the trade name is intended to include the trade name product formulation, its corresponding generic drug, and the active pharmaceutical ingredient of the trade name product.

[0283] As used herein, "antibody" is used in its broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments, as long as they exhibit the desired biological activity. Antibodies can be murine, human, humanized, chimeric antibodies or derived from other species. Antibodies are proteins produced by the immune system that can recognize and bind to specific antigens. Target antigens generally have a large number of binding sites, also known as epitopes, that are recognized by the CDRs of multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Therefore, an antigen can have more than one corresponding antibody. Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain an antigen or a portion thereof that specifically binds to a target of interest, such targets including, but not limited to, cancer cells or cells that produce autoimmune antibodies associated with autoimmune diseases. The immunoglobulins described herein can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecules. Immunoglobulins can be derived from any species. However, in one aspect, the immunoglobulins are derived from humans, mice, or rabbits. "Antibody fragments" can comprise a portion of a full-length antibody, generally its antigen-binding region or variable region. Examples of antibody fragments include: Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; minibodies; fragments prepared from Fab expression libraries; anti-idiotypic (anti-Id) antibodies; CDRs (complementarity determining regions); and any of the above epitope-binding fragments that immunospecifically bind to cancer cell antigens, viral antigens, or microbial antigens; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. The above antibodies can also be modified with natural amino acids using THIOMAB technology to perform site-specific modification of unpaired cysteines to achieve more coupling sites and site-specific coupling. The antibodies constituting the antibody-drug conjugates of the present invention can maintain their original antigen-binding ability in the wild-type state. Therefore, the antibodies of the present invention can, for example, bind specifically to antigens. The antigens involved include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival regulatory factors, cell proliferation regulatory factors, molecules related to tissue growth and differentiation (such as those known or predicted to have functional properties), lymphokines, cytokines, molecules involved in cell cycle regulation, molecules involved in angiogenesis, and molecules related to angiogenesis (such as those known to bind to antibodies). The antigens bound by the antibodies can be one or a subset of the above categories, while other subsets contain other molecules / antigens with special properties (compared to the target antigen). The antibodies used in the antibody-drug conjugates include, but are not limited to, antibodies against cell surface receptors and tumor-associated antigens.Such tumor-associated antigens are well known in the art and can be prepared using well-known antibody preparation methods and information. These targets can be specifically expressed on the surface of one or more cancer cells, while showing little or no expression on the surface of one or more non-cancerous cells. Typically, such tumor-associated polypeptides are more overexpressed on the surface of cancer cells than on the surface of non-cancerous cells.

[0284] In the present invention, the term "polypeptide residue" generally refers to a residue comprising one or more amino acid residues linked together. For example, one or more amino acids in a polypeptide residue may be optionally substituted.

[0285] In the present invention, the term "polyethylene glycol group" generally refers to a residue comprising one or more ethylene glycol residues linked together. For example, a polyethylene glycol group may comprise -(CH2CH2O) p -, wherein p is a number from 1 to 10. For example, the polyethylene glycol group in the present invention may be optionally substituted.

[0286] In the present invention, the term "glycol" generally refers to a polyethylene glycol group. For example, the glycol group in the present invention can be optionally substituted. For example, the number preceding the glycol group can represent the number of ethylene glycol units in the glycol group, for example, a diethylene glycol group can refer to the residue of two ethylene glycol units.

[0287] In the present invention, the term "cyclodextrin" generally refers to α-, β-, and γ-cyclodextrin, which are cyclic oligomers composed of 6, 7, and 8 D(+)-pyranose glucopyranose, respectively.

[0288] In the present invention, the term "polysarcosine residue" generally refers to a residue comprising one or more sarcosine residues linked together. For example, a polysarcosine residue may comprise -(COCH2N(CH3)) q -, wherein q is a number of at least 1. For example, the polysarcosine residues in the present invention may be optionally substituted. For example, the structure containing the polysarcosine residues may be wherein n2 is a number from 4 to 18, and R is an alkyl group, an alkyl group substituted with a hydrophilic group such as a polyhydroxyl group, a sulfonic acid group, a phosphoric acid group, or a carboxyl group.

[0289] In the present invention, the term "sodium dodecyl sulfate polyacrylamide gel electrophoresis" generally refers to a substance analysis and characterization technique. For example, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) can detect the molecular weight of a substance.

[0290] In the present invention, the term "hydrophobic chromatography" generally refers to an analytical technique based on the difference in hydrophobicity of substances.

[0291] In the present invention, the term "liquid chromatography-mass spectrometry" generally refers to an analytical method for identifying the components of a substance. For example, liquid chromatography-mass spectrometry can analyze the molecular weight of a substance by combining liquid chromatography-mass spectrometry.

[0292] In the present invention, the term "tumor" generally refers to any new, pathological tissue proliferation. For the purposes of the present invention, angiogenesis is part of the characteristics of tumors. Tumors can be benign or malignant. The term "tumor" is generally used to refer to benign or malignant tumors, while the term "cancer" is generally used to refer to malignant tumors, which can be metastatic or non-metastatic.

[0293] In the present invention, the term "multi-drug" (e.g., "dual-drug") refers to two or more drug molecules with the same or different chemical formulas covalently attached to the same site or linker in an ADC that is linked to an antibody. When the chemical formulas are different, the two or more drug molecules may have the same mechanism of action (e.g., both are TOPO1 inhibitors) or different mechanisms of action (e.g., a TOPO1 inhibitor and a DDR inhibitor, respectively).

[0294] Multidrug conjugates

[0295] One aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula I:

[0296] in,

[0297] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0298] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0299] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0300] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0301] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0302] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0303] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0304] When a=0, B1 is a direct key and T1 is not a direct key;

[0305] When b=0, B1 is not a direct key.

[0306] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula Ia:

[0307] in:

[0308] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0309] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0310] B1 is a branching group;

[0311] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0312] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0313] D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different;

[0314] a is 1, 2 or 3.

[0315] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula Ib:

[0316] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0317] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0318] B2 is a branching group;

[0319] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0320] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0321] D1 and D3 are the first and third drug units, respectively, and are the same or different;

[0322] b is 1, 2, or 3.

[0323] In other embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure represented by Formula I:

[0324] in,

[0325] Q is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0326] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0327] B1 and B2 are independently branching groups;

[0328] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0329] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0330] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; and

[0331] a and b are independently 1, 2 or 3.

[0332] In some embodiments, in Formulas I, Ia, and Ib, Q is selected from the group consisting of: optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted and optionally substituted Wherein * represents the position connected to C1, and the W group in Q7 is bromine, Ar-S group, wherein Ar is phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from alkyl, alkoxy, halogen, ester, nitro and -C(O)NR1R2-, R1 and R2 in the group are independently selected from a chemical bond, H and alkyl, or R1 and R2 form a 5-7 membered heterocycle, and the heteroatom is selected from one or more of O, N and S.

[0333] In some embodiments, in Formulas I, Ia, and Ib, Q is selected from the group consisting of: Wherein * represents the position connected to C1, and the W group in Q7 is bromine, Ar-S group, wherein Ar is phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from alkyl, alkoxy, halogen, ester, nitro and -C(O)NR1R2-, R1 and R2 in the group are independently selected from a chemical bond, H and alkyl, or R1 and R2 form a 5-7 membered heterocycle, and the heteroatom is selected from one or more of O, N and S.

[0334] In a preferred embodiment, in Formulas I, Ia and Ib, Q is Q1.

[0335] In a preferred embodiment, in Formulas I, Ia and Ib, C1 is selected from: a direct bond, -(CH2)m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 - NHC(O)-(CH2) m2 - and -(CC-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q on the left side and to B1 or P1 on the right side.

[0336] In a preferred embodiment, in Formula I and Ia, B1 is selected from the group consisting of a direct bond, wherein connection point 1 is connected to C1, connection point 2 is connected to P1, connection points * and 3 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6.

[0337] In a preferred embodiment, in Formula I or Ia, when C1 is a direct bond, B1 is Wherein connection point 1 is connected to Q, connection point 2 is connected to P1, connection point 3 is connected to P2, and L6 is -(CH2) m1 -or -(CH2-CH2-O)m2, wherein m1 and m2 are each independently 1, 2, 3, 4, 5 or 6.

[0338] In a preferred embodiment, in Formula I and Ia, B1 is selected from the group consisting of a direct bond, Connection point 1 is connected to C1, connection point 2 is connected to P1, and connection points 3, 4, and 5 are connected to P2.

[0339] In some embodiments, in Formulas I and Ib, B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following groups: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

[0340] In some embodiments, in Formula I, T1, T2, and T3 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1, P2 or P3, and connection point 2 is connected to D1, D2 or D3.

[0341] In some embodiments, in Formula Ia, T1 and T2 are independently selected from the following groups: a direct bond, Optionally substituted Connection point 1 is connected to P1 or P2, and connection point 2 is connected to D1 or D2.

[0342] In some embodiments, in Formula Ib, T1 is selected from the following group: and optionally substituted Wherein connection point 1 is connected to P1, connection point 2 is connected to D1, and T3 is selected from the following group: direct bond, and optionally substituted Connection point 1 is connected to P3, and connection point 2 is connected to D3.

[0343] In some embodiments, in Formulas I, Ia, and Ib, P1, P2, and P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine.

[0344] In a preferred embodiment, in Formulas I, Ia and Ib, P1, P2, P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine.

[0345] In a preferred embodiment, in Formulas I, Ia and Ib, P1, P2, and P3, when present, independently comprise an optionally substituted polypeptide residue selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit), In a preferred embodiment, in Formulas I, Ia and Ib, P1, P2, and P3, when present, are independently phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), and glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly).

[0346] In one embodiment, in Formulas I, Ia, and Ib, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

[0347] In a preferred embodiment, in Formulas I, Ia and Ib, the hydrophilic group is selected from: a substituted polysarcosine residue, a polyglycerol, a polyol, a glycosyl group, a cyclodextrin, a substituted ethylene glycol fragment, a substituted glycosylated polyethylene glycol, a substituted glycosylated polyglycerol, a substituted cyclodextrin polyethylene glycol or a combination thereof.

[0348] In some preferred embodiments, in Formulas I, Ia and Ib, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, for example, an integer between 4 and 16, and R is selected from the group consisting of: C1-C6 alkyl, C1-C6 cycloalkyl, and C1-C6 alkoxy.

[0349] In some preferred embodiments, in Formulas I, Ia and Ib, the substituted glycosylated polyglycerol fragment is Wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10.

[0350] In some preferred embodiments, in Formulas I, Ia and Ib, the substituted polyethylene glycol segment is Wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18.

[0351] In other preferred embodiments, in Formulas I, Ia and Ib, the substituted glycosylated polyethylene glycol fragment is Wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12.

[0352] In other preferred embodiments, in Formula I, at least one of T1, T2, and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 through X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

[0353] In other preferred embodiments, in Formula Ia, at least one of T1 and T2 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T2 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T2.

[0354] In other preferred embodiments, in Formula Ib, at least one of T1 and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T3 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T3.

[0355] In a preferred embodiment, in Formulas I, Ia and Ib, D1, D2, and D3, when present, are respectively the first anticancer agent, the second anticancer agent, and the third anticancer agent; preferably, at least two of the first anticancer agent, the second anticancer agent, and the third anticancer agent have a synergistic anticancer effect.

[0356] In a preferred embodiment, D1, D2 and D3, when present, are independently cytotoxic drugs or tumor-targeting therapeutic drugs.

[0357] In some embodiments, in Formulas I, Ia, and Ib, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs. In some embodiments, in Formulas I, Ia, and Ib, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs and have the same structural formula. In some embodiments, in Formulas I, Ia, and Ib, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs, but have different structural formulas.

[0358] In a preferred embodiment, at least one of D1, D2, and D3 is a cytotoxic drug, and at least one other is a tumor-targeted therapeutic drug. In a preferred embodiment, at least two of D1, D2, and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects. In a preferred embodiment, at least two of D1, D2, and D3 are cytotoxic drugs.

[0359] Preferably, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a drug unit targeting tubulin, a nucleoside antimetabolite anticancer drug unit, and a drug unit targeting DNA;

[0360] In a preferred embodiment, the tumor targeted therapeutic drug is selected from a drug unit targeting a DNA damage response (DDR) or "synthetic lethality" related pathway, or a drug unit targeting an epigenetic pathway, or a drug unit targeting apoptosis-related pathway, a drug unit targeting a transcription factor, or a drug unit targeting an immune activation pathway-related target, including inhibitors of EFGR pathway-related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0361] In a preferred embodiment, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another one is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways.

[0362] Therefore, in some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase, a drug targeting microtubules and a drug targeting DNA, and at least another is a tumor-targeted therapeutic drug, the tumor-targeted therapeutic drug is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting microtubules, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting DNA, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway.

[0363] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting topoisomerase, a drug targeting tubulin, and a drug targeting DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting topoisomerase, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting tubulin, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting DNA, and at least one other is a drug targeting epigenetic.

[0364] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA-targeted drug, and at least one other is a drug targeting an apoptosis-related pathway.

[0365] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug with a target related to an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA, and at least one other is a drug targeting an immune activation pathway.

[0366] In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to DNA damage response (DDR) or "synthetic lethality." In some embodiments, at least two of D1, D2, and D3 are drugs that target epigenetic pathways. In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to apoptosis. In some embodiments, at least two of D1, D2, and D3 are drugs that target immune activation pathways.

[0367] In some embodiments, at least two of D1, D2, and D3 are drugs that target topoisomerase. In some embodiments, at least two of D1, D2, and D3 are nucleoside antimetabolite anticancer drugs. In some embodiments, at least two of D1, D2, and D3 are drugs that target tubulin. In some embodiments, at least two of D1, D2, and D3 are drugs that target DNA.

[0368] In some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, which is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another is a tumor-targeted therapeutic drug, which is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, and Rad51 inhibitors.

[0369] In some embodiments, at least two of D1, D2, and D3 are cytotoxic drugs and are independently selected from topoisomerase-targeted drugs and tubulin-targeted drug units, such as TOPO1 inhibitors, TOPO2 inhibitors, and tubulin inhibitors.

[0370] In some embodiments, at least two or all three of D1, D2, and D3 are tumor-targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, Drug units targeting epigenetics, drug units targeting apoptosis-related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors.

[0371] In some embodiments, one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase and a drug targeting tubulin, such as a TOPO1 inhibitor or a tubulin inhibitor, and the other one or two are tumor-targeted therapeutic drugs, the tumor-targeted therapeutic drugs are selected from a drug unit targeting DNA damage response (DDR) or "synthetic lethality" related pathways, a drug unit targeting epigenetic, a drug unit targeting apoptosis-related pathways, a drug unit targeting cell cycle pathways, a drug unit targeting transcription factors and a drug unit targeting immune activation pathways. The drug unit includes targets including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors.

[0372] In a preferred embodiment, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs. In a preferred embodiment, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives. In a preferred embodiment, the drug unit targeting DNA is a DNA minor groove binder (PBD), DNA alkylating agent (Duocarmycin), trabectedin, rubectin or its derivatives.

[0373] In a preferred embodiment, the drug unit targeting the DNA damage response (DDR) or "synthetic lethality" related pathway is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor, or a Rad51 inhibitor; the PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or an analog thereof; the ATR inhibitor is preferably Berzosertib, Ceralasertib or an analog thereof; and / or the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs; and / or the WEE1 inhibitor is preferably ZN-C3, Adavosertib (AZD1775) or its analogs;

[0374] Preferably, the analogue of AZD5305 comprises the following structure: where R a Selected from -C(O)NH-R b or -NHC(O)-R b , R b Selected from: C substituted with at least one primary or secondary amino group 2-7 Alkyl, C 3-7 Monocyclic alkyl, C 4-10 Bicyclic cycloalkyl, C 5-9 Spirocyclic cycloalkyl and C 5-9 Bridged cycloalkyl, or R b It is a 4-6 membered monoheterocyclic alkyl containing 1-5 nitrogen, oxygen, or sulfur atoms, C 4-10 Bicyclic heterocycloalkyl, C 5-9 Spiroheterocycloalkyl, C 5-9 A bridged heterocycloalkyl group, wherein the Rb group contains at least one primary or secondary amine group;

[0375] Preferably, the AZD5305 analogue is selected from the following structures:

[0376] In a preferred embodiment, the PKMYT1 inhibitor is preferably RP-6306 and GSK-1520489A or analogs thereof.

[0377] In a preferred embodiment, the analogs of the WEE1 inhibitor Adavosertib (AZD1775, CAS 955365-80-7) and Debio 0123 (CAS 2243882-74-6) are selected from the following structures:

[0378] In a preferred embodiment, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor, which includes a BCL-2 inhibitor, a BCL-XL inhibitor, and a MCL-1 inhibitor, preferably Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), a Navitoclax analog (CAS 2143096-93-7), ABT-737 (CAS 852808-04-9), A-1331852 (CAS 1430844-80-6), S64315 (CAS 1799631-75-6), or an analog thereof.

[0379] Preferably, the A-1331852 and S64315 analogs are selected from the following structures:

[0380] In a preferred embodiment, the epigenetic-targeted drug unit is a LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor, or a PRMT1 inhibitor. In a preferred embodiment, the LSD1 inhibitor is preferably Tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG-7289, INCB059872 or TAK-418 or an analog thereof; the EZH2 inhibitor is preferably Tazemetostat (CAS 1403254-99-8), GSK2816126, CPI-1205, PF-06821497, SHR2554, XNW5004, HH2853 or an analog thereof; the BRD4 inhibitor is BI-2536 analogues, Birabresib; the PRMT5 inhibitor is preferably GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001 or their analogs. The PRMT1 inhibitor is preferably GSK3368715 (CAS 1629013-22-4), MS023 (CAS 1831110-54-3) or their analogs.

[0381] In a preferred embodiment, the inhibitors of the Ras-Raf-MAPK pathway include: SOS1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS 2230836-55-0) or analogs thereof; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS 2621928-55-8) or analogs thereof; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1035555-63-5), and the like. 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS 2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS 2055597-12-9) or its analogs.

[0382] In a preferred embodiment, the cell cycle pathway inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs;

[0383] In a preferred embodiment, the PI3K / AKT / mTOR pathway inhibitor includes: PKI-587 (CAS 1197160-78-3), demethyl PKI-587 (CAS 1950569-63-7), AZD8055 (CAS 1009298-09-2), Afuresertib (CAS 1047644-62-1) or analogs thereof.

[0384] In a preferred embodiment, the estrogen receptor antagonist / degrader is Fulvestrant (CAS 129453-61-8), Elacestrant (CAS 1349723-93-8); androgen receptor antagonist abiraterone (CAS 154229-19-3), JNJ-63576253 (CAS 2110428-64-1) or an analog thereof.

[0385] In a preferred embodiment, the autophagy inhibitor is hydroxychloroquine (HCQ, CAS 118-42-3) and chloroquine (CQ, CAS 54-05-7) or analogs thereof.

[0386] In a preferred embodiment, the drug targeting the transcription factor is a GSPT1 degrader (molecular glue), and the GSPT1 degrader is selected from the following structures:

[0387] Preferably, the PLK1 inhibitor is BI2536 (CAS 755038-02-9), Volasertib (CAS 755038-65-4), GSK461364 (CAS 929095-18-1), Onvansertib (CAS 1034616-18-6) or an analog thereof.

[0388] In a preferred embodiment, the N-myristoyltransferase (NMT) inhibitor is MYX1715 (CAS 2445448-66-6) or an analog thereof.

[0389] In a preferred embodiment, D1, D2 and D3 are selected from the following combinations:

[0390] In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0391] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs, at least one other selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0392] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs; at least one other selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0393] In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is an LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0394] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives, and at least another one is selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0395] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof, and at least another is selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0396] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: PBD or Duocarmycin, and at least another one is selected from: PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0397] In a preferred embodiment, at least one of D1, D2 and D3 is PBD or Duocarmycin, and at least one other is selected from Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0398] In a preferred embodiment, at least two of D1, D2 and D3 are drugs targeting DNA damage response (DDR) or "synthetic lethality" related pathways. In a preferred embodiment, at least two of D1, D2 and D3 are selected from the group consisting of: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0399] In a preferred embodiment, D1, D2 and D3 can be selected from the combinations shown in Table A.

[0400] Table A. Exemplary combinations of D1, D2, and D3

[0401] In the present invention, the embodiments or preferred embodiments of the above components (such as Q, C1, B1, B2, T1, T2, T3, P1, P2, P3, D1, D2, D3, hydrophilic group) can be applied individually to Formula I, Ia or Ib, or in various combinations to Formula I, Ia or Ib. When applicable in combination, the embodiments or preferred embodiments of the components can be combined in whole or in part.

[0402] In a preferred embodiment, the present invention provides a compound selected from Formulae A1 to A190, or a tautomer, meso racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0403] Another aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula II:

[0404] in,

[0405] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0406] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0407] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0408] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0409] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0410] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0411] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0412] When a=0, B1 is a direct key and T1 is not a direct key;

[0413] When b=0, B1 is not a direct key.

[0414] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIa:

[0415] in:

[0416] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0417] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0418] B1 is a branching group;

[0419] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0420] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0421] D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different;

[0422] a is 1, 2 or 3.

[0423] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIb:

[0424] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0425] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0426] B2 is a branching group;

[0427] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0428] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0429] D1 and D3 are the first and third drug units, respectively, and are the same or different;

[0430] b is 1, 2, or 3.

[0431] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula II:

[0432] in,

[0433] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0434] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0435] B1 and B2 are independently branching groups;

[0436] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0437] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0438] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0439] a and b are independently 1, 2 or 3.

[0440] In a preferred embodiment, in Formula II, IIa and IIb, the Selected from the group consisting of: optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted and optionally substituted The * represents the site of connection with C1, and the wavy line represents the site of connection with the antibody.

[0441] In a preferred embodiment, in Formula II, IIa and IIb, the Selected from the following groups: Wherein * represents the position connected to C1, and the wavy line represents the position connected to the antibody. Preferably, in Formula II, IIa and IIb, for

[0442] In a preferred embodiment, in Formula II, IIa and IIb, C1 is selected from: a direct bond, -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(CC-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q' on the left side and to B1 or P1 on the right side.

[0443] In a preferred embodiment, in Formula II and IIa, B1 is selected from the following groups: a direct bond, wherein connection point 1 is connected to C1, connection point 2 is connected to P1, connection points * and 3 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6.

[0444] In a preferred embodiment, in Formula II or IIa, when C1 is a direct bond, B1 is Wherein connection point 1 is connected to Q', connection point 2 is connected to P1, connection point 3 is connected to P2, and L6 is -(CH2) m1 -or -(CH2-CH2-O)m2, wherein m1 and m2 are each independently 1, 2, 3, 4, 5 or 6.

[0445] In a preferred embodiment, in Formula II and IIa, B1 is selected from the following groups: a direct bond, Connection point 1 is connected to C1, connection point 2 is connected to P1, and connection points 3, 4, and 5 are connected to P2.

[0446] In some embodiments, in Formula II and IIb, B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following groups: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

[0447] In some embodiments, in Formula II, T1, T2, and T3 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1, P2 or P3, and connection point 2 is connected to D1, D2 or D3.

[0448] In some embodiments, in Formula IIa, T1 and T2 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1 or P2, and connection point 2 is connected to D1 or D2.

[0449] In some embodiments, in Formula IIb, T1 is selected from the following group: and optionally substituted Wherein connection point 1 is connected to P1, connection point 2 is connected to D1, and T3 is selected from the following group: direct bond, and optionally substituted Connection point 1 is connected to P3, and connection point 2 is connected to D3.

[0450] In some embodiments, in Formula II, IIa and IIb, P1, P2, and P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine.

[0451] In a preferred embodiment, in Formula II, IIa and IIb, P1, P2, P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine.

[0452] In a preferred embodiment, in Formula II, IIa and IIb, P1, P2, and P3, when present, independently comprise an optionally substituted polypeptide residue selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit), and glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly). In a preferred embodiment, in Formula II, IIa and IIb, P1, P2, and P3, when present, are independently phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly), or glycine-proline (Gly-Pro).

[0453] In one embodiment, in Formula II, IIa and IIb, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

[0454] In a preferred embodiment, in Formula II, IIa and IIb, the hydrophilic group is selected from: a substituted polysarcosine residue, a polyglycerol, a polyol, a glycosyl group, a cyclodextrin, a substituted ethylene glycol fragment, a substituted glycosylated polyethylene glycol, a substituted glycosylated polyglycerol, a substituted cyclodextrin polyethylene glycol or a combination thereof.

[0455] In some preferred embodiments, in Formula II, IIa and IIb, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, for example, an integer between 4 and 16, and R is selected from the group consisting of: C1-C6 alkyl, C1-C6 cycloalkyl, and C1-C6 alkoxy.

[0456] In other preferred embodiments, in Formula II, IIa and IIb, the substituted glycosylated polyethylene glycol fragment is Wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12.

[0457] In a preferred embodiment, the substituted glycosylated polyglycerol fragment is Wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10.

[0458] In a preferred embodiment, the substituted polyethylene glycol segment is Wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18.

[0459] In other preferred embodiments, in Formula II, at least one of T1, T2, and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 through X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

[0460] In other preferred embodiments, in Formula IIa, at least one of T1 and T2 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T2 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T2.

[0461] In other preferred embodiments, in Formula IIb, at least one of T1 and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T3 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T3.

[0462] In a preferred embodiment, in Formula II, IIa and IIb, D1, D2 and D3, when present, are respectively the first anticancer agent, the second anticancer agent and the third anticancer agent; preferably, at least two of the first anticancer agent, the second anticancer agent and the third anticancer agent have a synergistic anticancer effect.

[0463] In a preferred embodiment, D1, D2 and D3, when present, are independently cytotoxic drugs or tumor-targeting therapeutic drugs.

[0464] In some embodiments, in Formula II, IIa, and IIb, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs. In some embodiments, in Formula II, IIa, and IIb, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs and have the same structural formula. In some embodiments, in Formula II, IIa, and IIb, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs, but have different structural formulas.

[0465] In a preferred embodiment, at least one of D1, D2, and D3 is a cytotoxic drug, and at least one other is a tumor-targeted therapeutic drug. In a preferred embodiment, at least two of D1, D2, and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects. In a preferred embodiment, at least two of D1, D2, and D3 are cytotoxic drugs.

[0466] In a preferred embodiment, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a drug unit targeting tubulin, a nucleoside antimetabolite anticancer drug unit, or a drug unit targeting DNA.

[0467] In a preferred embodiment, the tumor targeted therapeutic drug is selected from a drug unit targeting a DNA damage response (DDR) or "synthetic lethality" related pathway, or a drug unit targeting an epigenetic pathway, or a drug unit targeting apoptosis-related pathway, a drug unit targeting a transcription factor, or a drug unit targeting an immune activation pathway-related target, including inhibitors of EFGR pathway-related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0468] In a preferred embodiment, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another one is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways.

[0469] Therefore, in some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase, a drug targeting microtubules and a drug targeting DNA, and at least another is a tumor-targeted therapeutic drug, the tumor-targeted therapeutic drug is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting microtubules, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting DNA, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway.

[0470] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting topoisomerase, a drug targeting tubulin, and a drug targeting DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting topoisomerase, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting tubulin, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting DNA, and at least one other is a drug targeting epigenetic.

[0471] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA-targeted drug, and at least one other is a drug targeting an apoptosis-related pathway.

[0472] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug with a target related to an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA, and at least one other is a drug targeting an immune activation pathway.

[0473] In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to DNA damage response (DDR) or "synthetic lethality." In some embodiments, at least two of D1, D2, and D3 are drugs that target epigenetic pathways. In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to apoptosis. In some embodiments, at least two of D1, D2, and D3 are drugs that target immune activation pathways.

[0474] In some embodiments, at least two of D1, D2, and D3 are drugs that target topoisomerase. In some embodiments, at least two of D1, D2, and D3 are drugs that target tubulin. In some embodiments, at least two of D1, D2, and D3 are nucleoside antimetabolite anticancer drugs. In some embodiments, at least two of D1, D2, and D3 are drugs that target DNA.

[0475] In some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, which is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another is a tumor-targeted therapeutic drug, which is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, and Rad51 inhibitors.

[0476] In some embodiments, at least two of D1, D2, and D3 are cytotoxic drugs and are independently selected from topoisomerase-targeted drugs and tubulin-targeted drug units, such as TOPO1 inhibitors, TOPO2 inhibitors, and tubulin inhibitors.

[0477] In some embodiments, at least two or all three of D1, D2 and D3 are tumor targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetic pathways, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including targets including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0478] In some embodiments, one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase and a drug targeting tubulin, such as a TOPO1 inhibitor or a tubulin inhibitor, and the other one or two are tumor-targeted therapeutic drugs, the tumor-targeted therapeutic drugs are selected from a drug unit targeting DNA damage response (DDR) or "synthetic lethality" related pathways, a drug unit targeting epigenetic, a drug unit targeting apoptosis-related pathways, a drug unit targeting cell cycle pathways, a drug unit targeting transcription factors and a drug unit targeting immune activation pathways. The drug unit includes targets including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors.

[0479] In a preferred embodiment, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs. In a preferred embodiment, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives. In a preferred embodiment, the drug unit targeting DNA is a DNA minor groove binder (PBD), DNA alkylating agent (Duocarmycin), trabectedin, rubectin or its derivatives.

[0480] In a preferred embodiment, the drug unit targeting the DNA damage response (DDR) or "synthetic lethality" related pathway is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor, or a Rad51 inhibitor; the PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or an analog thereof; the ATR inhibitor is preferably Berzosertib, Ceralasertib or an analog thereof; and / or the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs; and / or the WEE1 inhibitor is preferably ZN-C3, Adavosertib (AZD1775) or its analogs;

[0481] Preferably, the analogue of AZD5305 comprises the following structure: where R a Selected from -C(O)NH-R b or -NHC(O)-R b , R b Selected from: C substituted with at least one primary or secondary amino group 2-7 Alkyl, C 3-7 Monocyclic alkyl, C 4-10 Bicyclic cycloalkyl, C 5-9 Spirocyclic cycloalkyl and C 5-9 Bridged cycloalkyl, or R b It is a 4-6 membered monoheterocyclic alkyl containing 1-5 nitrogen, oxygen, or sulfur atoms, C 4-10 Bicyclic heterocycloalkyl, C 5-9 Spiroheterocycloalkyl, C 5-9 Bridged heterocycloalkyl, wherein the R b The group contains at least one primary or secondary amine group;

[0482] Preferably, the AZD5305 analogue is selected from the following structures:

[0483] In a preferred embodiment, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor, which includes a BCL-2 inhibitor, a BCL-XL inhibitor, and a MCL-1 inhibitor, preferably Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), a Navitoclax analog (CAS 2143096-93-7), ABT-737 (CAS 852808-04-9), A-1331852 (CAS 1430844-80-6), S64315 (CAS 1799631-75-6), or an analog thereof.

[0484] Preferably, the A-1331852 and S64315 analogs are selected from the following structures:

[0485] In a preferred embodiment, the epigenetic-targeted drug unit is a LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor, or a PRMT1 inhibitor. In a preferred embodiment, the LSD1 inhibitor is preferably Tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG-7289, INCB059872 or TAK-418 or an analog thereof; the EZH2 inhibitor is preferably Tazemetostat (CAS 1403254-99-8), GSK2816126, CPI-1205, PF-06821497, SHR2554, XNW5004, HH2853 or an analog thereof; the BRD4 inhibitor is BI-2536 analogues, Birabresib; the PRMT5 inhibitor is preferably GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001 or their analogs. The PRMT1 inhibitor is preferably GSK3368715 (CAS 1629013-22-4), MS023 (CAS 1831110-54-3) or their analogs. In a preferred embodiment, the drug unit for the target related to the immune activation pathway is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist or a STING agonist.

[0486] In a preferred embodiment, the inhibitors of the Ras-Raf-MAPK pathway include: SOS1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS 2230836-55-0) or analogs thereof; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS 2621928-55-8) or analogs thereof; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1035555-63-5), and selumetinib (CAS 606143-52-6). 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS 2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS 2055597-12-9) or its analogs.

[0487] In a preferred embodiment, the cell cycle pathway inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs;

[0488] In a preferred embodiment, the PI3K / AKT / mTOR pathway inhibitor includes: PKI-587 (CAS 1197160-78-3), demethyl PKI-587 (CAS 1950569-63-7), AZD8055 (CAS 1009298-09-2), Afuresertib (CAS 1047644-62-1) or analogs thereof.

[0489] In a preferred embodiment, the estrogen receptor antagonist / degrader is Fulvestrant (CAS 129453-61-8), Elacestrant (CAS 1349723-93-8); androgen receptor antagonist abiraterone (CAS 154229-19-3), JNJ-63576253 (CAS 2110428-64-1) or an analog thereof.

[0490] In a preferred embodiment, the autophagy inhibitor is hydroxychloroquine (HCQ, CAS 118-42-3) and chloroquine (CQ, CAS 54-05-7) or analogs thereof.

[0491] In a preferred embodiment, the drug targeting the transcription factor is a GSPT1 degrader (molecular glue), and the GSPT1 degrader is selected from the following structures:

[0492] Preferably, the PLK1 inhibitor is BI2536 (CAS 755038-02-9), Volasertib (CAS 755038-65-4), GSK461364 (CAS 929095-18-1), Onvansertib (CAS 1034616-18-6) or an analog thereof.

[0493] Preferably, the N-myristoyltransferase (NMT) inhibitor is MYX1715 (CAS 2445448-66-6) or an analog thereof;

[0494] In a preferred embodiment, D1, D2 and D3 are selected from the following combinations:

[0495] In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, a PTPN2 / 1 inhibitor, or a STING agonist.

[0496] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs, at least one other selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0497] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs; at least one other selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0498] In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is an LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0499] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives, and at least another one is selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0500] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof, and at least another one is selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0501] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: PBD or Duocarmycin, and at least another one is selected from: PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0502] In a preferred embodiment, at least one of D1, D2 and D3 is PBD or Duocarmycin, and at least one other is selected from Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0503] In a preferred embodiment, at least two of D1, D2 and D3 are drugs targeting DNA damage response (DDR) or "synthetic lethality" related pathways. In a preferred embodiment, at least two of D1, D2 and D3 are selected from the group consisting of: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0504] In a preferred embodiment, D1, D2 and D3 can be selected from the combinations shown in Table A.

[0505] Table A. Exemplary combinations of D1, D2, and D3

[0506] In the present invention, the embodiments or preferred embodiments of the above components (such as Q', C1, B1, B2, T1, T2, T3, P1, P2, P3, D1, D2, D3, and hydrophilic groups) can be applied individually to Formula II, IIa, or IIb, or in various combinations. When applicable in combination, the embodiments or preferred embodiments of the components can be combined in whole or in part.

[0507] In a preferred embodiment, the present invention provides a compound selected from formula B1 to B190, or a tautomer, meso racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0508] In the present invention, the structures represented by Formula II, IIa and IIb and their embodiments (including B1 to B190) are also referred to as "drug-linker fragment", "linker-drug fragment", or "LP".

[0509] Another aspect of the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the structural formula of the linker is shown in Formula IV below:

[0510] in,

[0511] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0512] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0513] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0514] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0515] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0516] Connection points 2, 3, and 4 are connected to the drug unit;

[0517] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0518] When a=0, B1 is a direct key and T1 is not a direct key;

[0519] When b=0, B1 is not a direct key.

[0520] In some embodiments, the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IVa:

[0521] in:

[0522] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0523] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0524] B1 is a branching group;

[0525] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0526] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0527] Connection points 2 and 3 connect to the drug unit;

[0528] a is 1, 2 or 3.

[0529] In some embodiments, the present invention provides a linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IVb:

[0530] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody;

[0531] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0532] B2 is a branching group;

[0533] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0534] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0535] Connection points 2 and 3 connect to the drug unit;

[0536] b is 1, 2, or 3.

[0537] In some embodiments, in Formula IV, IVa and IVb, Q' is selected from the group consisting of: optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted and optionally substituted The * represents the site connected to C1, and the wavy line represents the site connected to the antibody molecule.

[0538] In some embodiments, in Formula IV, IVa, and IVb, Q' is selected from the group consisting of: Wherein * represents the position of connection with C1, and the wavy line represents the position of connection with the antibody molecule. More preferably, in Formula IV, IVa and IVb, Q' is Q1'.

[0539] In some embodiments, in Formula IV, IVa, and IVb, C1 is selected from: -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(C≡C-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q' on the left side and to B1 or P1 on the right side.

[0540] In a preferred embodiment, in formula IV and IVa, B1 is selected from the group consisting of a direct bond, wherein connection point 1 is connected to C1, connection point 2 is connected to P1, connection points * and 3 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6.

[0541] In a preferred embodiment, in Formula IV or IVa, when C1 is a direct bond, B1 is Wherein connection point 1 is connected to Q', connection point 2 is connected to P1, connection point 3 is connected to P2, and L6 is -(CH2) m1 -or -(CH2-CH2-O)m2, wherein m1 and m2 are each independently 1, 2, 3, 4, 5 or 6.

[0542] In a preferred embodiment, in formula IV and IVa, B1 is selected from the group consisting of a direct bond, Connection point 1 is connected to C1, connection point 2 is connected to P1, and connection points 3, 4, and 5 are connected to P2.

[0543] In some embodiments, in Formula IV and IVb, B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following groups: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

[0544] In some embodiments, in Formula IV, T1, T2, and T3 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1, P2 or P3, and connection point 2 is connected to D1, D2 or D3.

[0545] In some embodiments, in Formula IVa, T1 and T2 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1 or P2, and connection point 2 is connected to D1 or D2.

[0546] In some embodiments, in Formula IVb, T1 is selected from the following group: and optionally substituted Wherein connection point 1 is connected to P1, connection point 2 is connected to D1, and T3 is selected from the following group: direct bond, and optionally substituted Connection point 1 is connected to P3, and connection point 2 is connected to D3.

[0547] In some embodiments, in Formulas IV, IVa, and IVb, P1, P2, and P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine.

[0548] In a preferred embodiment, in Formulas IV, IVa and IVb, P1, P2, P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine.

[0549] In a preferred embodiment, in Formulas IV, IVa and IVb, P1, P2, and P3, when present, independently comprise an optionally substituted polypeptide residue selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit), In a preferred embodiment, in Formulas IV, IVa and IVb, P1, P2 and P3, when present, are independently phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit) and glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly).

[0550] In one embodiment, in Formula IV, IVa and IVb, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

[0551] In a preferred embodiment, in Formulas IV, IVa and IVb, the hydrophilic group is selected from: a substituted polysarcosine residue, a polyglycerol, a polyol, a glycosyl group, a cyclodextrin, a substituted ethylene glycol fragment, a substituted glycosylated polyethylene glycol, a substituted glycosylated polyglycerol, a substituted cyclodextrin polyethylene glycol or a combination thereof.

[0552] In some preferred embodiments, in Formulas IV, IVa and IVb, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, for example, an integer between 4 and 16, and R is selected from the group consisting of: C1-C6 alkyl, C1-C6 cycloalkyl, and C1-C6 alkoxy.

[0553] In other preferred embodiments, in Formula IV, IVa and IVb, the substituted glycosylated polyethylene glycol fragment is Wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12.

[0554] In a preferred embodiment, the substituted glycosylated polyglycerol fragment is Wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10.

[0555] In a preferred embodiment, the substituted polyethylene glycol segment is Wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18.

[0556] In other preferred embodiments, in Formula IV, at least one of T1, T2, and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 through X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

[0557] In other preferred embodiments, in Formula IVa, at least one of T1 and T2 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T2 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T2.

[0558] In other preferred embodiments, in Formula IVb, at least one of T1 and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T3 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T3.

[0559] In some embodiments, the present invention provides a linker as shown in D1 to D38, or a tautomer, meso-racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0560] Antibody-drug conjugates (ADCs)

[0561] Another aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula III:

[0562] Wherein, Ab is an antibody molecule, and m is an integer or decimal from 1 to 8;

[0563] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0564] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0565] B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond;

[0566] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0567] T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group;

[0568] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0569] a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and

[0570] When a=0, B1 is a direct key and T1 is not a direct key;

[0571] When b=0, B1 is not a direct key.

[0572] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIIa:

[0573] in:

[0574] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0575] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0576] B1 is a branching group;

[0577] P1 and P2 are independently optionally substituted polypeptide residues or glucose moieties;

[0578] T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group;

[0579] D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different;

[0580] a is 1, 2 or 3.

[0581] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises the structure shown in Formula IIIb:

[0582] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0583] C1 is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy;

[0584] B2 is a branching group;

[0585] P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety;

[0586] T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group;

[0587] D1 and D3 are the first and third drug units, respectively, and are the same or different;

[0588] b is 1, 2, or 3.

[0589] In some embodiments, the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure represented by Formula III:

[0590] Wherein, Ab is an antibody molecule, and m is an integer or decimal from 1 to 8;

[0591] Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule;

[0592] C1 is selected from the group consisting of a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy;

[0593] B1 and B2 are independently branching groups;

[0594] P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety;

[0595] T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group;

[0596] D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different;

[0597] a and b are independently 1, 2 or 3.

[0598] In a preferred embodiment, in formula III, IIIa and IIIb, said Q' is selected from the following groups: optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted and optionally substituted The * represents the site of connection with C1, and the wavy line represents the site of connection with Ab.

[0599] In a preferred embodiment, in Formula III, IIIa and IIIb, Q' is selected from the following groups: Wherein * represents the position of connection with C1, and the wavy line represents the position of connection with Ab. Preferably, in formula III, IIIa and IIIb, the Q' is

[0600] In a preferred embodiment, in Formula III, IIIa and IIIb, C1 is selected from: -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2)m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(C≡C-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q' on the left side and to B1 or P1 on the right side.

[0601] In a preferred embodiment, in formula III and IIIa, B1 is selected from the following groups: a direct bond, wherein connection point 1 is connected to C1, connection point 2 is connected to P1, connection points * and 3 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6.

[0602] In a preferred embodiment, in Formula III or IIIa, when C1 is a direct bond, B1 is Wherein connection point 1 is connected to Q', connection point 2 is connected to P1, connection point 3 is connected to P2, and L6 is -(CH2) m1 -or -(CH2-CH2-O)m2, wherein m1 and m2 are each independently 1, 2, 3, 4, 5 or 6.

[0603] In a preferred embodiment, in formula III and IIIa, B1 is selected from the following groups: a direct bond, Connection point 1 is connected to C1, connection point 2 is connected to P1, and connection points 3, 4, and 5 are connected to P2.

[0604] In some embodiments, in Formula III and IIIb, B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following groups: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

[0605] In some embodiments, in Formula III, T1, T2, and T3 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1, P2 or P3, and connection point 2 is connected to D1, D2 or D3.

[0606] In some embodiments, in Formula IIIa, T1 and T2 are independently selected from the following groups: a direct bond, and optionally substituted Connection point 1 is connected to P1 or P2, and connection point 2 is connected to D1 or D2.

[0607] In some embodiments, in Formula IIIb, T1 is selected from the following group: and optionally substituted Wherein connection point 1 is connected to P1, connection point 2 is connected to D1, and T3 is selected from the following group: direct bond, and optionally substituted Connection point 1 is connected to P3, and connection point 2 is connected to D3.

[0608] In some embodiments, in Formula III, IIIa and IIIb, P1, P2, and P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine.

[0609] In a preferred embodiment, in Formula III, IIIa and IIIb, P1, P2, P3, when present, independently comprise polypeptide residues consisting of optionally substituted amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine.

[0610] In a preferred embodiment, in Formula III, IIIa and IIIb, P1, P2, and P3, when present, independently comprise an optionally substituted polypeptide residue selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit), Glycine-Glycine-Phenylalanine-Glycine (Gly-Gly-Phe-Gly), Glycine-Proline (Gly-Pro). In a preferred embodiment, In Formula III, IIIa and IIIb, P1, P2, and P3, when present, are independently phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit) and glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly).

[0611] In one embodiment, in formula III, IIIa and IIIb, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

[0612] In a preferred embodiment, in Formula III, IIIa and IIIb, the hydrophilic group is selected from: a substituted polysarcosine residue, a polyglycerol, a polyol, a glycosyl group, a cyclodextrin, a substituted ethylene glycol fragment, a substituted glycosylated polyethylene glycol, a substituted glycosylated polyglycerol, a substituted cyclodextrin polyethylene glycol or a combination thereof.

[0613] In some preferred embodiments, in Formula III, IIIa and IIIb, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, for example, an integer between 4 and 16, and R is selected from the group consisting of: C1-C6 alkyl, C1-C6 cycloalkyl, and C1-C6 alkoxy.

[0614] In other preferred embodiments, in Formula III, IIIa and IIIb, the substituted glycosylated polyethylene glycol fragment is Wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12.

[0615] In a preferred embodiment, the substituted glycosylated polyglycerol fragment is Wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10.

[0616] In a preferred embodiment, the substituted polyethylene glycol segment is Wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18.

[0617] In other preferred embodiments, in Formula III, at least one of T1, T2, and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 through X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

[0618] In other preferred embodiments, in Formula IIIa, at least one of T1 and T2 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T2 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T2.

[0619] In other preferred embodiments, in Formula IIIb, at least one of T1 and T3 is wherein X is optionally substituted The hydrophilic group is connected to T1 or T3 via X, wherein the connection point 1 in X is connected to the hydrophilic group, and the connection point 2 is connected to one of T1 and T3.

[0620] In a preferred embodiment, in Formula III, IIIa and IIIb, D1, D2, and D3, when present, are respectively the first anticancer agent, the second anticancer agent, and the third anticancer agent; preferably, at least two of the first anticancer agent, the second anticancer agent, and the third anticancer agent have a synergistic anticancer effect.

[0621] In a preferred embodiment, D1, D2 and D3, when present, are independently cytotoxic drugs or tumor-targeting therapeutic drugs.

[0622] In some embodiments, in Formula III, IIIa, and IIIb, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs. In some embodiments, in Formula II, IIa, and IIb, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs and have the same structural formula. In some embodiments, in Formula III, IIIa, and IIIb, D1, D2, and D3, when present, are all cytotoxic drugs or are all targeted tumor therapeutic drugs, but have different structural formulas.

[0623] In a preferred embodiment, at least one of D1, D2, and D3 is a cytotoxic drug, and at least one other is a tumor-targeted therapeutic drug. In a preferred embodiment, at least two of D1, D2, and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects. In a preferred embodiment, at least two of D1, D2, and D3 are cytotoxic drugs.

[0624] In a preferred embodiment, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a nucleoside antimetabolite anticancer drug unit, a drug unit targeting tubulin, or a drug unit targeting DNA.

[0625] In a preferred embodiment, the tumor targeted therapeutic drug is selected from a drug unit targeting a DNA damage response (DDR) or "synthetic lethality" related pathway, or a drug unit targeting an epigenetic pathway, or a drug unit targeting apoptosis-related pathway, a drug unit targeting a transcription factor, or a drug unit targeting an immune activation pathway-related target, including inhibitors of EFGR pathway-related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0626] In a preferred embodiment, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another one is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways.

[0627] Therefore, in some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase, a drug targeting microtubules and a drug targeting DNA, and at least another is a tumor-targeted therapeutic drug, the tumor-targeted therapeutic drug is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting microtubules, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting DNA, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway.

[0628] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting topoisomerase, a drug targeting tubulin, and a drug targeting DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting topoisomerase, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting tubulin, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting DNA, and at least one other is a drug targeting epigenetic.

[0629] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA-targeted drug, and at least one other is a drug targeting an apoptosis-related pathway.

[0630] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug with a target related to an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA, and at least one other is a drug targeting an immune activation pathway.

[0631] In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to DNA damage response (DDR) or "synthetic lethality." In some embodiments, at least two of D1, D2, and D3 are drugs that target epigenetic pathways. In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to apoptosis. In some embodiments, at least two of D1, D2, and D3 are drugs that target immune activation pathways.

[0632] In some embodiments, at least two of D1, D2, and D3 are drugs that target topoisomerase. In some embodiments, at least two of D1, D2, and D3 are drugs that target tubulin. In some embodiments, at least two of D1, D2, and D3 are nucleoside antimetabolite anticancer drugs. In some embodiments, at least two of D1, D2, and D3 are drugs that target DNA.

[0633] In some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, which is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another is a tumor-targeted therapeutic drug, which is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, and Rad51 inhibitors.

[0634] In some embodiments, at least two of D1, D2, and D3 are cytotoxic drugs and are independently selected from topoisomerase-targeted drugs and tubulin-targeted drug units, such as TOPO1 inhibitors, TOPO2 inhibitors, and tubulin inhibitors.

[0635] In some embodiments, at least two or all three of D1, D2 and D3 are tumor targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetic pathways, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including targets including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0636] In some embodiments, one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase and a drug targeting tubulin, such as a TOPO1 inhibitor or a tubulin inhibitor, and the other one or two are tumor-targeted therapeutic drugs, the tumor-targeted therapeutic drugs are selected from a drug unit targeting DNA damage response (DDR) or "synthetic lethality" related pathways, a drug unit targeting epigenetic, a drug unit targeting apoptosis-related pathways, a drug unit targeting cell cycle pathways, a drug unit targeting transcription factors and a drug unit targeting immune activation pathways. The drug unit includes targets including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors.

[0637] In a preferred embodiment, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs. In a preferred embodiment, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives. In a preferred embodiment, the drug unit targeting DNA is a DNA minor groove binder (PBD), DNA alkylating agent (Duocarmycin), trabectedin, rubectin or its derivatives.

[0638] In a preferred embodiment, the drug unit targeting the DNA damage response (DDR) or "synthetic lethality" related pathway is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor, or a Rad51 inhibitor; the PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or an analog thereof; the ATR inhibitor is preferably Berzosertib, Ceralasertib or an analog thereof; and / or the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs; and / or the WEE1 inhibitor is preferably ZN-C3, Adavosertib (AZD1775) or its analogs;

[0639] Preferably, the analogue of AZD5305 comprises the following structure: where R a Selected from -C(O)NH-R b or -NHC(O)-R b , R b Selected from: C substituted with at least one primary or secondary amino group 2-7 Alkyl, C 3-7 Monocyclic alkyl, C 4-10 Bicyclic cycloalkyl, C 5-9 Spirocyclic cycloalkyl and C 5-9 Bridged cycloalkyl, or R b It is a 4-6 membered monoheterocyclic alkyl containing 1-5 nitrogen, oxygen, or sulfur atoms, C 4-10 Bicyclic heterocycloalkyl, C 5-9 Spiroheterocycloalkyl, C 5-9 A bridged heterocycloalkyl group, wherein the Rb group contains at least one primary or secondary amine group;

[0640] Preferably, the AZD5305 analogue is selected from the following structures:

[0641] In a preferred embodiment, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor, which includes a BCL-2 inhibitor, a BCL-XL inhibitor, and a MCL-1 inhibitor, preferably Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), a Navitoclax analog (CAS 2143096-93-7), ABT-737 (CAS 852808-04-9), A-1331852 (1430844-80-6), S64315 (CAS 1799631-75-6), or an analog thereof.

[0642] In a preferred embodiment, the epigenetic-targeted drug unit is a LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor, or a PRMT1 inhibitor. In a preferred embodiment, the LSD1 inhibitor is preferably Tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG-7289, INCB059872 or TAK-418 or an analog thereof; the EZH2 inhibitor is preferably Tazemetostat (CAS 1403254-99-8), GSK2816126, CPI-1205, PF-06821497, SHR2554, XNW5004, HH2853 or an analog thereof; the BRD4 inhibitor is BI-2536 analogues, Birabresib; the PRMT5 inhibitor is preferably GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001 or their analogs. The PRMT1 inhibitor is preferably GSK3368715 (CAS 1629013-22-4), MS023 (CAS 1831110-54-3) or their analogs.

[0643] In a preferred embodiment, the inhibitors of the Ras-Raf-MAPK pathway include: SOS1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS 2230836-55-0) or analogs thereof; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS 2621928-55-8) or analogs thereof; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1035555-63-5), and the like. 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS 2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS 2055597-12-9) or its analogs.

[0644] In a preferred embodiment, the cell cycle pathway inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs;

[0645] In a preferred embodiment, the PI3K / AKT / mTOR pathway inhibitor includes: PKI-587 (CAS 1197160-78-3), demethyl PKI-587 (CAS 1950569-63-7), AZD8055 (CAS 1009298-09-2), Afuresertib (CAS 1047644-62-1) or analogs thereof.

[0646] In a preferred embodiment, the estrogen receptor antagonist / degrader is Fulvestrant (CAS 129453-61-8), Elacestrant (CAS 1349723-93-8); androgen receptor antagonist abiraterone (CAS 154229-19-3), JNJ-63576253 (CAS 2110428-64-1) or an analog thereof.

[0647] In a preferred embodiment, the autophagy inhibitor is hydroxychloroquine (HCQ, CAS 118-42-3) and chloroquine (CQ, CAS 54-05-7) or analogs thereof.

[0648] In a preferred embodiment, the drug targeting the transcription factor is a GSPT1 degrader (molecular glue), and the GSPT1 degrader is selected from the following structures:

[0649] Preferably, the PLK1 inhibitor is BI2536 (CAS 755038-02-9), Volasertib (CAS 755038-65-4), GSK461364 (CAS 929095-18-1), Onvansertib (CAS 1034616-18-6) or an analog thereof.

[0650] In a preferred embodiment, the N-myristoyltransferase (NMT) inhibitor is MYX1715 (CAS 2445448-66-6) or an analog thereof.

[0651] In a preferred embodiment, D1, D2 and D3 are selected from the following combinations:

[0652] In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0653] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs, at least one other selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0654] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs; at least one other selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0655] In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is an LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0656] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives, and at least another one is selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0657] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof, and at least another one is selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0658] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: PBD or Duocarmycin, and at least another one is selected from: PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0659] In a preferred embodiment, at least one of D1, D2 and D3 is PBD or Duocarmycin, and at least one other is selected from Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0660] In a preferred embodiment, at least two of D1, D2 and D3 are drugs targeting DNA damage response (DDR) or "synthetic lethality" related pathways. In a preferred embodiment, at least two of D1, D2 and D3 are selected from the group consisting of: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0661] In a preferred embodiment, D1, D2 and D3 can be selected from the combinations shown in Table A.

[0662] Table A. Exemplary combinations of D1, D2, and D3

[0663] In a preferred embodiment, the present invention provides a compound selected from formula C1 to C190, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0664] In the present invention, in Formula III, IIIa, IIIb, C1 to C188, m can be 1 to 7.5, 1 to 7, 1 to 6.5, 1 to 6, 1 to 5.5, 1 to 5, 1 to 4.5, 1 to 4, 1 to 3.5, 1 to 2.5, 1 to 2, 1 to 1.5, 1.5 to 9, 1.5 to 8.5, 1-5 to 8, 1-5 to 7.5, 1-5 to 5.5, 1.5 to 5, 1.5 to 4.5, 1.5 to 4, 1.5 to 3.5, 1.5 to 3, 1.5 to 2.5, 1.5 to 2, 2 to 7.5, 2 to 7, 2 to 6.5, 2 to 6, 2 to 5.5, 2 to 5, 2 to 4.5, 2 to 4, 2 to 3.5, 2 to 3, 2 to 2.5, 2.5 to 8, 2.5 to 7.5, 2.5 to 7, 2.5 to 6.5, 2.5 to 6, 2.5 to 5.5, 2.5 to 4.5, 2.5 to 5, 2.5 to 2.5, 2.5 to 3.5, 3 to 7.5, 3 to 7, 3 to 6.5, 3 to 6, 3 to 5.5, 3 to 4.5, 3 to 4, 3 to 3.5, 3.5 to 7.5, 3.5 to 7, 3.5 to 6.5, 3.5 to 6, 3.5 to 5.5, 3.5 to 5, 3.5 to 4.5, 3.5 to 4, 4 to 8, 4 to 7.5, 4 to 7, 4 to 6.5, 4 to 6, 4 to 5.5, 4 to 5, or 4 to 4.5. For example, m can be about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8.

[0665] In the present invention, in Formula III, IIIa, IIIb, C1 to C190, Ab is a monoclonal antibody or an antigen-binding fragment thereof. In a preferred embodiment, the monoclonal antibody is an antibody against the following antigens: HER2, HER3, TROP2, B7-H3, B7-H4, GPC20, GPRC5D, CDH6, EGFR, EGFRvIII, AXL, Nectin-4, Tissue factor, TIM-1, PSMA, PTK7, EpCAM, MUC1, STEAP1, GPNMB, FGF2, FOLR1, c-MET, GFR, AGS-16, Guanylyl cyclase C, Mesothelin, SLC44A4, EphA2, AGS-5, GPC-3, c-KIT, ROR1, ROR2, PD-L1, CD27L, 5T4, MerTK, Mucin 16, NaPi2b, STEAP, SLITRK6, ETBR, BCMA, CEACAM5, ICAM1, SC-16, SLC39A6, Delta-like protein 3, Claudin 18.2, Claudin 3, Claudin 6, Claudin 9, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD73, CD74, CD79b, CD123, CD138, CD147, CD166, CD223, MUC16, MSLN, ENPP3, SLTRK6, FGFR, LIV-1, Lewis Y, av-integrin, ITGB6(integrin beta-6), ASCT2, C4.4a, CA-IX, CD324, CD352, CD44v6, CD48a, CLL-1, Cripto, CS1, DPEP3, Ephrin-A2, Ephrin-A4, ETBR, FGFR2, FGFR3, FLT3, GD3, Globo H, GPC3, LAMP-1, LRRC15, Ly6E, TM4SF1, MFI2, NOTCH3, p-cadherin, PRLR, CLDN1, CD228, CUB domain-containing protein 1 (CDCP1), CXCR4, LGR4, FZD7, CTR, GPR56, CCR7, DDR1 and RNF43.

[0666] In a preferred embodiment, the monoclonal antibody is an anti-HER2 antibody or an anti-TROP2 antibody. In some embodiments, the anti-HER2 antibody is trastuzumab, pertuzumab or magetuzumab. In some embodiments, the anti-TROP2 antibody is datopotamab or sacituzumab.

[0667] In the present invention, the embodiments or preferred embodiments of the above components (such as Q', C1, B1, B2, T1, T2, T3, P1, P2, P3, D1, D2, D3, hydrophilic group, m and Ab) can be applied individually to Formula III, IIIa or IIIb, or in various combinations to Formula III, IIIa or IIIb. When applicable in combination, the embodiments or preferred embodiments of the components can be combined in whole or in part.

[0668] Another aspect of the present invention provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound is an antibody-drug conjugate, comprising an antibody molecule and at least two compounds attached to the antibody molecule, wherein the at least two compounds attached to the antibody molecule are independently selected from the linker-drug fragment provided by the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0669] In a preferred embodiment, the ratio of the different drugs is any ratio from 1:1 to 1:24.

[0670] In a preferred embodiment, the at least two compounds attached to the antibody molecule are attached to different coupling sites of the antibody molecule; preferably, the different coupling sites are selected from the natural or modified sulfhydryl, amino and non-natural amino acids of the antibody.

[0671] Pharmaceutical compositions, uses and methods

[0672] One aspect of the present invention also provides a pharmaceutical composition comprising any compound of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, prodrug or solvate, and a pharmaceutically acceptable carrier.

[0673] The pharmaceutically acceptable carrier is selected from the group consisting of fillers (diluents), binders, wetting agents, disintegrants, excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the compound of the present invention.

[0674] The pharmaceutical composition may be in a form suitable for oral administration, such as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup. The oral composition may be prepared according to any method known in the art for preparing a pharmaceutical composition. The composition may contain a binder, a filler, a lubricant, a disintegrant, or a pharmaceutically acceptable wetting agent. The composition may also contain one or more ingredients selected from the group consisting of a sweetener, a flavoring agent, a colorant, and a preservative.

[0675] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that may be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution may then be added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. For example, the device may be an intravenous pump.

[0676] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be prepared using suitable dispersants or wetting agents and suspending agents as described herein, as known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a parenterally acceptable nontoxic diluent or solvent. Alternatively, a sterile fixed oil may be conveniently used as a solvent or suspending medium.

[0677] The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thereby dissolves and releases the drug in the rectum. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0678] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode, such as the mode of treatment, the daily dosage of the compound of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0679] The pharmaceutical composition of the present invention may contain a safe and effective amount of the antibody-drug conjugate of the present invention and a pharmaceutically acceptable carrier. Such carriers may include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof. The effective amount of the antibody-drug conjugate of the present invention may vary depending on the mode of administration and the severity of the disease to be treated. The selection of the effective amount can be determined by a person of ordinary skill in the art based on various factors (e.g., through clinical trials). Such factors may include, but are not limited to: pharmacokinetic parameters of the antibody-drug conjugate, such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated, the patient's weight, the patient's immune status, the route of administration, etc. Generally, when the antibody-drug conjugate of the present invention is administered daily at an appropriate dose, satisfactory results can be achieved. For example, depending on the urgency of the treatment condition, several divided doses may be administered daily, or the dose may be reduced proportionally.

[0680] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention may be applied to a mammal (e.g., a human) in need of treatment. The dosage during administration may be a pharmaceutically effective dosage. The specific dosage may also take into account factors such as the route of administration and the patient's health status.

[0681] Another aspect of the present invention provides the use of a compound of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for treating and / or preventing tumors.

[0682] Another aspect of the present invention provides a compound of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or a pharmaceutical composition of the present invention for use in treating and / or preventing tumors.

[0683] Yet another aspect of the present invention provides a method for treating and / or preventing a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or a pharmaceutical composition of the present invention.

[0684] In any of the above aspects, in some embodiments, the tumor is a solid tumor or a hematological tumor. In any of the above aspects, in a preferred embodiment, the tumor is a homologous recombination repair deficiency (HRD)-related tumor. In any of the above aspects, in a more preferred embodiment, the tumor is a tumor selected from the following target positive or high expression: HER2, HER3, TROP2, B7-H3, B7-H4, GPC20, GPRC5D, CDH6, EGFR, EGFRvIII, AXL, Nectin-4, Tissue factor, TIM-1, PSMA, PTK7, EpCAM, MUC1, STEAP1, GPNMB, FGF2, FOLR1, c-MET, GFR, AGS-16, Guanylyl cyclase C, Mesothelin, SLC44A4, EphA2, AGS-5, GPC-3, c-KIT, ROR1, ROR2, PD-L1, CD27L, 5T4, MerTK, Mucin16, NaPi2b, STEAP, SLITRK6, ETBR, BCMA, CEACAM5, ICAM1, SC-16, SLC39A6, Delta-like protein3, Claudin 18.2, Claudin 3, Claudin 6, Claudin 9, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD73, CD74, CD79b, CD123, CD138, CD147, CD166, CD223, MUC16, MSLN, ENPP3, SLTRK6, FGFR, LIV-1, Lewis Y, av-integrin, ITGB6(integrin beta-6), ASCT2, C4.4a, CA-IX, CD324, CD352, CD44v6, CD48a, CLL-1, Cripto, CS1, DPEP3, Ephrin-A2, Ephrin-A4, ETBR, FGFR2, FGFR3, FLT3, GD3, Globo H, GPC3, LAMP-1, LRRC15, Ly6E, TM4SF1, MFI2, NOTCH3, p-cadherin, PRLR, CLDN1, CD228, CUB domain-containing protein 1 (CDCP1), CXCR4, LGR4, FZD7, CTR, GPR56, CCR7, DDR1 and RNF43.

[0685] In any of the above aspects, in some embodiments, the tumor is selected from breast cancer, ovarian cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, pancreatic cancer, prostate cancer, colorectal cancer, gastric cancer, bladder cancer, gastrointestinal stromal tumors, cervical cancer, esophageal cancer, peritoneal cancer, liver cancer, colon cancer, glioma, mesothelioma, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, malignant lymphoma, plasmacytoma, myeloma and sarcoma.

[0686] In some aspects, the present invention provides a method of combined administration, wherein the combined administration comprises delivering at least two selected from a first drug (D1), a second drug (D2) and a third drug (D3) as the same molecule, and the method comprises forming at least two of D1, D2 and D3 into ADC compounds shown in Formula III, IIIa and IIIb of the present invention.

[0687] In a preferred embodiment, D1, D2, and D3, when present, are respectively a first anticancer agent, a second anticancer agent, and a third anticancer agent, wherein the first anticancer agent, the second anticancer agent, and the third anticancer agent are the same or different.

[0688] In a preferred embodiment, at least two of the first anticancer agent, the second anticancer agent, and the third anticancer agent have a synergistic anticancer effect.

[0689] In a preferred embodiment, at least one of D1, D2, and D3 is a cytotoxic drug, and at least one other is a tumor-targeted therapeutic drug. In a preferred embodiment, at least two of D1, D2, and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects. In a preferred embodiment, at least two of D1, D2, and D3 are cytotoxic drugs.

[0690] In a preferred embodiment, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a nucleoside antimetabolite anticancer drug unit, a drug unit targeting tubulin, or a drug unit targeting DNA.

[0691] In a preferred embodiment, the tumor targeted therapeutic drug is selected from a drug unit targeting a DNA damage response (DDR) or "synthetic lethality" related pathway, or a drug unit targeting an epigenetic pathway, or a drug unit targeting apoptosis-related pathway, a drug unit targeting a transcription factor, or a drug unit targeting an immune activation pathway-related target, including inhibitors of EFGR pathway-related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0692] In a preferred embodiment, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another one is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways.

[0693] Therefore, in some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from a drug targeting topoisomerase, a drug targeting microtubules and a drug targeting DNA, and at least another is a tumor-targeted therapeutic drug, the tumor-targeted therapeutic drug is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting topoisomerase, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting microtubules, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway. For example, at least one of D1, D2 and D3 is a drug targeting DNA, and at least another is a drug targeting DNA damage response (DDR) or a "synthetic lethality" related pathway.

[0694] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting topoisomerase, a drug targeting tubulin, a nucleoside antimetabolite anticancer drug unit, and a drug targeting DNA, and at least one other is a tumor-targeted therapeutic drug, wherein the tumor-targeted therapeutic drug is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting topoisomerase, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting tubulin, and at least one other is a drug targeting epigenetic. For example, at least one of D1, D2, and D3 is a drug targeting DNA, and at least one other is a drug targeting epigenetic.

[0695] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an apoptosis-related pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA-targeted drug, and at least one other is a drug targeting an apoptosis-related pathway.

[0696] In some embodiments, at least one of D1, D2, and D3 is a cytotoxic drug selected from a drug targeting a topoisomerase, a drug targeting a microtubule, and a drug targeting a DNA, and at least one other is a tumor-targeted therapeutic drug, and the tumor-targeted therapeutic drug is a drug with a target related to an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a topoisomerase, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a microtubule, and at least one other is a drug targeting an immune activation pathway. For example, at least one of D1, D2, and D3 is a drug targeting a DNA, and at least one other is a drug targeting an immune activation pathway.

[0697] In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to DNA damage response (DDR) or "synthetic lethality." In some embodiments, at least two of D1, D2, and D3 are drugs that target epigenetic pathways. In some embodiments, at least two of D1, D2, and D3 are drugs that target pathways related to apoptosis. In some embodiments, at least two of D1, D2, and D3 are drugs that target immune activation pathways.

[0698] In some embodiments, at least two of D1, D2, and D3 are drugs that target topoisomerase. In some embodiments, at least two of D1, D2, and D3 are drugs that target tubulin. In some embodiments, at least two of D1, D2, and D3 are nucleoside antimetabolite anticancer drugs. In some embodiments, at least two of D1, D2, and D3 are drugs that target DNA.

[0699] In some embodiments, at least one of D1, D2 and D3 is a cytotoxic drug, which is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another is a tumor-targeted therapeutic drug, which is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, and Rad51 inhibitors.

[0700] In some embodiments, at least two of D1, D2, and D3 are cytotoxic drugs and are independently selected from topoisomerase-targeted drugs and tubulin-targeted drug units, such as TOPO1 inhibitors, TOPO2 inhibitors, and tubulin inhibitors.

[0701] In some embodiments, at least two or all three of D1, D2 and D3 are tumor targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetic pathways, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including targets including: inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 regulators; N-myristoyltransferase (NMT) inhibitors.

[0702] In some embodiments, one of D1, D2, and D3 is a cytotoxic drug selected from drugs targeting topoisomerase and drugs targeting tubulin, such as TOPO1 inhibitors or tubulin inhibitors, and the other one or two are tumor-targeting therapeutic drugs selected from drugs targeting DNA. Drug units targeting damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including: inhibitors of EFGR pathway related targets; inhibitors of Ras-Raf-MAPK pathway related targets; inhibitors of PI3K / AKT / mTOR pathway related targets; inhibitors of cell cycle pathway related targets; agonists of cGAS-STING signaling pathway related targets; estrogen receptor antagonists, androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors.

[0703] In a preferred embodiment, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs. In a preferred embodiment, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives. In a preferred embodiment, the drug unit targeting DNA is a DNA minor groove binder (PBD), DNA alkylating agent (Duocarmycin), trabectedin, rubectin or its derivatives.

[0704] In a preferred embodiment, the drug unit targeting the DNA damage response (DDR) or "synthetic lethality" related pathway is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor, or a Rad51 inhibitor; the PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or an analog thereof; the ATR inhibitor is preferably Berzosertib, Ceralasertib or an analog thereof; and / or the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs. In a preferred embodiment, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor. In a preferred embodiment, the drug unit targeting epigenetic targets is an LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, the drug unit targeting immune activation pathways is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0705] In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a topoisomerase inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0706] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs, at least one other selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0707] In a preferred embodiment, at least one of D1, D2 and D3 is selected from the group consisting of: Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogs; at least one other selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0708] In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PARP inhibitor, an ATR inhibitor, or a CHK1 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a Bcl-2 family protein inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is an LSD1 inhibitor, an EZH2 inhibitor, or a PRMT5 inhibitor. In a preferred embodiment, at least one of D1, D2, and D3 is a tubulin inhibitor, and at least one other is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, or a STING agonist.

[0709] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives, and at least another one is selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0710] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof, and at least another one is selected from: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0711] In a preferred embodiment, at least one of D1, D2 and D3 is selected from: PBD or Duocarmycin, and at least another one is selected from: PARP inhibitors, ATR inhibitors, CHK1 inhibitors, Bcl-2 family protein inhibitors, LSD1 inhibitors, EZH2 inhibitors, BRD4 inhibitors, PRMT5 inhibitors, PD-L1 inhibitors, CBL-B inhibitors, TLR7 / 8 agonists and STING agonists.

[0712] In a preferred embodiment, at least one of D1, D2 and D3 is PBD or Duocarmycin, and at least one other is selected from Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0713] In a preferred embodiment, at least two of D1, D2 and D3 are drugs targeting DNA damage response (DDR) or "synthetic lethality" related pathways. In a preferred embodiment, at least two of D1, D2 and D3 are selected from the group consisting of: Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib, Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575), Berzosertib, Ceralasertib, RP-6306, GSK-1520489A and analogs thereof.

[0714] In some aspects, the present invention provides a method for increasing the DAR value of an ADC, comprising forming a drug into any one of the ADCs of Formulas III, IIIa, and IIIb of the present invention. In a preferred embodiment, the DAR value is an integer or decimal from 16 to 56, such as an integer or decimal from 16 to 24, an integer or decimal from 24 to 40, or an integer or decimal from 40 to 56. For example, the DAR is about 16, about 24, about 32, about 40, about 48, about 56, or any integer or decimal therebetween.

[0715] In a preferred embodiment, the drug is a cytotoxic drug or a tumor-targeted therapeutic drug.

[0716] In a preferred embodiment, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a nucleoside antimetabolite anticancer drug unit, a drug unit targeting tubulin, or a drug unit targeting DNA.

[0717] In a preferred embodiment, the tumor targeted therapeutic drug is selected from a drug unit targeting a DNA damage response (DDR) or "synthetic lethality" related pathway, or a drug unit targeting an epigenetic target, or a drug unit targeting an apoptosis related pathway, or a drug unit targeting an immune activation pathway related target.

[0718] In a preferred embodiment, the drug unit targeting topoisomerase is exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or derivatives and analogs thereof. In a preferred embodiment, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or its derivatives. In a preferred embodiment, the drug unit targeting DNA is a DNA minor groove binder (PBD), DNA alkylating agent (Duocarmycin), Trabectedin, Rubectedin or its derivatives.

[0719] In a preferred embodiment, the nucleoside antimetabolite anticancer drug unit is gemcitabine, decitabine or an analogue thereof.

[0720] In a preferred embodiment, the drug unit targeting the DNA damage response (DDR) or "synthetic lethality" related pathway is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor, or a Rad51 inhibitor; the PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or an analog thereof; the ATR inhibitor is preferably Berzosertib, Ceralasertib or an analog thereof; and / or the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs; and / or the PKMYT1 inhibitor is preferably RP-6306 and GSK-1520489A or their analogs. In a preferred embodiment, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor. In a preferred embodiment, the drug unit targeting epigenetic targets is an LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor or a PRMT1 inhibitor. In a preferred embodiment, the drug unit targeting immune activation pathway-related targets is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist or a STING agonist.

[0721] In a preferred embodiment, D1, D2 and D3 can be selected from the combinations shown in Table A.

[0722] Table A. Exemplary combinations of D1, D2, and D3

[0723] Preparation method

[0724] Another aspect of the present invention provides a method for preparing an antibody-drug conjugate of any one of Formulas III, IIIa or IIIb of the present invention, comprising reducing the disulfide bonds of an antibody or antibody fragment, for example, in the hinge region, to generate a pair of cysteine ​​residues, and subjecting the thiol groups of the cysteine ​​residues to a substitution reaction with Q or Q' (e.g., a maleimide group) of a compound of Formulas I, Ia, Ib, II, IIa, IIb, IV, IVa or IVb provided herein, and then linking the compound of Formulas I, Ia, Ib, II, IIa, IIb, IV, IVa or IVb to the cysteine ​​thiol groups of the antibody or antibody fragment to obtain an antibody-drug conjugate of Formulas III, IIIa or IIIb.

[0725] In some embodiments, the drug-antibody coupling ratio DAR (m in Formula III, IIIa, or IIIb) is controlled according to the reaction conditions, for example, it is usually between 2 and 8.

[0726] In the present invention, m represents the molar ratio of cytotoxic drug molecules to Ab (also known as DAR, i.e., drug-antibody conjugation ratio). m can be an integer or a decimal and can be understood as the average molar ratio of drug molecules to monoclonal antibody molecules in the antibody-drug conjugate obtained after conjugation of a single monoclonal antibody molecule to a cytotoxic drug. It can generally be measured by hydrophobic-interaction chromatography (HIC), reverse phase high performance liquid chromatography (RP-HPLC), polyacrylamide-SDS gel electrophoresis (SDS PAGE, electrophoresis), liquid chromatograph-mass spectrometer (LC-MS), ultraviolet / visible spectroscopy (UV / Vis), etc.

[0727] In some embodiments, the present invention provides a method for preparing the compounds of the present invention, comprising the following steps: synthesizing a Q-C1-B1-P1-T1 intermediate fragment; activating the T1 group by reaction with di(p-nitrophenyl) carbonate / 4-nitrophenyl chloroformate, and further connecting it with the drug component D1 to obtain the intermediate Q-C1-B1-P1-T1-D1; the latter is further condensed / coupled with the P2-T2-D2 or P3-T3-D3 intermediate fragment after deprotection to obtain the final product.

[0728] In some embodiments, T1, T2 and T3 contain Boc / Fmoc protected amino, alkynyl, carboxyl, hydroxyl and other groups that can be condensed / coupled with other components directly or after activation.

[0729] In some embodiments, the Boc-protected amino groups of T1, T2 and T3 or P1, P2, and P3 are contacted with trifluoroacetic acid and then condensed with substituted polysarcosine residues, polyols, polyglycerols, glycosyls, cyclodextrins, substituted ethylene glycol fragments, substituted glycosylated polyethylene glycols, substituted glycosylated polyglycerols, substituted cyclodextrin polyethylene glycols, or a combination thereof.

[0730] In some embodiments, the antibody is contacted with a compound of the invention under conditions suitable for forming a bond between the antibody and the compound. In some embodiments, the antibody is contacted with the compound of the invention in a mixture of a buffer and an organic solvent. In some embodiments, the antibody is contacted with the compound of the invention at a temperature of about 0°C to about 37°C. In one embodiment, the step of reacting the antibody with a reducing agent in a buffer to obtain a reduced antibody is included before contacting the antibody with the compound of the invention.

[0731] In some embodiments, after obtaining the reduced antibody and before contacting the antibody with the compound of the present invention, the step of removing the reducing agent is included. In the case of an antibody, removing the reducing agent comprises subjecting the reaction product to a desalting column and / or ultrafiltration.

[0732] In some embodiments, the reducing agent is selected from the following group: tris(2-carboxyethyl)phosphine hydrochloride (TCEP), beta-mercaptoethanol, beta-mercaptoethylamine hydrochloride and dithiothreitol (DTT). In some embodiments, the buffer is selected from the following group: potassium dihydrogen phosphate-sodium hydroxide (KH2PO4-NaOH) / sodium chloride (NaCl) / diethyltriaminepentaacetic acid (DTPA) buffer, disodium hydrogen phosphate-citric acid / sodium chloride (NaCl) / diethyltriaminepentaacetic acid (DTPA), boric acid-borax / sodium chloride (NaCl) / diethyltriaminepentaacetic acid (DTPA), histidine-sodium hydroxide / sodium chloride (NaCl) / diethyltriaminepentaacetic acid (DTPA) and PBS / diethyltriaminepentaacetic acid (DTPA). In some embodiments, the organic solvent is selected from the following group: acetonitrile (ACN), dimethylformamide (DMF), dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO). In some embodiments, the volume proportion of the organic solvent in the mixture of the buffer and the organic solvent does not exceed 30%.

[0733] In some embodiments, the antibody coupling reaction steps are as shown in FIG39 .

[0734] Wherein A is a drug-linker fragment represented by Formula I, Ia, or Ib, which is defined as above, and the specific implementation method is the same as described above.

[0735] In some embodiments, the antibody is an engineered antibody thiomab, in which additional disulfide bonds are introduced at specific positions, and more possible antibody drug conjugates can be obtained by using the drug-linker fragments A or B represented by Formulas I, Ia, and Ib described in the present invention. Engineered antibody thiomabs include but are not limited to LC-V205C, LC-214C, LC-K149C, HC-A114C, HC-174C, HC-373C / 375C, Fc-S396C, etc., and the antibody-drug conjugate is obtained by step A (Figure 41): reduction → oxidation → conjugation of drug-linker fragment A → reduction → conjugation of drug-linker fragment B, or step B (Figure 42): selective reduction → conjugation of drug-linker fragment B → reduction → conjugation of drug-linker fragment A to obtain the antibody-drug conjugate.

[0736] Wherein A and B are drug-linker fragments represented by Formula I, Ia, and Ib, and are defined as above, and the specific implementation method is the same as described above. Beneficial effects

[0737] The design of multi-loaded drug-antibody conjugates requires consideration of multiple factors. First, it is necessary to select two or more drugs with different mechanisms of action that are expected to produce synergistic effects, while fully considering factors such as the safety and effectiveness of the drug-loaded molecules. Secondly, these drug molecules are stably bound to the antibody molecules respectively to achieve precise targeted therapy. Finally, the stability and activity of the drug molecules and antibody molecules need to be guaranteed to ensure the therapeutic effect and safety. The inventors have adopted a new chemical modification method that can bind multiple drug molecules to antibody molecules separately without affecting the structure, stability and affinity of the antibody to form multi-loaded drug-antibody conjugates. This design method can achieve precise positioning and modification of drug molecules, thereby improving the targeting and therapeutic effect of the drug.

[0738] The multi-drug antibody conjugates described in the present invention use two or more different drug molecules to achieve synergistic effects with different mechanisms of action, thereby enhancing the therapeutic effect. One of the drug molecules is usually a chemotherapy drug, such as a topoisomerase 1 (TOPO1) inhibitor or a topoisomerase 2 (TOP2) inhibitor. TOPO1 inhibitors are an important chemotherapy drug. TOPO1 inhibitors can bind to TOPO1 to form a stable TOPO1-DNA-drug complex, preventing the reconnection of DNA chains and leading to DNA single-strand breaks. DNA single-strand breaks can interfere with DNA replication, transcription, and repair, inducing cell apoptosis or necrosis. TOPO1 inhibitors can selectively act on rapidly proliferating tumor cells. Combining with other DDR inhibitors can increase the targetedness and effectiveness of treatment, thereby improving the therapeutic effect. For example, PARP inhibitors and ATR-CHK1-WEE1 pathway inhibitors are commonly used DDR inhibitors, which can inhibit basic cell repair, leading to the accumulation of DNA damage and cell apoptosis. Therefore, another type of drug payload is selected from targeted drugs that can produce synergistic effects, such as DDR inhibitors (PARP inhibitors, CHK1 inhibitors, ATR inhibitors, WEE1 inhibitors, DNA-PK inhibitors, etc.). Such combinations are expected to greatly enhance the efficacy of homologous recombination deficiency (HRD)-related tumors. Known genes encoding homologous recombination proteins include: BRCA1, BRCA2, ATM, ATR, BARD1, BAP1, BLM, RAD51B / C / D, DSS1, RPA1, BRIP1, FANCA, FANCC, FANCD2, FANCE, FANCF, PALB2, MRE11A, NBN, CHK1 / 2, CDK12, etc. HRD is common in different tumors. HRD was present in 13% of tumors studied, with the most common mutational lineages including ovarian (14.1%), bladder (9.7%), breast (8.0%), endometrial (7.4%), prostate (7.1%), and pancreatic (6.5%).

[0739] In addition, by activating the immune system and enhancing the body's immune surveillance and clearance of tumor cells, immunotherapy can effectively control and treat a variety of tumors. Combining with chemotherapy drugs can enhance the therapeutic effect through multiple pathways. First, chemotherapy drugs can release antigens and nucleic acid molecules by killing tumor cells, further activating the immune system's immune response to tumor cells. In addition, chemotherapy drugs can also enhance the effect of immunotherapy by inhibiting the immune escape mechanism of tumor cells, as well as targeted small molecule drugs that can produce immune activation effects, such as PD-L1 inhibitors, CBL-B inhibitors, TLRs agonists, STING agonists, epigenetic-related inhibitors LSD1 inhibitors and EZH2 inhibitors.

[0740] In addition, by coupling targeting molecules targeting tumor-related signaling pathways with antibodies, such as inhibitors of EFGR pathway-related targets; inhibitors of Ras-Raf-MAPK pathway-related targets; inhibitors of PI3K / AKT / mTOR pathway-related targets; inhibitors of cell cycle pathway-related targets; agonists of cGAS-STING signaling pathway-related targets; estrogen receptor antagonists; androgen receptor antagonists; autophagy inhibitors; FAK inhibitors, and drugs targeting transcription factors such as GSPT1 degraders, etc., we can target mutations and drug resistance generated in the treatment of specific tumors to obtain better or unexpected effects, such as pancreatic cancer, HER2+ / ER- breast cancer, prostate cancer, melanoma, etc.

[0741] Experiments have shown that the main advantages of the present disclosure lie in one or more of the following aspects:

[0742] 1) The linker technology employed in the present disclosure can flexibly adjust the drug-antibody ratio (DAR) of antibody-drug conjugates through different construction methods. It can also fine-tune the physicochemical properties, efficacy, and toxicity profile of ADCs based on disease type and therapeutic intent, fully leveraging the advantages of ADC dual-drug / multi-drug delivery and enhancing ADC activity. Furthermore, from an atom-economics perspective, it can reduce the molar dosage of reagents required to construct highly homogeneous multi-load ADC drugs, thereby improving efficacy while reducing production costs.

[0743] 2) Through the present invention, drug molecules with different pharmacological mechanisms and properties are rationally designed and combined, and antibody-drug conjugates targeting different tumors / indications can be designed and screened, which are more "programmable" than traditional antibody-drug conjugates.

[0744] 3) Compared with the prior art, some embodiments of the present disclosure use a combination of targeted inhibitors and chemotherapeutic toxins for multi-warhead loading of antibody-drug conjugates, which is expected to achieve better therapeutic effects against drug resistance, insensitivity to existing treatments, and increased targeting of tumors associated with homologous recombination defects.

[0745] 4) The existing technology generally adopts a dual toxin combination, which increases the safety risk of antibody-drug conjugates (ADCs) to a certain extent. In contrast, the present disclosure innovatively uses chemotherapy drugs with low to medium toxicity and tumor-targeted inhibitors. Through the synergistic effect of the two, it not only significantly improves the therapeutic effect, but also greatly broadens the safety window of ADCs. Furthermore, the present disclosure introduces a unique connection strategy that can efficiently and stably connect dual toxins, triple toxins, and even multiple toxins to antibodies, thereby preparing ADCs with excellent uniformity and stability. In addition, combined with the existing thiomab conjugation technology, we can achieve a variety of ratio combinations between different drugs (from 1:1 to 1:10), and even obtain more diverse drug combination conjugates through thiomab conjugation technology. This innovation not only improves the efficacy of ADC drugs, but also expands their therapeutic window, providing a new combination targeted therapy strategy for future tumor treatment.

[0746] 5) Compared with the existing technology, the present invention adopts a specific linker technology, which can effectively reduce the problems of increased hydrophobicity and decreased stability of antibody-drug conjugates caused by multiple loaded drugs through the "ortho-protection effect" of hydrophilic groups, while improving the uniformity of the conjugated drugs. It does not require antibody engineering modification and is compatible with most monoclonal antibodies, bispecific antibodies, polyclonal antibodies, nanoantibodies, nucleic acid aptamers and other targeting carriers.

[0747] 6) Provides a linker technology that can load multiple drugs on the same antibody, increase the concentration of drugs in tumor cells, and achieve synergistic / superimposed effects of different drug combinations in tumor cells and / or tumor microenvironment, which will further improve the efficacy of drugs in tumors with low antigen expression.

[0748] Sequence Listing

[0749] Example

[0750] Example 1 Synthesis and preparation of compounds

[0751] The raw materials described in the present invention are commercially available products, or are prepared by methods known in the art or according to the methods described herein.

[0752] 1) Synthesis of Compound A2

[0753] Synthesis route:

[0754] Synthesis steps:

[0755] Synthesis of intermediate A2-2

[0756] Intermediate A2-1 (1.0 g, 1.8 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL). A carboxylic acid compound (198561-07-8, 600 mg, 1.8 mmol, 1.0 eq) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (890 mg, 3.6 mmol, 2.0 eq) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (PE / EA = 4 / 6) to afford intermediate A2-2 (1.3 g, 89%) as a light yellow solid. LCMS: [M+Na] + =890.3

[0757] Synthesis of intermediate A2-3

[0758] Intermediate A2-2 (1.2 g, 3.6 mmol, 1.0 eq) was dissolved in DMF (4 mL). Piperidine (0.8 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford Intermediate A2-3 (0.7 g, 78%) as a light yellow solid. LCMS: [M+H] + =646.4

[0759] Synthesis of intermediate A2-4

[0760] Intermediate A2-3 (660 mg, 1.02 mmol, 1.0 eq) was dissolved in DMF (4 mL), and Mc-OSu (314 mg, 1.02 mmol, 1.0 eq) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford Intermediate A2-4 (850 mg, 99%) as a light yellow solid. LCMS: [M+Na] + =861.3

[0761] Synthesis of intermediate A2-5

[0762] Intermediate A2-4 (800 mg, 0.95 mmol, 1.0 eq) was dissolved in THF (10 mL). The reaction mixture was cooled to 0°C and pyridine hydrofluoride (1160 mg, 7.62 mmol, 8.0 eq, 65% w / w) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. After the reaction was complete as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated ammonium chloride and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield Intermediate A2-5 (650 mg, 94%) as a light yellow solid. LCMS: [M+Na] + =747.3

[0763] Synthesis of intermediate A2-6

[0764] Intermediate A2-5 (600 mg, 0.83 mmol, 1.0 eq) and di(p-nitrobenzene) carbonate (503 mg, 1.65 mmol, 2.0 eq) were dissolved in DMF (5 mL). The reaction mixture was cooled to 0°C and diisopropylethylamine (214 mg, 1.65 mmol, 2.0 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After completion of the reaction as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford Intermediate A2-6 (650 mg, 88%) as a light yellow solid. LCMS: [M+Na] + =912.3

[0765] Synthesis of intermediate A2-7

[0766] Intermediate A2-7 (600 mg, 0.67 mmol, 1.0 eq), HOBt (91 mg, 0.67 mmol, 1.0 eq), and pyridine (533 mg, 6.70 mmol, 10.0 eq) were dissolved in DMF (8 mL). Exatecan mesylate (376 mg, 0.71 mmol, 1.05 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After completion of the reaction, LC-MS monitored the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 6 / 1) to afford Intermediate A2-7 (300 mg, 37%) as a white solid. LCMS: [M+Na] + =1186.4

[0767] Synthesis of intermediate A2-8

[0768] Intermediate A2-1 (1.0 g, 1.8 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL). Compound 12 (180 mg, 1.8 mmol, 1.0 eq) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (890 mg, 3.6 mmol, 2.0 eq) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was directly concentrated and the residue was purified by silica gel column chromatography (DCM / EA = 3 / 7) to obtain intermediate A2-8 as a light yellow solid. LCMS: [M+H] + =634.4

[0769] Synthesis of intermediate A2-9

[0770] Compound 13 (1100 mg, 1.73 mmol, 1.0 eq) was dissolved in THF (20 mL). The reaction mixture was cooled to 0°C and pyridine hydrofluoride (1320 mg, 8.66 mmol, 5.0 eq, 65% w / w) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. After the reaction was complete as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated ammonium chloride and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 7 (700 mg, 77%) as a light yellow solid. LCMS: [M+Na] + =542.3

[0771] Synthesis of intermediate A2-10

[0772] Intermediate A2-9 (400 mg, 0.77 mmol, 1.0 eq) and di(p-nitrobenzene) carbonate (468 mg, 1.54 mmol, 2.0 eq) were dissolved in dichloromethane (4 mL). The reaction mixture was cooled to 0°C and diisopropylethylamine (198 mg, 1.54 mmol, 2.0 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. LC-MS monitored the reaction completion. After the reaction was complete, the organic phase was concentrated and the residue was recrystallized from diethyl ether to yield Intermediate A2-10 (330 mg, 63%) as a white gummy solid. LCMS: [M+Na] + =707.3

[0773] Synthesis of intermediate A2-11

[0774] Intermediate A2-10 (600 mg, 0.87 mmol, 1.0 eq), HOBt (118 mg, 0.87 mmol, 1.0 eq), and pyridine (692 mg, 8.75 mmol, 10.0 eq) were dissolved in DMF (8 mL). Rucaparib (376 mg, 0.71 mmol, 1.05 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After completion of the reaction, LC-MS monitored the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford Intermediate A2-11 (500 mg, 66%) as a light yellow solid. LCMS: [M+H] + =869.3

[0775] Synthesis of intermediate A2-12

[0776] Intermediate A2-7 (150 mg, 0.13 mmol, 1.0 eq) and intermediate A2-11 (115 mg, 0.13 mmol, 1.0 eq) were dissolved in dichloromethane / methanol / water (3 / 2 / 1 mL). Copper sulfate pentahydrate (3.16 mg, 0.013 mmol, 0.1 eq in 100 μL water) and sodium ascorbate (6.26 mg, 0.032 mmol, 0.25 eq in 100 μL water) were added under a nitrogen atmosphere. After the addition was complete, the reaction was stirred at room temperature under a nitrogen atmosphere for 4 hours. After completion of the reaction, LC-MS monitored the reaction. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate A2-12 (100 mg, 38%) as a yellow solid. LCMS: [M+H] + =1028.1(half peak)

[0777] Synthesis of intermediate A2-13

[0778] Intermediate A2-12 (950 mg, 0.046 mmol, 1.0 eq) was dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction as monitored by LC-MS, the organic phase was concentrated to afford crude intermediate A2-13, which was used directly in the next reaction.

[0779] LCMS: [M+H] + =928.1(half peak)

[0780] Synthesis of compound A2

[0781] Intermediate A2-13 was dissolved in DMF (3 mL). Ac-PSAR10-OH (71 mg, 0.092 mmol, 2.0 eq) and diisopropylethylamine (60 mg, 0.46 mmol, 10.0 eq) were added to the reaction mixture. Finally, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (37 mg, 0.097 mmol, 2.1 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to afford compound A2 (6.5 mg, 7%) as a yellow solid.

[0782] LCMS: [M+H]+ =1681.2 (half peak)

[0783] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.38(s,3H),8.25(s,2H),8.20-8.12(m,2H),7.79-7.75(m,4H),7.59-7.54(m,4H),7.43(s,1H),7.40( s,4H),7.40-7.36(m,4H),6.98(s,2H),6.52(s,2H),5.44(s,3H),5.28 (s,4H),5.14-5.11(m,8H),4.65-4.54(m,10H),4.49(s,3H),4.42-4.14 (m,34H),4.06-3.89(m,28H),2.89-2.81(m,55H),2.76-2.66(m,30H), 2.37(s,2H),2.22-2.15(m,2H),2.07(s,8H),2.06-2.04(m,1H),1.99-1 .97(m,4H),1.89-1.86(m,1H),1.83(s,2H),1.76-1.72(m,2H),1.45-1 .39(m,6H),1.31-1.23(m,10H),1.17-1.09(m,4H),0.92-0.77(m,19H).

[0784] 2) Synthesis of Compound A10

[0785] Synthesis route:

[0786] Synthesis steps

[0787] Synthesis of intermediate A10-1

[0788] Intermediate A2-10 (300 mg, 0.44 mmol, 1.0 eq), HOBt (59 mg, 0.44 mmol, 1.0 eq), and pyridine (692 mg, 8.75 mmol, 20.0 eq) were dissolved in DMF (4 mL). Niraparib (147 mg, 0.46 mmol, 1.05 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After completion of the reaction, as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford Intermediate A10-1 (300 mg, 79%) as a light yellow solid.

[0789] LCMS: [M+H] + =866.4

[0790] Synthesis of intermediate A10-2

[0791] Intermediate compounds A2-7 (55 mg, 0.046 mmol, 1.0 eq) and A10-1 (42 mg, 0.048 mmol, 1.05 eq) were dissolved in dichloromethane / methanol / water (3 / 2 / 1 mL). Copper sulfate pentahydrate (1.16 mg, 0.0046 mmol, 0.1 eq in 100 μL water) and sodium ascorbate (1.83 mg, 0.0093 mmol, 0.20 eq in 100 μL water) were added under a nitrogen atmosphere. After addition, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After completion of the reaction, which was monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate A10-2 (90 mg, 90%) as a yellow solid.

[0792] LCMS: [M+H] + =1027.2 (half peak)

[0793] Synthesis of intermediate A10-3

[0794] Intermediate A10-2 (90 mg, 0.048 mmol, 1.0 eq) was dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture and stirred at room temperature for 5 minutes. After completion of the reaction as monitored by LC-MS, the organic phase was concentrated to afford crude intermediate A10-3, which was used directly in the next step.

[0795] LCMS: [M+H] + =926.4 (half peak)

[0796] Synthesis of compound A10

[0797] Intermediate A10-3 from the previous step was dissolved in DMF (3 mL). Ac-PSAR10-OH (75 mg, 0.097 mmol, 2.0 eq) and diisopropylethylamine (63 mg, 0.49 mmol, 10.0 eq) were added to the reaction mixture. Finally, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (39 mg, 0.10 mmol, 2.1 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to afford compound A-10 (11.08 mg, 12%) as a pale yellow solid.

[0798] LCMS: [M+H] + =1679.4 (half peak); 1 H NMR(400MHz,DMSO-d6)δ10.07-9.99(m,2H),9.28(s,1H),8.63-8.33(m,6H),8.24-7.97(m,5H),7 .82-7.58(m,4H),7.52-7.50(m,4H),7.45-7.20(m,5H),7.10(s,1H),6.98(s,1H),6.60-6.42(m,2 H),5.44-5.07(m,10H),4.65-4.53(m,6H),4.49-3.80(m,45H),3.12-2.62(m,66H),2.40-2.33(m ,3H),2.08-1.74(m,16H),1.61-1.40(m,4H),1.35-1.23(m,6H),1.13(s,1H),0.93-0.72(m,14H).

[0799] III) Synthesis of Compound A11

[0800] Synthesis route:

[0801] Synthesis steps

[0802] Synthesis of intermediate A11-1

[0803] Z-Val-Ala (4.0 g, 12.4 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL) and methanol (10 mL). p-Aminobenzyl alcohol (1.99 g, 16.12 mmol, 1.3 eq) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (6.13 g, 24.8 mmol, 2.0 eq) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated directly, and the residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to obtain compound A11-1 (4.9 g, 90%) as a white solid. LCMS: [M+H] + =428.2

[0804] Synthesis of intermediate A11-2

[0805] Intermediate A11-1 (4.9 g, 11.5 mmol, 1.0 eq) was dissolved in MeOH (50 mL). Palladium on carbon (0.49 g, 10% mass fraction) was added to the reaction solution. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was filtered and concentrated to obtain compound A11-2 (3.5 g, 98%) as a colorless, transparent oil. LCMS: [M+H] + =294.4

[0806] Synthesis of intermediate A11-3

[0807] Intermediate A11-2 (3.4 g, 11.6 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL). Azidoacetic acid (1.41 g, 13.92 mmol, 1.2 eq) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (5.74 g, 23.2 mmol, 2.0 eq) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to give A11-3 (3.4 g, 77%) as a white solid. LCMS: [M+H] + =377.2

[0808] Synthesis of intermediate A11-4

[0809] Intermediate A11-3 (1.5 g, 4.00 mmol, 1.0 eq) and diisopropylethylamine (1.55 g, 12.00 mmol, 3.0 eq) were dissolved in DMF (10 mL) and stirred for a period of time. Di(p-nitrobenzene) carbonate (2.43 g, 8.00 mmol, 2.0 eq) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford Intermediate A11-4 (1.7 g, 78%) as a white solid. LCMS: [M+Na] + =564.2

[0810] Synthesis of intermediate A11-5

[0811] Intermediate A11-4 (88.8 mg, 0.277 mmol, 1.0 eq) and diisopropylethylamine (107.4 mg, 0.831 mmol, 3.0 eq) were dissolved in DMF (5 mL) and stirred until clear. Niraparib (CAS 1038915-60-4, 150 mg, 0.277 mmol, 1.0 eq) and HOBt (37.4 mg, 0.277 mmol, 1.0 eq) were then added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford compound A11-5 (170 mg, 85%) as a white solid. LCMS: [M+H] + =723.3

[0812] Synthesis of intermediate A11-6

[0813] Compound A2-7 (100 mg, 0.0842 mmol, 1 eq) and compound A11-5 (61 mg, 0.0842 mmol, 1 eq) were dissolved in MeOH / DCM / water (10 / 10 / 2.5 mL). Then, 100 μL of aqueous copper sulfate pentahydrate (2.1 mg, 0.00842 mmol, 0.1 eq) and 100 μL of aqueous sodium ascorbate (3.34 mg, 0.01684 mmol, 0.2 eq) were added. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After completion of the reaction, LC-MS monitored the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound A11-6 (160 mg, 100%), which was used directly in the next reaction. LCMS: [M+H] + =954.9 (half peak)

[0814] Synthesis of intermediate A11-7

[0815] Compound A11-6 (160 mg, 0.0842 mmol) was dissolved in DCM (6 mL). Trifluoroacetic acid (2 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete as monitored by LC-MS, the organic phase was concentrated to obtain the crude compound Compound A11-7, which was used directly in the next reaction. LCMS: [M+H] + =905.1 (half peak) Synthesis of Compound A11

[0816] Compound A11-7 from the previous step was dissolved in DMF (3 mL). Ac-PSAR10-OH (41 mg, 0.0842 mmol, 1.0 eq) and diisopropylethylamine (69 mg, 0.842 mmol, 10.0 eq) were added to the reaction mixture. Finally, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (22 mg, 0.0926 mmol, 1.1 eq) was added. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered and the filtrate was purified by pre-HPLC (mobile phase: (0.05% HCOOH / CH3CN / H2O)) to afford compound A11 (24.2 mg, 11%) as a white solid. LCMS: [M+H] + =1281.2 (half peak).

[0817] 4) Synthesis of Compound A12

[0818] Synthesis route:

[0819] Synthesis steps

[0820] Synthesis of intermediate A12-1

[0821] Intermediate compound A11-4 (101.5 mg, 0.314 mmol, 1.0 eq) and diisopropylethylamine (121.7 mg, 0.942 mmol, 3.0 eq) were dissolved in DMF (5 mL) and stirred until the mixture became clear. Rucaparib (CAS 283173-50-2, 88.8 mg, 0.277 mmol, 1.0 eq) and HOBt (42.4 mg, 0.314 mmol, 1.0 eq) were then added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford intermediate A12-1 (200 mg, 88%) as a white solid. LCMS: [M+H] + =726.3

[0822] Synthesis of intermediate A12-2

[0823] Compound A2-7 (100 mg, 0.0842 mmol, 1.0 eq) and compound A12-1 (61.1 mg, 0.0842 mmol, 1.0 eq) were dissolved in methanol / dichloromethane / water (8:8:1 mL). 100 μL of aqueous copper sulfate (2.08 mg, 0.0084 mmol, 0.1 eq) and 100 μL of aqueous sodium ascorbate (3.34 mg, 0.0168 mmol, 0.2 eq) were added to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, LC-MS monitored the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to yield crude compound A12-2 (140 mg, 78%), which was used directly in the next reaction. LCMS: [M+H] + =956.0 (half peak)

[0824] Synthesis of intermediate A12-3

[0825] Compound A12-2 (140 mg, 0.0732 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated to obtain crude compound A12-3 (120 mg, 81.4%), which was used directly in the next reaction. LCMS: [M+H] + =906.0 (half peak)

[0826] Synthesis of compound A12

[0827] Compound A12-3 (120 mg, 0.0663 mmol) was dissolved in DMF (3 mL), and DIEA (171 mg, 1.33 mmol, 20 eq) was added. The mixture was stirred for 2 minutes, followed by the addition of Ac-PSAR10-OH (43 mg, 0.0842 mmol, 1.0 eq) and HATU (23 mg, 0.0608 mmol, 1.1 eq). After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 hours. LC-MS monitored the reaction completion. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified using pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to afford compound A12 (30.5 mg, 24%) as a white solid. LCMS: [M+H] + =1282.6 (half peak)

[0828] V) Synthesis of Compound A14

[0829] Synthesis route:

[0830] Synthesis steps

[0831] Synthesis of intermediate A14-1

[0832] Veliparib (53.5 mg, 0.219 mmol, 1.0 eq) and diisopropylethylamine (84.8 mg, 0.656 mmol, 3.0 eq) were dissolved in DMF (3 mL) and stirred until clear. Compound A11-4 (150 mg, 0.219 mmol, 1.0 eq) and HOBt (29.6 mg, 0.277 mmol, 1.0 eq) were then added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, LC-MS monitored the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford compound A14-1 (140 mg, 81%) as a white solid. LCMS: [M+H]+ = 790.3

[0833] Synthesis of intermediate A14-2

[0834] Compound A2-7 (100 mg, 0.0842 mmol, 1.0 eq) and compound A14-1 (66.6 mg, 0.0842 mmol, 1.0 eq) were dissolved in MeOH / DCM / water (8 / 8 / 2 mL). Then, 100 μL of aqueous copper sulfate pentahydrate (2.1 mg, 0.00842 mmol, 0.1 eq) and 100 μL of aqueous sodium ascorbate (3.34 mg, 0.01684 mmol, 0.2 eq) were added. After the addition was complete, the reaction was stirred at room temperature under a nitrogen atmosphere for 4 hours. After completion of the reaction, as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound A14-2 (166 mg, 100%), which was used directly in the next reaction. LCMS: [M+H] + =988.5 (half peak)

[0835] Synthesis of intermediate A14-3

[0836] Compound A14-2 (166 mg, 0.0842 mmol) was dissolved in DCM (6 mL). Trifluoroacetic acid (2 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete as monitored by LC-MS, the organic phase was concentrated to obtain crude compound A14-3, which was used directly in the next reaction. LCMS: [M+H] + =888.8 (half peak)

[0837] Synthesis of compound A14

[0838] Compound A14-3 was dissolved in DMF (3 mL). Ac-PSAR10-OH (129.8 mg, 0.1684 mmol, 2.0 eq) and diisopropylethylamine (217.5 mg, 0.842 mmol, 20.0 eq) were added to the reaction mixture. Finally, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (67.3 mg, 0.1768 mmol, 2.1 eq) was added. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered and the filtrate was purified using pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to afford compound A14 (5.11 mg, 1.8%) as a white solid. LCMS: [M+H] + =1641.2 (half peak)

[0839] VI) Synthesis of Compound A15

[0840] Synthesis route:

[0841] Synthesis steps

[0842] Synthesis of compound A15-3

[0843] Compound A15-1 (1 g, 0.035 mol, 1.0 eq) was dissolved in MeOH (50 mL), and A15-2 (4.77 g, 0.035 mol, 1 eq), HOAc (4.21 g, 0.035 mol, 1.0 eq), and NaBH3CN (11 g, 0.175 mol, 5.0 eq) were added. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. LC-MS monitored the reaction completion. After the reaction was complete, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 92 / 8) to afford compound 3 (2.3 g, 33%) as a colorless oil. LCMS: [M+H] + =178.2

[0844] Synthesis of compound A15-5

[0845] Compound A15-3 (0.96 g, 0.0054 mol, 1.0 eq), compound A15-4 (1 g, 0.0054 mol, 1.0 eq), and acetic acid (0.32 g, 0.0054 mol, 1.0 eq) were dissolved in methanol (20 mL). Sodium cyanoborohydride (1.7 g, 0.027 mol, 5.0 eq) was added. After the addition was complete, the reaction solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. LC-MS monitored the reaction completion. After the reaction was complete, the organic phase was concentrated, and the residue was purified by reverse-phase column chromatography (H2O / MeCN = 80 / 20) to obtain compound A15-5 (700 mg, 37%) as a colorless oil. LCMS: [M+H] + =347.2

[0846] Synthesis of compound A15-6

[0847] Compound A15-5 (700 mg, 1.57 mmol, 1.0 eq) was dissolved in DCM (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated to obtain the crude compound A15-6 (500 mg, 100%), which was used directly in the next reaction. LCMS: [M+H] + =247.2

[0848] Synthesis of compound A15-8

[0849] Compound A15-6 (500 mg, 2.03 mmol, 1 eq) and DIEA (1311 mg, 10.1 mmol, 5.0 eq) were dissolved in DMF (4 mL) and stirred for 2 minutes. Compound A15-7 (605 mg, 2.03 mmol, 1.0 eq) and HATU (848 mg, 2.23 mmol, 1.1 eq) were then added. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, LC-MS monitored the reaction. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford compound A15-8 (550 mg, 52%) as a yellow solid. LCMS: [M+H] + =527.2

[0850] Synthesis of compound A15-9

[0851] Compound A15-8 (500 mg, 0.47 mmol, 1 eq) was dissolved in methanol (10 mL), and Pd / C (100 mg) and 5 drops of trifluoroacetic acid were added. After the addition was complete, the reaction was replaced with H2 three times, and the reaction solution was stirred under an H2 atmosphere for 12 hours. After the reaction was completed by LC-MS, the filtrate was filtered through Celite and concentrated to give compound A15-9 (380 mg, 90%) as a white solid. 180 mg of the crude product was purified by pre-HPLC (mobile phase: 0.05% NH3·H2O / CH3CN / H2O) to give compound A15-9 (70 mg, 39%) as a white solid. LCMS: [M+H] + =407.2

[0852] Synthesis of compound A15-11

[0853] Compound A15-9 (190 mg, 0.468 mmol, 1 eq) and DIEA (302 mg, 2.34 mmol, 5.0 eq) were dissolved in DMF (2 mL) and stirred for 2 minutes. Compound A15-10 (320 mg, 0.468 mmol, 1.0 eq) and HOBt (69 mg, 0.514 mmol, 1.1 eq) were then added. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, LC-MS monitored the reaction. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford compound A15-11 (220 mg, 49%) as a white solid. LCMS: [M+H] + =974.3

[0854] Synthesis of compound A15-12

[0855] Compound A2-7 (100 mg, 0.0842 mmol, 1.0 eq) and compound A15-11 (80.44 mg, 0.0842 mmol, 1.0 eq) were dissolved in methanol / dichloromethane / water (3:3:0.5 mL). 100 μL of aqueous copper sulfate (2.08 mg, 0.0084 mmol, 0.1 eq) and 100 μL of aqueous sodium ascorbate (3.34 mg, 0.0168 mmol, 0.2 eq) were added to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After completion of the reaction, as monitored by LC-MS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford crude compound A15-12 (170 mg, 80%), which was used directly in the next reaction. LCMS: [M+H] + =1069.9 (half peak)

[0856] Synthesis of compound A15-13

[0857] Compound A15-12 (150 mg, 0.0702 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated to obtain crude compound A15-13 (150 mg, 88%), which was used directly in the next reaction. LCMS: [M+H] + =970.0 (half peak)

[0858] Synthesis of compound A15

[0859] Compound A15-13 (150 mg, 0.0774 mmol) was dissolved in DMF (2 mL), and DIEA (200 mg, 1.54 mmol, 20 eq) was added. The mixture was stirred for 2 minutes, followed by the addition of Ac-PSAR10-OH (125 mg, 0.162 mmol, 2.0 eq) and HATU (64.75 mg, 0.170 mmol, 2.1 eq). After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, EA (20 mL) was added to the reaction mixture, which was filtered. The filter cake was dissolved in DMF and purified using pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to afford compound A15 (14 mg, 12%) as a white solid. LCMS: [M+H] + =1723.7 (half peak)

[0860] VII) Synthesis of Compound A16

[0861] Synthesis route:

[0862] Synthesis steps

[0863] Synthesis of compound A16-2

[0864] Compounds A2-7 (100 mg, 0.0842 mmol, 1.0 eq) and A16-1 (85 mg, 0.0842 mmol, 1.0 eq) were dissolved in methanol / dichloromethane / water (8:8:1 mL). 100 μL of aqueous copper sulfate (2.08 mg, 0.0084 mmol, 0.1 eq) and 100 μL of aqueous sodium ascorbate (3.34 mg, 0.0168 mmol, 0.2 eq) were added to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion of the reaction, LC-MS was used to monitor the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to yield crude compound 3 (140 mg, 72%), which was used directly in the next step. LCMS: [M+H] + =1098.3 (half peak)

[0865] Synthesis of compound A16-3

[0866] Compound A16-2 (140 mg, 0.0637 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated to obtain crude compound 4 (110 mg, 72%), which was used directly in the next reaction. LCMS: [M+H] + =998.1(half peak)

[0867] Synthesis of compound A16

[0868] Compound A16-3 (110 mg, 0.055 mmol, 1 eq) was dissolved in DMF (3 mL), and DIEA (171 mg, 1.326 mmol, 20 eq) was added. The mixture was stirred for 2 minutes, followed by the addition of Ac-PSAR10-OH (85 mg, 0.168 mmol, 2.0 eq) and HATU (46 mg, 0.122 mmol, 2.1 eq). After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 hours. LC-MS monitored the reaction completion. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified using pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to afford compound A16 (48 mg, 43.5%) as a yellow solid. LCMS: [M+H] + =1750.7 (half peak)

[0869] VIII) Synthesis of Compound A17

[0870] Synthesis route:

[0871] Synthesis steps

[0872] Synthesis of compound A17-1

[0873] Compound A11-4 (100 mg, 0.27 mmol, 1.0 eq) and diisopropylethylamine (106 mg, 0.82 mmol, 3.0 eq) were dissolved in DMF (4 mL) and stirred until clear. Compound 1 (188 mg, 0.27 mmol, 1.0 eq) and HOBt (37 mg, 0.28 mmol, 1.0 eq) were then added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, LC-MS was used to monitor the reaction. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to yield compound A17-1 (200 mg, 80%) as a white solid. LCMS: [M+H] + =911.4

[0874] Synthesis of compound A17-2

[0875] Compound A2-7 (100 mg, 0.084 mmol, 1.0 eq) and compound A17-1 (77 mg, 0.084 mmol, 1.0 eq) were dissolved in MeOH / DCM / water (4 / 4 / 1 mL), and then 100 μL of aqueous copper sulfate pentahydrate (2.5 mg, 0.0099 mmol, 0.1 eq) and 100 μL of aqueous sodium ascorbate (3.9 mg, 0.0198 mmol, 0.2 eq) were added. After the addition was completed, the reaction solution was stirred at 45 °C under a nitrogen atmosphere for 8 hours. After the reaction was complete and the product was detected by LC-MS, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to obtain compound A17-2 (40 mg, 20%). LCMS: [M+H] + =1049.5 (half peak)

[0876] Synthesis of compound A17-3

[0877] Compound A17-2 (40 mg, 0.019 mmol, 1.0 eq) was dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete as monitored by LC-MS, the organic phase was concentrated to obtain crude compound A17-3, which was used directly in the next reaction. LCMS: [M+H] + =999.6 (half peak)

[0878] Synthesis of compound A17

[0879] Compound A17-3 from the previous step was dissolved in DMF (3 mL). Ac-PSAR10-OH (29 mg, 0.038 mmol, 2.0 eq) and diisopropylethylamine (49 mg, 0.38 mmol, 20.0 eq) were added to the reaction mixture. Finally, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (79 mg, 0.040 mmol, 2.1 eq) was added under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered and the filtrate was purified using pre-HPLC (mobile phase: 0.05% HCOOH / CH3CN / H2O) to yield compound A17 (4.5 mg, 10%) as a white solid. LCMS: [M+H] + =1701.7 (half peak)

[0880] IX) Synthesis of Compound A21

[0881] Synthesis route:

[0882] Synthesis of compound 21-1

[0883] Compound Rabusertib (100 mg, 0.229 mmol, 1.0 eq) was dissolved in DMF (2 mL), and DIEA (88.9 mg, 0.688 mmol, 3 eq) was added. The mixture was stirred for 2 minutes until completely clear, followed by the addition of compound A11-4 (154 mg, 0.2...

Claims

1. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula I: in, Q is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group; D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and When a=0, B1 is a direct bond and T1 is not a direct bond; When b=0, B1 is not a direct bond.

2. The compound according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula Ia: in: Q is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphoric acid and alkoxy; B1 is a branching group; P1 and P2 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group; D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different; a is 1, 2 or 3.

3. The compound according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula Ib: Q is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy; B2 is a branching group; P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group; D1 and D3 are the first drug unit and the third drug unit, respectively, and are the same or different; b is 1, 2, or 3.

4. The compound according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 and B2 are independently branching groups; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group; D1, D2, D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; and a and b are independently 1, 2 or 3.

5. A compound according to any one of claims 1 to 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: Q is selected from the following group: optionally substituted (Q1), optionally substituted (Q2), optionally substituted (Q3), optionally substituted (Q4), optionally substituted (Q5), optionally substituted (Q6), optionally substituted (Q7), optionally substituted (Q8), optionally substituted (Q9), wherein * represents the position connected to C1, the W group in Q7 is bromine, Ar-S group, wherein Ar is phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from alkyl, alkoxy, halogen, ester, nitro and -C(O)NR1R2-, R1 and R2 in the group are independently selected from a chemical bond, H and alkyl, or R1 and R2 form a 5-7 membered heterocycle, and the heteroatom is selected from one or more of O, N and S.

6. A compound according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: C1 is selected from: direct bond, -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(C≡C-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q on the left side and to B1 or P1 on the right side.

7. A compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 is selected from the group consisting of direct keys, Preferably Wherein connection point 1 is connected to C1 or Q (when C1 is a direct bond), connection point 2 is connected to P1, connection points *, 3, 4 and 5 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, L6 is -(CH2) m1 - or -(CH2-CH2-O)m2, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6； Preferably, when C1 is a direct bond, B1 is 8. A compound according to any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following group: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

9. A compound according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: T1, T2, T3 are independently selected from the following group: direct bond, and optionally substituted The connection point 1 is connected to P1, P2 or P3, and the connection point 2 is connected to D1, D2 or D3.

10. A compound according to any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine; preferably, P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine; More preferably, P1, P2, P3 comprise optionally substituted polypeptide residues selected from the following group: phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit)、 Glycine-Glycine-Phenylalanine-Glycine (Gly-Gly-Phe-Gly), Glycine-Proline (Gly-Pro); Alternatively, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

11. A compound according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: The hydrophilic group is selected from: substituted polysarcosine residues, polyglycerol, polyol, glycosyl, cyclodextrin, substituted ethylene glycol fragments, substituted glycosylated polyethylene glycol, substituted glycosylated polyglycerol, substituted cyclodextrin polyethylene glycol or a combination thereof; Preferably, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, such as an integer between 4 and 16, and R is selected from: C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy; Preferably, the substituted glycosylated polyethylene glycol fragment is wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12; Preferably, the substituted glycosylated polyglycerol fragment is wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10; Preferably, the substituted polyethylene glycol fragment is wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18; Preferably, at least one of T1, T2, and T3 is Wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 via X, wherein the connection point 1 is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

12. A compound according to any one of claims 1 to 11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: D1, D2, and D3 are a first anticancer agent, a second anticancer agent, and a third anticancer agent; preferably, at least two of the first anticancer agent, the second anticancer agent, and the third anticancer agent have a synergistic anticancer effect; Preferably, D1, D2, and D3 are independently cytotoxic drugs or tumor-targeted therapeutic drugs; preferably, at least one of D1, D2, and D3 is a cytotoxic drug, and at least another one is a tumor-targeted therapeutic drug; further preferably, at least two of D1, D2, and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects; Preferably, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a drug unit targeting tubulin, a nucleoside antimetabolite anticancer drug unit and a drug unit targeting DNA; Preferably, the tumor targeted therapeutic drug is selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting transcription factors, and drug units targeting immune activation pathways, including inhibitors of EFGR pathway related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyl transferase (NMT) inhibitors; Preferably, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogues; Preferably, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof; Preferably, the nucleoside antimetabolite anticancer drug is gemcitabine or decitabine; Preferably, the drug unit targeting DNA is a DNA minor groove binder (PBD), a DNA alkylating agent (Duocarmycin), Trabectedin, Rubitidine or a derivative thereof; Preferably, the drug unit targeting the DNA damage response (DDR) or "synthetic lethality" related pathway is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors or Rad51 inhibitors; The PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or their analogs; the ATR inhibitor is preferably Berzosertib, Ceralasertib or their analogs; the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs; and / or the WEE1 inhibitor is preferably ZN-C3 (CAS 2376146-48-2), Adavosertib (AZD1775, CAS 955365-80-7), Debio 0123 (CAS 2243882-74-6) or their analogs; Preferably, the analogue of AZD5305 comprises the following structure: Where R a Selected from -C(O)NH-R b or -NHC(O)-R b , R b Selected from: C substituted with at least one primary or secondary amino group 2-7 Alkyl, C 3-7 Monocyclic alkyl, C 4-10 Bicyclic cycloalkyl, C 5-9 Spirocyclic cycloalkyl and C 5-9 A bridged cycloalkyl group, or R b It is a 4-6 membered monoheterocyclic alkyl containing 1-5 nitrogen, oxygen, sulfur atoms, C 4-10 Bicyclic heterocycloalkyl, C 5-9 Spiroheterocycloalkyl, C 5-9 A bridged heterocycloalkyl group, wherein the Rb group contains at least one primary or secondary amine group; Preferably, the AZD5305 analogue is selected from the following structures: Preferably, the PKMYT1 inhibitor is preferably RP-6306 and GSK-1520489A or their analogs; Preferably, the analogs of the WEE1 inhibitor Adavosertib (AZD1775, CAS 955365-80-7) and Debio 0123 (CAS 2243882-74-6) are selected from the following structures: Preferably, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor; the Bcl-2 family protein inhibitor includes a BCL-2 inhibitor, a BCL-XL inhibitor and a MCL-1 inhibitor, preferably Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), a Navitoclax analog (CAS 2143096-93-7), ABT-737 (CAS 852808-04-9), A-1331852 (CAS 1430844-80-6), S64315 (CAS 1799631-75-6) or an analog thereof; Preferably, the A-1331852 and S64315 analogs are selected from the following structures: Preferably, the epigenetic-targeted drug unit is a LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor or a PRMT1 inhibitor; The LSD1 inhibitor is preferably Tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG-7289, INCB059872 or TAK-418 or their analogs; the EZH2 inhibitor is preferably Tazemetostat (CAS 1403254-99-8), GSK2816126, CPI-1205, PF-06821497, SHR2554, XNW5004, HH2853 or their analogs; the BRD4 inhibitor is BI-2536 analogs, Birabresib; the PRMT5 inhibitor is preferably GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001 or their analogs; the PRMT1 inhibitor is preferably GSK3368715 (CAS 1629013-22-4), MS023 (CAS 1831110-54-3) or their analogs; Preferably, the drug unit for the target related to the immune activation pathway is a PD-L1 inhibitor, a CBL-B inhibitor, TLR7 / 8 agonists, PTPN2 / 1 inhibitors, or STING agonists; Preferably, the inhibitors of the Ras-Raf-MAPK pathway include: SOS 1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS 2230836-55-0) or their analogs; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS 2621928-55-8) or their analogs; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS 2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS 2055597-12-9) or its analogs; Preferably, the cell cycle pathway inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs; Preferably, the PI3K / AKT / mTOR pathway inhibitor includes: PKI-587 (CAS 1197160-78-3), demethyl PKI-587 (CAS 1950569-63-7), AZD8055 (CAS 1009298-09-2), Afuresertib (CAS 1047644-62-1) or analogs thereof; Preferably, the estrogen receptor antagonist / degrader is Fulvestrant (CAS 129453-61-8), Elacestrant (CAS 1349723-93-8); androgen receptor antagonist abiraterone (CAS 154229-19-3), JNJ-63576253 (CAS 2110428-64-1) or an analog thereof; Preferably, the autophagy inhibitor is hydroxychloroquine (HCQ, CAS 118-42-3) and chloroquine (CQ, CAS 54-05-7) or their analogs; Preferably, the drug targeting the transcription factor is a GSPT1 degrader (molecular glue), and the GSPT1 degrader is selected from the following structures: Preferably, the FAK inhibitor is Ifebemtinib (CAS 1227948-82-4), Defactinib (CAS 1073154-85-4), PF-562271 (CAS 717907-75-0) or an analog thereof, selected from the following structures: Preferably, the PLK1 inhibitor is BI2536 (CAS 755038-02-9), Volasertib (CAS 755038-65-4), GSK461364 (CAS 929095-18-1), Onvansertib (CAS 1034616-18-6) or an analog thereof; Preferably, the N-myristoyltransferase (NMT) inhibitor is MYX1715 (CAS 2445448-66-6) or an analog thereof; More preferably, D1, D2 and D3 are selected from the following combinations: More preferably, (i) at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another one is a tumor targeted therapeutic drug, the tumor targeted therapeutic drug is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, Rad51 inhibitors; (ii) at least two of D1, D2 and D3 are cytotoxic drugs and are independently selected from topoisomerase-targeting drugs and tubulin-targeting drug units, such as TOPO1 inhibitors, TOPO2 inhibitors and tubulin inhibitors; (iii) at least two or all three of D1, D2 and D3 are tumor targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including targeting: inhibitors of EFGR pathway related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors; (iv) one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from drugs targeting topoisomerase and drugs targeting tubulin, such as TOPO1 inhibitors or tubulin inhibitors, and the other one or two are tumor-targeted therapeutic drugs, the tumor-targeted therapeutic drugs are selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis-related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune stimulators. Drug units targeting targets related to active pathways, including inhibitors targeting targets related to the EFGR pathway; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors; More preferably, D1, D2 and D3 are selected from the combination shown in Table A.

13. A compound according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is selected from formula A1 to A190:

14. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula II: in, Q' is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group; D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and When a=0, B1 is a direct bond and T1 is not a direct bond; When b=0, B1 is not a direct bond.

15. The compound according to claim 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula IIa: in: Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 is a branching group; P1 and P2 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group; D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different; a is 1, 2 or 3.

16. The compound according to claim 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula IIb: Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic heterocyclic group, an optionally substituted arylene group and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxy, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy; B2 is a branching group; P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group; D1 and D3 are the first drug unit and the third drug unit, respectively, and are the same or different; b is 1, 2, or 3.

17. The compound according to claim 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 and B2 are independently branching groups; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group; D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; a and b are independently 1, 2 or 3.

18. A compound according to any one of claims 14 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: Said Selected from the group consisting of: optionally substituted (Q1'), optionally substituted (Q2'), optionally substituted (Q3'), optionally substituted (Q4'), optionally substituted (Q5'), optionally substituted (Q6'), optionally substituted (Q7') and optionally substituted (Q8'), where * represents the site of connection with C1, and the wavy line represents the site of connection with the antibody.

19. A compound according to any one of claims 14 to 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: C1 is selected from: direct bond, -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(C≡C-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q' on the left side and to B1 or P1 on the right side.

20. A compound according to any one of claims 14 to 19, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 is selected from the group consisting of direct keys, Preferably wherein connection point 1 is connected to C1 or Q' (when C1 is a direct bond), connection point 2 is connected to P1, connection points *, 3, 4 and 5 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, L6 is -(CH2) m1 - or -(CH2-CH2-O)m2, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6; Preferably, when C1 is a direct bond, B1 is 21. A compound according to any one of claims 14 to 20, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following group: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

22. A compound according to any one of claims 14 to 21, or a tautomer, meso racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: T1, T2, T3 are independently selected from the following group: direct bond, and optionally substituted The connection point 1 is connected to P1, P2 or P3, and the connection point 2 is connected to D1, D2 or D3.

23. A compound according to any one of claims 14 to 22, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine; preferably, P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine; More preferably, P1, P2, and P3 comprise optionally substituted polypeptide residues selected from the following group: phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit)、 Glycine-Glycine-Phenylalanine-Glycine (Gly-Gly-Phe-Gly), Glycine-Proline (Gly-Pro); Alternatively, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

24. A compound according to any one of claims 14 to 23, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: The hydrophilic group is selected from: substituted polysarcosine residues, polyglycerol, polyol, glycosyl, cyclodextrin, substituted ethylene glycol fragments, substituted glycosylated polyethylene glycol, substituted glycosylated polyglycerol, substituted cyclodextrin polyethylene glycol or a combination thereof; Preferably, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, such as an integer between 4 and 16, and R is selected from: C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy; Preferably, the substituted glycosylated polyethylene glycol fragment is wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12; Preferably, the substituted glycosylated polyglycerol fragment is wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10; Preferably, the substituted polyethylene glycol fragment is wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18; Preferably, at least one of T1, T2, and T3 is Wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 via X, wherein the connection point 1 is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

25. A compound according to any one of claims 14 to 24, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: D1, D2 and D3 are a first anticancer agent, a second anticancer agent and a third anticancer agent; preferably, at least two of the first anticancer agent, the second anticancer agent and the third anticancer agent have a synergistic anticancer effect; Preferably, D1, D2 and D3 are independently cytotoxic drugs or tumor-targeted therapeutic drugs; preferably, at least one of D1, D2 and D3 is a cytotoxic drug, and at least another one is a tumor-targeted therapeutic drug; further preferably, at least two of D1, D2 and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects; Preferably, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a drug unit targeting tubulin, a nucleoside antimetabolite anticancer drug unit and a drug unit targeting DNA; Preferably, the tumor targeted therapeutic drug is selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting transcription factors, and drug units targeting immune activation pathways, including inhibitors of EFGR pathway related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyl transferase (NMT) inhibitors; Preferably, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), berotelecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (CAS 171335-80-1), berotelecan (CAS 171335-80-1), DXd (CAS 1599440-3 ... 7-ethyl-10-hydroxycamptothecin (CAS 171335-80-1), (Belotecan, CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or their derivatives and analogs; Preferably, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof; Preferably, the nucleoside antimetabolite anticancer drug is gemcitabine or decitabine; Preferably, the drug unit targeting DNA is a DNA minor groove binder (PBD) or a DNA alkylating agent (Duocarmycin), Trabectedin, Rubitidine or a derivative thereof; Preferably, the drug unit targeting DNA damage response (DDR) or "synthetic lethality" related pathways is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor or a Rad51 inhibitor; The PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or their analogs; the ATR inhibitor is preferably Berzosertib, Ceralasertib or their analogs; the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or their analogs; and / or the WEE1 inhibitor is preferably ZN-C3 (CAS 2376146-48-2), Adavosertib (AZD1775, CAS 955365-80-7), Debio 0123 (CAS 2243882-74-6) or their analogs; Preferably, the analogue of AZD5305 comprises the following structure: Where R a Selected from -C(O)NH-R b or -NHC(O)-R b , R b Selected from: C substituted with at least one primary or secondary amino group 2-7 Alkyl, C 3-7 Monocyclic alkyl, C 4-10 Bicyclic cycloalkyl, C 5-9 Spirocyclic cycloalkyl and C 5-9 A bridged cycloalkyl group, or R b It is a 4-6 membered monoheterocyclic alkyl containing 1-5 nitrogen, oxygen, sulfur atoms, C 4-10 Bicyclic heterocycloalkyl, C 5-9 Spiroheterocycloalkyl, C 5-9 A bridged heterocycloalkyl group, wherein the Rb group contains at least one primary or secondary amine group; Preferably, the AZD5305 analogue is selected from the following structures: Preferably, the PKMYT1 inhibitor is preferably RP-6306 and GSK-1520489A or their analogs; Preferably, the analogs of the WEE1 inhibitor Adavosertib (AZD1775, CAS 955365-80-7) and Debio 0123 (CAS 2243882-74-6) are selected from the following structures: Preferably, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor; the Bcl-2 family protein inhibitor includes a BCL-2 inhibitor, a BCL-XL inhibitor and a MCL-1 inhibitor, preferably Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), ABT-737 (CAS 852808-04-9), A-1331852 (CAS 1430844-80-6), S64315 (CAS 1799631-75-6) or their analogs; Preferably, the A-1331852 and S64315 analogs are selected from the following structures: Preferably, the epigenetic-targeted drug unit is a LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor or a PRMT1 inhibitor; The LSD1 inhibitor is preferably Tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG- 7289, INCB059872 or TAK-418 or their analogs; the EZH2 inhibitor is preferably Tazemetostat (CAS 1403254-99-8), GSK2816126, CPI-1205, PF-06821497, SHR2554, XNW5004, HH2853 or their analogs; the BRD4 inhibitor is BI-2536 analogs, Birabresib; the PRMT5 inhibitor is preferably GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001 or their analogs; the PRMT1 inhibitor is preferably GSK3368715 (CAS 1629013-22-4), MS023 (CAS 1831110-54-3) or its analogues; Preferably, the drug unit for the immune activation pathway-related target is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, a PTPN2 / 1 inhibitor or a STING agonist; Preferably, the inhibitors of the Ras-Raf-MAPK pathway include: SOS 1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS 2230836-55-0) or their analogs; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS 2621928-55-8) or their analogs; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS 2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS 2055597-12-9) or its analogs; Preferably, the cell cycle pathway inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs; Preferably, the PI3K / AKT / mTOR pathway inhibitor includes: PKI-587 (CAS 1197160-78-3), demethyl PKI-587 (CAS 1950569-63-7), AZD8055 (CAS 1009298-09-2), Afuresertib (CAS 1047644-62-1) or analogs thereof; Preferably, the estrogen receptor antagonist / degrader is Fulvestrant (CAS 129453-61-8), Elacestrant (CAS 1349723-93-8); androgen receptor antagonist abiraterone (CAS 154229-19-3), JNJ-63576253 (CAS 2110428-64-1) or an analog thereof; Preferably, the autophagy inhibitor is hydroxychloroquine (HCQ, CAS 118-42-3) and chloroquine (CQ, CAS 54-05-7) or their analogs; Preferably, the drug targeting the transcription factor is a GSPT1 degrader (molecular glue), and the GSPT1 degrader is selected from the following structures: Preferably, the FAK inhibitor is Ifebemtinib (CAS 1227948-82-4), Defactinib (CAS 1073154-85-4), PF-562271 (CAS 717907-75-0) or an analog thereof, selected from the following structures: Preferably, the PLK1 inhibitor is BI2536 (CAS 755038-02-9), Volasertib (CAS 755038-65-4), GSK461364 (CAS 929095-18-1), Onvansertib (CAS 1034616-18-6) or an analog thereof; Preferably, the N-myristoyltransferase (NMT) inhibitor is MYX1715 (CAS 2445448-66-6) or an analog thereof; More preferably, D1, D2 and D3 are selected from the following combinations: More preferably, (i) at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another one is a tumor targeted therapeutic drug, the tumor targeted therapeutic drug is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, Rad51 inhibitors; (ii) at least two of D1, D2 and D3 are cytotoxic drugs and are independently selected from topoisomerase-targeting drugs and tubulin-targeting drug units, such as TOPO1 inhibitors, TOPO2 inhibitors and tubulin inhibitors; (iii) at least two or all three of D1, D2 and D3 are tumor targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including targeting: inhibitors of EFGR pathway related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors; (iv) one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from drugs targeting topoisomerase and drugs targeting tubulin, such as TOPO1 inhibitors or tubulin inhibitors, and the other one or two are tumor-targeted therapeutic drugs, the tumor-targeted therapeutic drugs are selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis-related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune stimulators. Drug units targeting targets related to active pathways, including inhibitors targeting targets related to the EFGR pathway; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors; More preferably, D1, D2 and D3 are selected from the combination shown in Table A.

26. A compound according to any one of claims 14 to 25, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is selected from formula B1 to B190:

27. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the compound comprises a structure shown in Formula III: in, Ab is an antibody molecule, and m is an integer or decimal from 1 to 8; Q' is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group; D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and When a=0, B1 is a direct bond and T1 is not a direct bond; When b=0, B1 is not a direct bond.

28. The compound according to claim 27, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula IIIa: in: Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 is a branching group; P1 and P2 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group; D1 and D2 are the first drug unit and the second drug unit, respectively, and are the same or different; a is 1, 2 or 3.

29. The compound according to claim 27, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula IIIb: Q' is a functional group capable of coupling to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule; C1 is selected from the following group: optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy; B2 is a branching group; P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group; D1 and D3 are the first drug unit and the third drug unit, respectively, and are the same or different; b is 1, 2, or 3.

30. The compound according to claim 27, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or mixture form, or pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 and B2 are independently branching groups; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group; D1, D2, and D3 are the first drug unit, the second drug unit, and the third drug unit, respectively, and are the same or different; a and b are independently 1, 2 or 3.

31. A compound according to any one of claims 27 to 30, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: The Q' is selected from the following group: optionally substituted (Q1'), optionally substituted (Q2'), optionally substituted (Q3'), optionally substituted (Q4'), optionally substituted (Q5'), optionally substituted (Q6'), optionally substituted (Q7') and optionally substituted (Q8'), where * represents the position connected to C1, and the wavy line represents the position connected to Ab.

32. A compound according to any one of claims 27 to 31, or a tautomer, meso racemate, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: C1 is selected from: direct bond, -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(C≡C-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q' on the left side and to B1 or P1 on the right side.

33. A compound according to any one of claims 27 to 32, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: B1 is selected from the group consisting of direct keys, Preferably Where connection point 1 is connected to C1 or Q' (when C1 is a direct bond), connection point 2 is connected to P1, connection points *, 3, 4 and 5 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, L6 is -(CH2) m1 - or -(CH2-CH2-O)m2, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6; Preferably, when C1 is a direct bond, B1 is 34. A compound according to any one of claims 27 to 33, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B2 is selected from the following group: Wherein connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following group: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

35. A compound according to any one of claims 27 to 34, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: T1, T2, T3 are independently selected from the following group: direct bond, and optionally substituted The connection point 1 is connected to P1, P2 or P3, and the connection point 2 is connected to D1, D2 or D3.

36. A compound according to any one of claims 27 to 35, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine; preferably, P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine; More preferably, P1, P2, P3 comprise optionally substituted polypeptide residues selected from the following group: phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Val-Ala), valine-citrulline (Val-Cit ...Ala), glutamic acid-valine-ci Ala-Ala), Alanine-Alanine-Alanine (Ala-Ala-Ala), Alanine-Alanine-Asparagine (Ala-Ala-Asn), Alanine-Leucine (Ala-Leu), Leucine-Leucine (Leu-Leu), Phenylalanine-Arginine (Phe-Arg), Phenylalanine-Lysine (Phe-Lys), (cBu-Cit)、 Glycine-Glycine-Phenylalanine-Glycine (Gly-Gly-Phe-Gly), Glycine-Proline (Gly-Pro); Alternatively, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

37. A compound according to any one of claims 27 to 36, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: The hydrophilic group is selected from: substituted polysarcosine residues, polyglycerol, polyol, glycosyl, cyclodextrin, substituted ethylene glycol fragments, substituted glycosylated polyethylene glycol, substituted glycosylated polyglycerol, substituted cyclodextrin polyethylene glycol or a combination thereof; Preferably, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, such as an integer between 4 and 16, and R is selected from: C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy; Preferably, the substituted glycosylated polyethylene glycol fragment is wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12; Preferably, the substituted glycosylated polyglycerol fragment is wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10; Preferably, the substituted polyethylene glycol fragment is Where n5 is an integer between 4 and 24 A number, such as an integer between 8 and 18; Preferably, at least one of T1, T2, and T3 is Wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 via X, wherein the connection point 1 is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

38. A compound according to any one of claims 27 to 37, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: D1, D2 and D3 are a first anticancer agent, a second anticancer agent and a third anticancer agent; preferably, at least two of the first anticancer agent, the second anticancer agent and the third anticancer agent have a synergistic anticancer effect; Preferably, D1, D2 and D3 are independently cytotoxic drugs or tumor-targeted therapeutic drugs; preferably, at least one of D1, D2 and D3 is a cytotoxic drug, and at least another one is a tumor-targeted therapeutic drug; further preferably, at least two of D1, D2 and D3 are tumor-targeted therapeutic drugs, such as tumor-targeted therapeutic drugs that can produce synergistic or additive effects; Preferably, the cytotoxic drug is selected from a drug unit targeting topoisomerase, a drug unit targeting tubulin, a nucleoside antimetabolite anticancer drug unit and a drug unit targeting DNA; Preferably, the tumor targeted therapeutic drug is selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting transcription factors, and drug units targeting immune activation pathways, including inhibitors of EFGR pathway related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyl transferase (NMT) inhibitors; Preferably, the drug unit targeting topoisomerase is a topoisomerase I (TOPO1) inhibitor or a topoisomerase II (TOPO2) inhibitor, including Exatecan (CAS 171335-80-1), DXd (CAS 1599440-33-1), 7-ethyl-10-hydroxycamptothecin (SN38, CAS 86639-52-3), Belotecan (CAS 213819-48-8), (4-NH2)-Exatecan (AZD'0132, CAS 2495742-21-5), 7-MAD-MDCPT (CAS 765871-81-6), 7-aminomethyl-10-methyl-11-fluorocamptothecin (CAS 2378616-23-8), Voreloxin (CAS 175414-77-4) or its derivatives and analogues; Preferably, the drug unit targeting tubulin is Eribulin, vinblastine, paclitaxel, MMAE, MMAF, maytansine or a derivative thereof; Preferably, the nucleoside antimetabolite anticancer drug is gemcitabine or decitabine; Preferably, the drug unit targeting DNA is a DNA minor groove binder (PBD) or a DNA alkylating agent (Duocarmycin), Trabectedin, Rubitidine or a derivative thereof; Preferably, the drug unit targeting DNA damage response (DDR) or "synthetic lethality" related pathways is a PARP inhibitor, an ATR inhibitor, a CHK1 inhibitor, an ATM inhibitor, a DNA-PK inhibitor, a WEE1 inhibitor, a POLQ inhibitor, a CDK12 inhibitor, a USP1 inhibitor, a PKMYT1 inhibitor or a Rad51 inhibitor; The PARP inhibitor is preferably Rucaparib, Niraparib, Veliparib, A-966492, Talazoparib, AZD5305, Venadaparib, Mefuparib or an analog thereof; the ATR inhibitor is preferably Berzosertib, Ceralasertib or an analog thereof; and / or the CHK1 inhibitor is preferably Prexasertib (LY2606368), AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, CCT245737 (SRA737, PNT-737), GDC-0575 (ARRY-575) or an analog thereof; and / or the WEE1 inhibitor is preferably ZN-C3, Adavosertib (AZD1775) or an analog thereof; Preferably, the analogue of AZD5305 comprises the following structure: Where R a Selected from -C(O)NH-R b or -NHC(O)-R b , R b Selected from: C substituted with at least one primary or secondary amino group 2-7 Alkyl, C 3-7 Monocyclic alkyl, C 4-10 Bicyclic cycloalkyl, C 5-9 Spirocyclic cycloalkyl and C 5-9 A bridged cycloalkyl group, or R b It is a 4-6 membered monoheterocyclic alkyl containing 1-5 nitrogen, oxygen, sulfur atoms, C 4-10 Bicyclic heterocycloalkyl, C 5-9 Spiroheterocycloalkyl, C 5-9 A bridged heterocycloalkyl group, wherein the Rb group contains at least one primary or secondary amine group; Preferably, the AZD5305 analogue is selected from the following structures: Preferably, the PKMYT1 inhibitor is preferably RP-6306 and GSK-1520489A or their analogs; Preferably, the analogs of the WEE1 inhibitor Adavosertib (AZD1775, CAS 955365-80-7) and Debio 0123 (CAS 2243882-74-6) are selected from the following structures: Preferably, the drug unit targeting apoptosis-related pathways is a Bcl-2 family protein inhibitor; the Bcl-2 family protein inhibitor includes a BCL-2 inhibitor, a BCL-XL inhibitor and a MCL-1 inhibitor, preferably Venetoclax (CAS 1257044-40-8), Navitoclax (CAS 923564-51-6), a Navitoclax analog (CAS2143096-93-7), ABT-737 (CAS 852808-04-9), A-1331852 (CAS 1430844-80-6), S64315 (CAS 1799631-75-6) or an analog thereof; Preferably, the A-1331852 and S64315 analogs are selected from the following structures: Preferably, the epigenetic-targeted drug unit is a LSD1 inhibitor, an EZH2 inhibitor, a BRD4 inhibitor, a PRMT5 inhibitor or a PRMT1 inhibitor; The LSD1 inhibitor is preferably Tranylcypromine, ORY-1001 (Iadademstat, CAS 1431303-72-8), CC-90011 (Pulrodemstat, CAS 1821307-10-1), ORY-2001, GSK-2879552, IMG-7289, INCB059872 or TAK-418 or their analogs; the EZH2 inhibitor is preferably Tazemetostat (CAS 1403254-99-8), GSK2816126, CPI-1205, PF-06821497, SHR2554, XNW5004, HH2853 or their analogs; the BRD4 inhibitor is BI-2536 analogs, Birabresib; the PRMT5 inhibitor is preferably GSK3326595, AMG 193, MRTX1719, SKL27969, TNG908, SCR-6920, SH3765, SYHX2001 or their analogs; the PRMT1 inhibitor is preferably GSK3368715 (CAS 1629013-22-4), MS023 (CAS 1831110-54-3) or their analogs; Preferably, the drug unit for the immune activation pathway-related target is a PD-L1 inhibitor, a CBL-B inhibitor, a TLR7 / 8 agonist, a PTPN2 / 1 inhibitor or a STING agonist; Preferably, the inhibitors of the Ras-Raf-MAPK pathway include: SOS1 inhibitors BAY-293 (CAS 2244904-70-7), BI-3406 (CAS2230836-55-0) or their analogs; KRAS inhibitors BI-2493 (CAS 2937344-16-4), MRTX1133 (CAS2621928-55-8) or their analogs; MEK inhibitors Cobimetinib (CAS 934660-93-2), Selumetinib (CAS 606143-52-6), Mirdametinib (CAS 391210-10-9), Binimetinib (CAS 606143-89-9), TAK-733 (CAS 1035555-63-5), GDC-0623 (CAS 1168091-68-6), AZD8330 (CAS 869357-68-6), Trametinib (CAS 871700-17-3), Trametiglue (CAS2666940-97-0) or their analogs; ERK inhibitor ASN007 (CAS2055597-12-9) or its analogs; Preferably, the cell cycle pathway inhibitors include: CDK4 / 6 inhibitors Palbociclib (CAS 571190-30-2), Abemaciclib (CAS 1231929-97-7), Ribociclib (CAS 1211441-98-3), Dalpiciclib (CAS 1637781-04-4) or their analogs; pan-CDK inhibitor Dinaciclib (CAS 779353-01-4) or its analogs; Preferably, the PI3K / AKT / mTOR pathway inhibitor includes: PKI-587 (CAS 1197160-78-3), demethyl PKI-587 (CAS 1950569-63-7), AZD8055 (CAS 1009298-09-2), Afuresertib (CAS 1047644-62-1) or analogs thereof; Preferably, the estrogen receptor antagonist / degrader Fulvestrant (CAS 129453-61-8), Elacestrant (CAS 1349723-93-8); androgen receptor antagonist abiraterone (CAS 154229-19-3), JNJ-63576253 (CAS 2110428-64-1) or an analog thereof; Preferably, the autophagy inhibitor is hydroxychloroquine (HCQ, CAS 118-42-3) and chloroquine (CQ, CAS 54-05-7) or their analogs; Preferably, the drug targeting the transcription factor is a GSPT1 degrader (molecular glue), and the GSPT1 degrader is selected from the following structures: Preferably, the FAK inhibitor is Ifebemtinib (CAS 1227948-82-4), Defactinib (CAS 1073154-85-4), PF-562271 (CAS 717907-75-0) or its analogues, selected from the following structures: Preferably, the PLK1 inhibitor is BI2536 (CAS 755038-02-9), Volasertib (CAS 755038-65-4), GSK461364 (CAS 929095-18-1), Onvansertib (CAS 1034616-18-6) or an analog thereof; Preferably, the N-myristoyltransferase (NMT) inhibitor is MYX1715 (CAS2445448-66-6) or an analog thereof; More preferably, D1, D2 and D3 are selected from the following combinations: More preferably, (i) at least one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from drugs targeting topoisomerase, such as TOPO1 inhibitors, and at least another one is a tumor targeted therapeutic drug, the tumor targeted therapeutic drug is a drug targeting DNA damage response (DDR) or "synthetic lethality" related pathways, selected from PARP inhibitors, ATR inhibitors, CHK1 inhibitors, ATM inhibitors, DNA-PK inhibitors, WEE1 inhibitors, POLQ inhibitors, CDK12 inhibitors, USP1 inhibitors, PKMYT1 inhibitors, Rad51 inhibitors; (ii) at least two of D1, D2 and D3 are cytotoxic drugs and are independently selected from drugs targeting topoisomerase and drugs targeting tubulin, such as TOPO1 inhibitors, TOPO2 inhibitors and tubulin inhibitors. White inhibitor; (iii) at least two or all three of D1, D2 and D3 are tumor targeted therapeutic drugs, and are independently selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune activation pathways, including targeting: inhibitors of EFGR pathway related targets; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors; (iv) one of D1, D2 and D3 is a cytotoxic drug, the cytotoxic drug is selected from drugs targeting topoisomerase and drugs targeting tubulin, such as TOPO1 inhibitors or tubulin inhibitors, and the other one or two are tumor-targeted therapeutic drugs, the tumor-targeted therapeutic drugs are selected from drug units targeting DNA damage response (DDR) or "synthetic lethality" related pathways, drug units targeting epigenetics, drug units targeting apoptosis-related pathways, drug units targeting cell cycle pathways, drug units targeting transcription factors and drug units targeting immune stimulators. Drug units targeting targets related to active pathways, including inhibitors targeting targets related to the EFGR pathway; Ras-Raf-MAPK pathway inhibitors; PI3K / AKT / mTOR pathway inhibitors; cell cycle pathway inhibitors; cGAS-STING signaling pathway agonists; estrogen receptor antagonists; androgen receptor antagonists; glucocorticoid receptor modulators; autophagy inhibitors; FAK inhibitors; Smo inhibitors; BTK inhibitors; PDE4 inhibitors; Lck inhibitors; PLK1 inhibitors; TLR7 / 8 modulators; N-myristoyltransferase (NMT) inhibitors; More preferably, D1, D2 and D3 are selected from the combination shown in Table A.

39. A compound according to any one of claims 27 to 38, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is selected from Formula C1 to C190: Wherein Ab is an antibody or an antigen-binding fragment thereof, and m is an integer or decimal of 1-12.

40. A compound according to any one of claims 27 to 39, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the Ab is a monoclonal antibody or an antigen-binding fragment thereof; preferably, the monoclonal antibody is an antibody against the following antigens: HER2, HER3, TROP2, B7-H3, B7-H4, GPC20, GPRC5D, CDH6, EGFR, EGFRvIII, AXL, Nectin-4, Tissue factor, TIM-1, PSMA, PTK7, EpCAM, MUC1, STEAP1, GPNMB, FGF2, FOLR1, c-MET, GFR, AGS-16, Guanylyl cyclase C, Mesothelin, SLC44A4, EphA2, AGS-5, GPC-3, c-KIT, ROR1, ROR2, PD-L1, CD27L, 5T4, MerTK, Mucin 16, NaPi2b, STEAP, SLITRK6, ETBR, BCMA, CEACAM5, ICAM1, SC-16, SLC39A6, Delta-like protein3, Claudin 18.2, Claudin3, Claudin 6, Claudin 9, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD73, CD74, CD79b, CD123, CD138, CD147, CD166, CD223, MUC16, MSLN, ENPP3, SLTRK6, FGFR, LIV-1, Lewis Y, av-integrin, ITGB6(integrin beta-6), ASCT2, C4.4a, CA-IX, CD324, CD352, CD44v6, CD48a, CLL-1, Cripto, CS1, DPEP3, Ephrin-A2, Ephrin-A4, ETBR, FGFR2, FGFR3, FLT3, GD3, Globo H, GPC3, LAMP-1, LRRC15, Ly6E, TM4SF1, MFI2, NOTCH3, p-cadherin, PRLR, CLDN1, CD228, CUB domain-containing protein 1 (CDCP1), CXCR4, LGR4, FZD7, CTR, GPR56, CCR7, DDR1 and RNF43.

41. A linker, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the structural formula of the linker is shown in the following formula IV: in, Q' is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 and B2 are independently a direct bond or a branched group, provided that when C1 is a direct bond, B1 is not a direct bond; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, provided that at most two of T1, T2 and T3 are direct bonds and at least one of B2, T1, T2 and T3 is substituted with a hydrophilic group; Connection points 2, 3, and 4 are connected to the drug unit; a and b are independently 0, 1, 2 or 3, provided that a and b are not both 0; and When a=0, B1 is a direct bond and T1 is not a direct bond; When b=0, B1 is not a direct bond.

42. The linker according to claim 41, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula IVa: in: Q' is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody; C1 is selected from the following group: a direct bond, an optionally substituted alkylene group, an optionally substituted polyethylene glycol group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted alicyclic group, an optionally substituted alicyclic group, an optionally substituted arylene group, and an optionally substituted heteroarylene group; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate, and alkoxy; B1 is a branching group; P1 and P2 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 and T2 are each independently a direct bond or an optionally substituted spacer group, provided that at most one of T1 and T2 is a direct bond and at least one of T1 and T2 is substituted with a hydrophilic group; Connection points 2 and 3 are connected to the drug unit; a is 1, 2 or 3.

43. The linker according to claim 41, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound comprises the structure shown in Formula IVb: Q' is a functional group that can be coupled to cysteine, lysine, unnatural amino acid or sugar group of the antibody molecule, and the connection point 1 is connected to the antibody; C1 is selected from the following group: optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylene and optionally substituted heteroarylene; when substituted, the substituent is selected from halogen, hydroxyl, amino, carboxyl, sulfonic acid, sulfone, phosphate and alkoxy; B2 is a branching group; P1 and P3 are each independently a direct bond or an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T3 is a direct bond or an optionally substituted spacer group, and at least one of B2 and T3 is substituted with a hydrophilic group; Connection points 2 and 3 are connected to the drug unit; b is 1, 2, or 3.

44. The linker according to claim 41, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 and B2 are independently branching groups; P1, P2 and P3 are each independently an optionally substituted polypeptide residue or a glucose moiety; T1 is an optionally substituted spacer group, T2 and T3 are each independently a direct bond or an optionally substituted spacer group, and at least one of B2, T2 and T3 is substituted with a hydrophilic group; a and b are independently 1, 2 or 3.

45. The linker according to any one of claims 41 to 44, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: The Q' is selected from the following group: optionally substituted (Q1'), optionally substituted (Q2'), optional Replaced (Q3'), optionally substituted (Q4'), optionally substituted (Q5'), optionally substituted (Q6'), optionally substituted (Q7') and optionally substituted (Q8'), where * represents the site of connection with C1 and the wavy line represents the site of connection with the antibody molecule.

46. ​​The linker according to any one of claims 41 to 45, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: C1 is selected from: direct bond, -(CH2) m1 -、-(CH2) m1 -(O-CH2-CH2) m2 -、-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 - and -(C≡C-(CH2) m1 -, wherein m1, m2 and m3 are independently integers of 1 to 6, and the substituent is connected to Q' on the left side and to B1 or P1 on the right side.

47. The linker according to any one of claims 41 to 46, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B1 is selected from the group consisting of direct keys, Preferably wherein connection point 1 is connected to C1 or Q' (when C1 is a direct bond), connection point 2 is connected to P1, connection points *, 3, 4 and 5 are connected to P2, and L1 is selected from -(CH2) m1 -、-(CH2) m1 -C(O)NH-(CH2) m2 -、-(CH2) m1 -NHC(O)-(CH2) m2 -, L2, L3 and L4 are independently -(CH2) m1 -(O-CH2-CH2) m2 -or-(CH2) m1 -(O-CH2-CH2) m2 -(CH2) m3 -, L5 is -(CH2) m1 -, L6 is -(CH2) m1 - or -(CH2-CH2-O)m2, wherein m1, m2, m3, w and v are each independently 1, 2, 3, 4, 5 or 6; Preferably, when C1 is a direct bond, B1 is 48. The linker according to any one of claims 41 to 47, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: B2 is selected from the following group: Where connection point 1 is connected to T1, connection point 2 is connected to P3, connection point 3 is connected to the hydrophilic group, and M is selected from the following group: optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkoxy, optionally substituted C1-C5 alkenylene.

49. The linker according to any one of claims 41 to 48, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: T1, T2, T3 are independently selected from the following group: direct bond, and optionally substituted The connection point 1 is connected to P1, P2 or P3, and the connection point 2 is connected to D1, D2 or D3.

50. The linker according to any one of claims 41 to 49, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine; preferably, P1, P2, P3 comprise optionally substituted polypeptide residues consisting of amino acids selected from the following group: glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, asparagine and lysine; More preferably, P1, P2, and P3 comprise optionally substituted polypeptide residues selected from the following group: phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine (Val-Lys), alanine-alanine (Ala-Ala), alanine-alanine-alanine (Ala-Ala-Ala), alanine-alanine-asparagine (Ala-Ala-Asn), alanine-leucine (Ala-Leu), leucine-leucine (Leu-Leu), phenylalanine-arginine (Phe-Arg), phenylalanine-lysine (Phe-Lys), (cBu-Cit)、 Glycine-Glycine-Phenylalanine-Glycine (Gly-Gly-Phe-Gly), Glycine-Proline (Gly-Pro); Alternatively, one of the P2-T2 combination or the P3-T3 combination is Connection point 1 is connected to B1 or B2, and connection point 2 is connected to D2 or D3.

51. The linker according to any one of claims 41 to 50, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: The hydrophilic group is selected from: substituted polysarcosine residues, polyglycerol, polyol, glycosyl, cyclodextrin, substituted ethylene glycol fragments, substituted glycosylated polyethylene glycol, substituted glycosylated polyglycerol, substituted cyclodextrin polyethylene glycol or a combination thereof; Preferably, the substituted polysarcosine residue is wherein n2 is an integer between 4 and 20, such as an integer between 4 and 16, and R is selected from: C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy; Preferably, the substituted glycosylated polyethylene glycol fragment is wherein n3 is an integer between 4 and 18, for example, an integer between 4 and 12; Preferably, the substituted glycosylated polyglycerol fragment is wherein n4 is an integer between 4 and 12, for example, an integer between 4 and 10; Preferably, the substituted polyethylene glycol fragment is wherein n5 is an integer between 4 and 24, for example, an integer between 8 and 18; Preferably, at least one of T1, T2, and T3 is Wherein X is optionally substituted The hydrophilic group is connected to T1, T2 or T3 via X, wherein the connection point 1 is connected to the hydrophilic group, and the connection point 2 is connected to one of T1, T2 and T3.

52. The linker according to any one of claims 41 to 51, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the structural formula of the linker is shown in Formula D1 to D38:

53. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 13 or 27 to 40, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof; and a pharmaceutically acceptable carrier.

54. Use of the compound of any one of claims 1 to 40, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or the linker of any one of claims 41 to 52, or the pharmaceutical composition of claim 53, in the preparation of a medicament for treating and / or preventing tumors.

55. The use according to claim 54, wherein the tumor is a solid tumor or a hematological tumor; preferably, the tumor is a homologous recombination repair deficiency (HRD)-related tumor; more preferably, the tumor is a tumor selected from the following target positive or high expression: HER2, HER3, TROP2, B7-H3, B7-H4, GPC20, GPRC5D, CDH6, EGFR, EGFRvIII, AXL, Nectin-4, Tissue factor, TIM-1, PSMA, PTK7, EpCAM, MUC1, STEAP1, GPNMB, FGF2, FOLR1, c-MET, GFR, AGS-16, Guanylyl cyclase C, Mesothelin, SLC44A4, EphA2, AGS-5, GPC-3, c-KIT, ROR1, ROR2, PD-L1, CD27L, 5T4, MerTK, Mucin 16. NaPi2b, STEAP, SLITRK6, ETBR, BCMA, CEACAM5, ICAM1, SC-16, SLC39A6, Delta-like protein3, Claudin 18.2, Claudin 3, Claudin 6, Claudin 9, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD73, CD74, CD79b, CD123, CD138, CD147, CD166, CD223, MUC16, MSLN, ENPP3, SLTRK6, FGFR, LIV-1, Lewis Y, av-integrin, ITGB6 (integrin beta-6), ASCT2, C4.4a, CA-IX, CD324, CD352, CD44v6, CD48a, CLL-1, Cripto, CS1, DPEP3, Ephrin-A2, Ephrin-A4, ETBR, FGFR2, FGFR3, FLT3, GD3, Globo H, GPC3, LAMP-1, LRRC15, Ly6E, TM4SF1, MFI2, NOTCH3, p-cadherin, PRLR, CLDN1, CD228, CUB domain-containing protein1 (CDCP1), CXCR4, LGR4, FZD7, CTR, GPR56, CCR7, DDR1 and RNF43; more preferably, the tumor is selected from breast cancer, ovarian cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, pancreatic cancer, prostate cancer, colorectal cancer, gastric cancer, bladder cancer, gastrointestinal stromal tumors, cervical cancer, esophageal cancer, peritoneal cancer, liver cancer, colon cancer, glioma, mesothelioma, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, malignant lymphoma, plasma cell tumor, myeloma and sarcoma. .

56. A method of combined administration, the combined administration comprising delivering at least two selected from a first drug (D1), a second drug (D2) and a third drug (D3) to tumor tissue as the same molecule, the method comprising forming at least two of D1, D2 and D3 into a compound as described in any one of claims 27 to 40; preferably, D1, D2 and D3 are selected from the combination shown in Table A.

57. A method for improving the drug-antibody coupling ratio (DAR value) of an ADC compound, the method comprising forming a drug into the compound of any one of claims 27 to 40; preferably, the DAR value is an integer or decimal between 16 and 56.

58. A compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is an antibody-drug conjugate, comprising an antibody molecule and at least two compounds attached to the antibody molecule, wherein the at least two compounds attached to the antibody molecule are independently selected from the compound of any one of claims 14 to 26, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or deuterated compound form thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof; preferably, the ratio of different drugs is any ratio from 1:1 to 1:24; preferably, the at least two compounds attached to the antibody molecule are attached to different coupling sites of the antibody molecule; preferably, the different coupling sites are selected from natural or modified thiol, amino and non-natural amino acids of the antibody.

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