2-indolone compound, ligand-drug conjugate thereof, preparation method therefor, and use thereof

Abstract

The present disclosure relates to a 2-indolone compound, a ligand-drug conjugate thereof, a preparation method therefor, and use thereof. The present disclosure relates to a ligand-drug conjugate having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, or a compound having a structure represented by formula (IA), formula (IVA), or formula (IIA) or a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof, or a mixture form thereof, or a pharmaceutically acceptable salt thereof, a preparation scheme therefor, a composition thereof, and use thereof in the treatment and / or prevention of tumors.

Description

2-Indoleone compounds, their ligand-drug conjugates, their preparation methods and applications Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a 2-indole ketone compound and a ligand-drug conjugate using the 2-indole ketone compound as a cytotoxic drug, as well as its preparation method and application. Background Technology

[0002] Ligand-drug conjugates (e.g., ADCs) are molecular forms that conjugate a ligand (e.g., an antibody or fragment thereof) that recognizes a specific antigen on the surface of tumor cells to a biologically active payload (e.g., a small molecule drug) via a stable chemical linker. Utilizing the specific interaction between the ligand (e.g., a monoclonal antibody) and the antigen, ligand-drug conjugates can precisely deliver the payload to target cells, where it is cleaved and released at the tumor site. This alters the distribution and metabolism of the small molecule drug, reduces the minimum effective dose (MED) of the payload, and expands the therapeutic window.

[0003] Over the past 20 years, breakthroughs have been made in the development of ADC drugs, with 15 ADC drugs currently approved for marketing globally. Common payloads in successfully marketed ADC drugs include DNA topoisomerase I inhibitors such as camptothecin derivatives, and microtubule polymerization inhibitors, such as monomethylaurestatin E (MMAE). While these compounds have shown excellent efficacy in inhibiting tumor growth, they also exhibit high cytotoxicity to normal cells, and their off-target killing effects on normal tissues cannot be ignored. In clinical applications, existing ADC products have also been observed to kill rapidly dividing somatic cells (such as intestinal cells or hematopoietic stem cells). Therefore, existing ADC products still have shortcomings such as a narrow safety window, and there is an urgent need for ADC products with better efficacy and fewer side effects.

[0004] The estrogen receptor (ER) belongs to the nuclear receptor superfamily, mainly including ERα, ERβ, and GPER1, and is known for its role as a transcription factor in gene expression regulation. The two most important subtypes of the estrogen receptor, ERα and ERβ, both contain an AF domain, composed of the AF-1 (A / B domain) and AF-2 (E / F domain) activation functional domains (AF), which promote transcriptional activation of the receptor. The ER also includes a DNA-binding domain (C domain) that promotes DNA binding and a hinge domain (D domain) containing a nuclear localization sequence.

[0005] 17β-estradiol (E2) is the most potent endogenous estrogen, exhibiting high selectivity for estrogen receptors. When estrogen binds to the ER, the ER undergoes a conformational change, leading to homodimerization, and subsequently enters the cell nucleus. In the nucleus, the complex binds to EREs, Ap1, or Sp1, regulating downstream gene transcription. Ultimately, estrogen-mediated protein expression participates in multiple biological processes, including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation. In estrogen receptor-positive (ERα+) tumors, active ER signaling drives tumor cell proliferation; therefore, ERα remains a highly sought-after and utilized pharmacological target. Furthermore, ERα is closely associated with poor prognosis and malignancy in various cancers, such as breast cancer, ovarian cancer, and endometrial cancer. Clinically, endocrine therapy, such as aromatase inhibitors that reduce endogenous estrogen production and estrogen receptor modulators / degraders that directly antagonize ERα, can be used to target ERα-dependent tumors. Although these endocrine therapies that directly target ER have reduced tumor recurrence and mortality to some extent, the rapid acquisition of drug resistance by tumor cells still poses a serious challenge to the treatment of ERα-positive tumors.

[0006] Furthermore, when tumor cells encounter external stress, the E2-ERα complex can activate endoplasmic reticulum pressure sensors, triggering the anticipated unfolded protein response (a-UPR). After E2 binds to ERα, IP3 binds and opens the IP3 receptor calcium flow channel on the endoplasmic reticulum membrane, allowing calcium ions to flow out of the endoplasmic reticulum lumen and into the cytoplasm. According to literature reports, excessive activation of UPR can lead to phosphorylation of metabolic sensors AMPK, eEF2, and eIF2α in tumor cells, ATP depletion, and persistent calcium ion efflux. The continuous calcium flow generated by a-UPR further activates the TRPM4-bound calcium sensor, opening sodium ion channels. TRPM4 is a unique sodium-selective six-transmembrane ion channel, specifically highly expressed in various cancers, including breast cancer, colorectal cancer, gastric cancer, and prostate cancer. Its expression level is positively correlated with clinical stage and epithelial-mesenchymal transition. TRMP4 can be activated by cytoplasmic calcium ions but is inhibited by intracellular ATP. High concentrations of sodium ions outside the cell enter the cell through the TRPM4 channel. In order to balance the charge, chloride ions passively enter the cell through the chloride channel. Water molecules enter the cell to maintain osmotic pressure, causing cell swelling and cell necrosis.

[0007] A class of 2-indolone compounds, represented by BHPI and ErSO (Livezey et al., Front Endocrinol (Lausanne). 9:325. (2018), WO2020009958), selectively kill estrogen receptor-positive tumor cells, such as breast cancer, ovarian cancer, and endometrial cancer, through a unique mechanism of action, while exhibiting weak killing effects on normal cells and estrogen receptor-negative tumor cells. Their specific mechanisms of action include downregulation of estrogen receptor-mediated gene transcriptional activity and persistent anticipatory UPR (a-UPR) activation. Both mechanisms-mediated tumor-killing effects depend on estrogen receptor expression in tumor cells. Recent studies have also reported the crucial role of transient receptor potential cation channel subfamily M member 4 (TRPM4) in maintaining persistent UPR cytotoxicity (Ghosh et al., Cancer Res. 83:3115-3130. (2023)). The continuous calcium flow generated by α-UPR functions through a calcium sensor bound to TRPM4. High extracellular Na+ concentrations enter the cell through TRPM4 channels. To balance the charge, Cl- passively enters the cell through chloride channels, and water molecules enter the cell to maintain osmotic pressure, leading to cell swelling and necrosis. Therefore, the sustained activation of TRPM4-dependent α-UPR is also a key pathway for the tumor-killing effects of this class of 2-indoleone compounds. These compounds exhibited antitumor effects and good tolerability in mouse models. Summary of the Invention

[0008] This disclosure provides a compound or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which may have one or more effects selected from the group consisting of: (1) inhibitory activity against the in vitro proliferation of tumor cells, (2) targeted inhibition, (3) plasma stability, (4) in vivo tumor-suppressive effect, (5) bystander effect, (6) antitransporter transport capability, (7) in vivo tumor-targeting capability, and (8) good in vivo safety. The aforementioned compound provided in this disclosure can be used as a drug for treating cancer. This disclosure also provides methods and uses of the aforementioned compound for cancer treatment.

[0009] The first aspect of this disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has the structure shown in formula (I): B#—(L—D)n (Formula (I))

[0010] B# is the ligand that binds to the target.

[0011] n is the average coupling ratio of drug ligands, and n can be an integer or decimal from 1 to 16;

[0012] L represents the connection unit;

[0013] D is a drug with the structure shown in formula (IV):

[0014] in,

[0015] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0016] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0017] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0018] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0019] X is selected from O, S, and NH; and

[0020] The wavy line represents the key connecting L and D.

[0021] The first aspect of this disclosure also relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has the structure shown in formula (I): B#—(L—D)n Formula (I)

[0022] B# is the ligand that binds to the target.

[0023] n is the average coupling ratio of drug ligands, and n can be an integer or decimal from 1 to 16;

[0024] L represents the connection unit;

[0025] D is a drug with the structure shown in formula (II-S):

[0026] in,

[0027] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0028] R 2 Selected from hydrogen atoms and halogens, and

[0029] The wavy line represents the key connecting L and D.

[0030] Another aspect of this disclosure relates to a compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IA): L-D Formula (IA);

[0031] in,

[0032] L is a connecting unit with the following structure: L4'—L3—L2—L1—; wherein, L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4' is a ligand connecting unit, which can be used to connect with a ligand, and L4' is selected from:

[0033] Wherein, G is the leaving group for nucleophilic substitution;

[0034] L3, L2, L1, D, X, and Y are described in detail below.

[0035] This application relates to compounds of formula (IVA) as defined herein, which can act as inhibitors of tumor cell proliferation. This application also relates to compounds of formula (IVA) as defined herein, which can act as drugs for treating cancer. This application is characterized by a method for inhibiting tumor cell proliferation, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (IVA) (including formula (IIA)) as defined herein (or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug. The method of this application can be used for the treatment of cancer.

[0036] The third aspect of this application relates to a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has a structure represented by formula (IVA):

[0037] in:

[0038] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0039] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0040] R 4Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0041] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0042] X is selected from -OH, -SH, and -NH2.

[0043] A third aspect of this disclosure also relates to a compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound has the structure shown in formula (IIA):

[0044] Among them, R 1 and R 2 As detailed below.

[0045] A fourth aspect of this disclosure relates to a method for preparing the ligand-drug conjugate of this disclosure or a pharmaceutically acceptable salt thereof, the compound having the structure shown in formula (I), the method comprising contacting ligand B# with the structure shown in formula (IA) of this disclosure.

[0046] Another aspect of this application relates to a pharmaceutical composition comprising a compound of formula (IVA) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0047] This application further provides compounds and compositions with improved efficacy and / or safety profiles compared to known 2-indole ketone compounds in inhibiting tumor cell proliferation. The 2-indole ketone compounds provided in this application can specifically mediate rapid cell necrosis in tumor cells through sustained activation via TRMP4-dependent α-UPR, potentially overcoming drug resistance issues associated with traditional endocrine therapies.

[0048] Another aspect of this disclosure relates to a pharmaceutical composition comprising a ligand-drug conjugate of the present disclosure (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0049] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure (e.g., formula (IIA), formula (IVA)) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0050] Another aspect of this disclosure relates to the use of a ligand-drug conjugate containing the ligand-drug conjugate of this disclosure (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound of this disclosure (e.g., formula (IA), formula (IIA), formula (IVA)) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating and / or preventing tumors.

[0051] Another aspect of this application relates to a method for inhibiting tumor cell proliferation. The method comprises administering to a subject in need a ligand-drug conjugate of this disclosure (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound of this disclosure (e.g., formula (IIA), formula (IVA)) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0052] This disclosure also provides methods for treating and / or preventing tumors, including administering to a subject in need a ligand-drug conjugate of this disclosure (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound of this disclosure (e.g., formula (IIA), formula (IVA)) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0053] This disclosure also provides a ligand-drug conjugate of the present disclosure (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure (e.g., formula (IIA), formula (IVA)) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment and / or prevention of tumors.

[0054] This disclosure also provides a kit comprising a ligand-drug conjugate of the present disclosure (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure (e.g., formula (IIA), formula (IVA)) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0055] The details of this application are set forth in the accompanying description below. Although similar or equivalent methods and materials may be used in the practice or testing of this application, illustrative methods and materials are described hereafter. Other features, objects, and advantages of this application will be apparent from the description and claims. In the description and appended claims, the singular form also includes the plural form, unless the context clearly requires otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety.

[0056] All references cited throughout this application (including bibliographic references, granted patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly known to one of ordinary skill in the art. Attached Figure Description

[0057] Figure 1 shows the cell affinity experiment results of ADC-02a', ADC-02a and ADC-03a disclosed in this invention.

[0058] Figure 2 shows the experimental results of ADC-02a', ADC-02a and ADC-03a internalization of the present disclosure.

[0059] Figure 3 shows the experimental results of ADC-04e and ADC-01e internalization in this disclosure.

[0060] Figure 4 shows the results of experiments on the direct inhibition of proliferation of ADC-01a, ADC-01d, ADC-02a, ADC-02d, ADC-02a' and ADC-02d' in MCF7 cells.

[0061] Figure 5 shows the bystander effect experiment results of ADC-01a, ADC-01d, ADC-02a, ADC-02d, ADC-02a' and ADC-02d' in MCF7 cells.

[0062] Figure 6 shows the results of the experiment on the direct inhibition of proliferation of ADC-02e and ADC-02d in BT474 cells according to this disclosure.

[0063] Figure 7 shows the bystander effect experiment results of ADC-02e and ADC-02d in BT474 cells according to this disclosure.

[0064] Figure 8 shows the experimental results of the stability study of ADC-01a, ADC-02a and ADC-02a' in human plasma.

[0065] Figure 9 shows the experimental results of the stability study of ADC-01a, ADC-02a and ADC-02a' in monkey plasma according to this disclosure.

[0066] Figure 10 shows the experimental results of the stability study of ADC-01e, ADC-02e and ADC-02e' in human plasma according to this disclosure.

[0067] Figure 11 shows the experimental results of the stability study of ADC-01e, ADC-02e and ADC-02e' in monkey plasma of this disclosure.

[0068] Figure 12 shows the in vivo efficacy results of ADC-02d', ADC-02a', ADC-02a and ADC-02d in human breast cancer cell orthotopic xenografts.

[0069] Figure 13 shows the in vivo efficacy results of ADC-04b and ADC-04d in BT474 orthotopic xenografts of human breast cancer cells disclosed in this invention. Detailed Implementation

[0070] definition

[0071] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0072] In this disclosure, the term "ligand" generally refers to a macromolecular compound that recognizes and binds to antigens or receptors associated with target cells. The role of a ligand can be to present a drug to a target cell population that has bound the ligand. These ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, or other molecules that can bind to cells, receptors, and / or antigens. In this disclosure, a ligand may be represented as B#, and the ligand antigen forms a linker bond with a linker unit via a heteroatom on the ligand. The ligand may be an antibody or its antigen-binding fragment, and the antibody may be selected from chimeric antibodies, humanized antibodies, fully human antibodies, or murine antibodies; the antibody may be a monoclonal antibody. For example, the antibody may be an antibody targeting the following targets: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, or EGFR. For example, the antibody may be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5 , CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD 45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2. c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRv III, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1 , GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL -4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MP F, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, S LTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelial peptide receptors, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin α4β7, integrin α5β6, trophoblast cell glycoproteins, or tissue factor.

[0073] In this disclosure, the term "drug" generally refers to a cytotoxic drug, which is a chemical molecule that can strongly disrupt the normal growth of tumor cells. Cytotoxic drugs can kill tumor cells at sufficiently high concentrations. The "cytotoxic drug" may include toxins, such as small molecule toxins or enzyme-active toxins derived from bacteria, fungi, plants, or animals, and radioactive isotopes (e.g., At). 211 I 131 I 125Y 90 Re 186 Re 188 、Sm 153 Bi 212 P 32 (or radioactive isotopes of Lu), toxic drugs, chemotherapeutic agents, antibiotics, and ribolysins. The cytotoxic drugs in this disclosure are 2-indolone compounds.

[0074] In this disclosure, the term "linking unit" generally refers to a chemical structural fragment or bond that is linked to a ligand at one end and to a cytotoxic drug at the other end. It may also refer to a linking unit that is connected to other connectors before being linked to a cytotoxic drug. The direct or indirect linking to the ligand can mean that the group is directly linked to the ligand via a covalent bond, or that the ligand is linked via a linking unit. For example, the linking unit can be the structure shown in this disclosure as -L4-L3-L2-L1-. For example, chemical structural fragments or bonds containing acid-labile connector structures (e.g., hydrazones), protease-sensitive (e.g., peptidase-sensitive) connector structures, light-labile connector structures, dimethyl connector structures, and / or disulfide-containing connector structures can be used as linking units.

[0075] In this disclosure, the term "self-cleaving unit" refers to a linker structural unit embedded between a conditional cleavage unit and a cytotoxic drug. The mechanism of action of the self-cleavage unit is that when the conditional cleavage unit breaks under suitable conditions, the self-cleavage unit can spontaneously rearrange its structure, thereby releasing the linked cytotoxic drug. Common self-cleavage units include p-aminobenzyl alcohols (PABs) and substituted or unsubstituted aminomethylene groups. wait.

[0076] In this disclosure, the term "conditional cleavage unit" refers to a connecton structural unit that breaks under certain conditions within the target cell. Conditional cleavage units can be divided into two main categories: chemically unstable connecton structures and enzyme-instantaneous connecton structures. Chemically unstable connecton structures can selectively cleave due to differences in plasma and cytoplasmic properties. Such properties include pH value, glutathione concentration, etc. pH-sensitive connecton structures are also called acid-cracked connecton structures. Such connecton structures will be hydrolyzed in weakly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0), for example, hydrazones, carbonates, acetals, and ketals. Glutathione-sensitive connecton structures are also called disulfide-bonded connecton structures. In tumor cells, the low oxygen content leads to enhanced reductase activity, resulting in higher glutathione concentrations. The difference between the high concentration (millimolar range) of glutathione in tumor cells and the relatively low concentration (micromolar range) of glutathione in the blood will cause the cleavage of connecton structures. Unstable enzyme linker structures, such as peptide linkers, can be effectively cleaved by lysosomal proteases (such as cathepsin B) or plasmin (which is present in increased amounts in some tumor tissues). Typical unstable enzyme linker structures include Val-Cit (VC) and Phe-Lys.

[0077] In this disclosure, the term "hydrophilic unit" refers to a linker structural unit with a strongly hydrophilic group. Hydrophilic units can typically modulate the overall hydrophilicity of the molecule. Common hydrophilic groups include polyethylene glycol groups, etc.

[0078] In this disclosure, the term "ligand linker unit" refers to a linker structural unit that is directly connected to a ligand. Typical ligand linker units include maleimide groups, etc.

[0079] In this disclosure, the term "ligand-drug conjugate" generally refers to a ligand linked to a biologically active cytotoxic drug via a stable linker unit. In this disclosure, "ligand-drug conjugate" can also refer to an antibody-drug conjugate (ADC), where an ADC can refer to a monoclonal antibody or antibody fragment linked to a biologically active cytotoxic drug via a stable linker unit.

[0080] In this disclosure, the term "antibody or antigen-binding fragment thereof" generally refers to an immunologically binding agent extending to all antibodies from all species, including dimer, trimer, and multimer antibodies; bispecific antibodies; chimeric antibodies; fully human antibodies; humanized antibodies; recombinant and modified antibodies, and fragments thereof. The term "antibody or fragment thereof" can refer to any antibody-like molecule having an antigen-binding region, including small molecule fragments such as Fab′, Fab, F(ab′)2, single-domain antibodies (DABs), Fv, scFv (single-chain Fv), linear antibodies, biantibodies, etc. The term "antigen-binding fragment" can refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. For example, fragments of full-length antibodies can be used to perform the antigen-binding function of an antibody. Techniques for preparing and using various antibody-based constructs and fragments are well known in the art. The antibodies may include: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-TROP2 antibody, and anti-Claudin antibody. 18.2 Antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody or anti-Mesothelin antibody, for example, trastuzumab or pertuzumab.

[0081] In this disclosure, the term "chimeric antibody" generally refers to an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can alleviate the immune response induced by murine antibodies. To establish a chimeric antibody, a hybridoma that secretes murine-specific monoclonal antibodies can be created. The variable region gene can then be cloned from the murine hybridoma cells, and the constant region gene of a human antibody can be cloned as needed. The murine variable region gene and the human constant region gene can be linked to form a chimeric gene, which is then inserted into an expression vector. The chimeric antibody molecule can then be expressed in eukaryotic or prokaryotic systems.

[0082] In this disclosure, the term "humanized antibody," also known as a CDR-grafted antibody, generally refers to an antibody generated by grafting a mouse CDR sequence into a human antibody variable region framework, i.e., a human germline antibody framework sequence of different types. This can overcome the heterologous response induced by chimeric antibodies carrying a large number of mouse protein components. Such framework sequences can be obtained from public DNA databases containing germline antibody gene sequences or from publicly available references. Germline DNA sequences of human heavy chain and light chain variable region genes, for example, can be found in the VBase human germline sequence database.

[0083] In this disclosure, the terms "fully human antibody," "fully human antibody," or "completely human antibody," also known as "fully human monoclonal antibody," refer to antibodies whose variable and constant regions can both be human-derived, thus eliminating immunogenicity and toxic side effects. The development of monoclonal antibodies has gone through four stages: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully human monoclonal antibodies. The antibodies or ligands described in this disclosure can be fully human monoclonal antibodies. Related technologies for the preparation of fully human antibodies include: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology, etc.

[0084] In this disclosure, the term "CDR" generally refers to one of the six hypervariable regions within the variable domain of an antibody that primarily facilitate antigen binding. One of the most common definitions of the six CDRs is provided by Kabat EA et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242; Chothia et al., "Canonical Structures For the Hypervariable Regions of Immunoglobulins", J. Mol. Biol. 196:901 (1987); and MacCallum et al., "Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography", J. Mol. Biol. 262:732 (1996). As used in this disclosure, the Kabat definition of CDR can be applied to CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of light chain variable structural domains, and CDR1, CDR2, and CDR3 (CDR H1, CDR H2, CDR H3 or H1, H2, H3) of heavy chain variable structural domains.

[0085] In this disclosure, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 Alkyl groups, preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C14, C24, C34, C44, C44, C54, C64, C74, C84, C9 ... 1-20 Alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0086] In this disclosure, the term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C14, C24, C34, C44, C54, C64, C74, C84, C9 ... 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl group. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of the following: deuterium atom, alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclic oxy group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group.

[0087] In this disclosure, the term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0088] In this disclosure, the term "methylene" refers to a residue derived from a group containing one carbon atom by removing two hydrogen atoms. The methylene group can be substituted or unsubstituted, substituted or non-substituted. The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. It can be a straight-chain or branched group containing 1 to 20 carbon atoms, for example, containing 1 to 12 carbon atoms, such as 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-). The alkylene group can be substituted or unsubstituted, alternative or non-alternative. For example, when substituted, the substituent can be replaced at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo, for example, it can be 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.

[0089] In this disclosure, the term "halogen" generally refers to fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine.

[0090] In this disclosure, the term "hydroxyl" refers to -OH.

[0091] In this disclosure, the term "thiol" refers to -SH.

[0092] In this disclosure, the term "amino" refers to -NH2.

[0093] In this disclosure, the term "vinyl" refers to -CH=CH2.

[0094] In this disclosure, the term "cyano" refers to -CN.

[0095] In this disclosure, the term "nitro" refers to -NO2.

[0096] In this disclosure, the term "oxo" or "oxo" means "=O".

[0097] In this disclosure, the term "carbonyl" refers to C=O.

[0098] In this disclosure, the term "aldehyde group" refers to -C(O)H

[0099] In this disclosure, the term "carboxyl group" refers to -C(O)OH.

[0100] In this disclosure, the term "aliphatic group" generally refers to a straight-chain, branched, or cyclic hydrocarbon having 1-12 carbon atoms, which is either fully saturated or contains one or more unsaturated units, but the unsaturated units are not aromatic groups. For example, suitable aliphatic groups may include substituted or unsubstituted straight-chain, branched, or cyclic alkyl, alkenyl, alkynyl, and mixtures of these groups; such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. For example, aliphatic groups have 1-12, 1-8, 1-6, 1-4, or 1-3 carbon atoms.

[0101] In this disclosure, the terms “optional” or “optionally” generally mean that the event or environment described below may but does not have to occur, and the description includes situations in which the event or environment occurs or does not occur. For example, “optionally alkyl-substituted heterocyclic group” means that an alkyl group may but does not have to be present, and the description can include cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0102] In this disclosure, the term "substituted" generally refers to one or more hydrogen atoms in a group, for example, up to five, or for example, one to three hydrogen atoms, independently substituted by the 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 much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (e.g., alkene) bond.

[0103] In this disclosure, the term "replaced" for 0 or more (e.g., 0 or at least 1, 0 or 1, 0) methylene units generally means that when the structure contains 1 or more methylene units, the one or more methylene units may not be replaced, or may be replaced by one or more groups that are not methylene (e.g., -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -O-, -S-, -SO-, -SO2-, -PH-, -P(=O)H-, -NHSO2-, -SO2NH-, -C(=S)-, -C(=NH)-, -N=N-, -C=N-, -N=C- or -C(=N2)-).

[0104] One or more hydrogen atoms in a group, for example, up to five, or for example, one to three hydrogen atoms, are independently replaced by the corresponding number of substituents. The 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 much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an alkene).

[0105] On the other hand, the compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. Optically active (R)- and (S)- isomers, as well as D and L isomers, can be prepared by chiral synthesis or with chiral reagents or other conventional techniques. If an enantiomer of a compound of this disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomer mixture is isolated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a salt of the diastereomer with a suitable optically active acid or base, and then the diastereomer is resolved by conventional methods known in the art, and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is typically accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0106] In the chemical structure of the compounds disclosed herein, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or it may contain both configurations simultaneously. In the chemical structure of the compounds disclosed herein, the bonds... The configuration is not specified, meaning it can be Z-configuration, E-configuration, or both. In the chemical structure of the compounds disclosed herein, the bonds... Indicates a single bond or a double bond.

[0107] Furthermore, the compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

[0108] All compounds in this disclosure can be drawn as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0109] In this disclosure, the term "absent" generally indicates that there is no substituent at the position of the group, or that the two groups connected to the group are directly linked. For example, in the structure —CH2—R, when R is absent, it means that CH2 has no R substituent, i.e., the structure is —CH3; as another example, in the structure —L4—L3—L2—L1—, when L3 is absent, it means that L4 and L2 are directly linked, i.e., the structure is —L4—L2—L1—.

[0110] In this disclosure, the term "compound" generally refers to a substance having two or more different elements. For example, the compounds of this disclosure can be organic compounds, compounds with a molecular weight of less than 500, less than 1000, more than 1000, or more than 10,000 or 100,000. In this disclosure, a compound can also refer to a compound linked by chemical bonds, such as a compound in which one or more molecules with a molecular weight of less than 1000 are linked by chemical bonds to a biological macromolecule, which can be a polysaccharide, protein, nucleic acid, polypeptide, etc. For example, the compounds of this disclosure can include compounds in which a protein is linked to one or more molecules with a molecular weight of less than 1000, compounds in which a protein is linked to one or more molecules with a molecular weight of less than 10,000, or compounds in which a protein is linked to one or more molecules with a molecular weight of less than 100,000.

[0111] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are replaced by isotopes of the present disclosure with atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0112] The compounds disclosed herein may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 Deuterated drugs can be formed by replacing hydrogen with deuterium (H). The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0113] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0114] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. This disclosure also includes various deuterated forms of compounds of formula (I) (including formulas (I), (II), (III-1), and (III-2)). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) (including formulas (I), (II), (III-1), and (III-2)) by referring to relevant literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I) (including formulas (I), (II), (III-1), and (III-2)), or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0115] In this disclosure, the term "pharmaceutical composition" generally refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to organisms, promote the absorption of the active ingredient, and thereby exert its biological activity. Conventional methods for preparing pharmaceutical compositions can be found in the Chinese Pharmacopoeia.

[0116] In this disclosure, the terms "pharmaceutically acceptable salt" or "medicinal salt" generally refer to a salt of the compounds or ligand-drug conjugates of this disclosure, or a salt of the compounds described in this disclosure, which may be safe and / or effective when used in mammals and may have the intended biological activity. The ligand-drug conjugates of this disclosure may form salts with acids. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0117] In this disclosure, the terms "solvent" or "solvent compound" generally refer to a pharmaceutically usable solvate formed by the ligand-drug conjugate of this disclosure with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0118] The term "drug loading" typically refers to the average amount of cytotoxic drug loaded onto each ligand, and can also be expressed as the ratio of cytotoxic drug to antibody. The range of cytotoxic drug loading can be 0-12 cytotoxic drugs per ligand (Ab), for example, 1-10 cytotoxic drugs. In embodiments of this disclosure, drug loading is expressed as N. a Examples can be the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. The drug loading of each ADC molecule after the coupling reaction can be identified using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA, and HPLC characterization.

[0119] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. This suspension may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension prepared in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, a sterile fixative oil may be conveniently used as a solvent or suspension medium. For example, any blended fixative oil, including synthetic mono- or diglycerides of glycerol, may be used. Additionally, fatty acids such as oleic acid may also be used to prepare the injectable formulation.

[0120] In this disclosure, the term "comprising" generally means including the expressly specified features, but does not exclude other elements. The terms "above" and "below" generally mean including the stated number.

[0121] In this disclosure, the singular forms “a”, “an”, and “the” include plural objects, and vice versa, unless the context clearly indicates otherwise.

[0122] In this disclosure, the term "about" generally refers to a variation within 10% (i.e., ±10%) above or below a specified value, for example, a variation within 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 a specified value. For parameters such as pH, concentration, and temperature, it indicates that the parameter can vary within ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are generally given for illustrative purposes only and not as limitations.

[0123] The compounds disclosed herein

[0124] The first aspect of this disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has the structure shown in formula (I): B#—(L—D)n (Formula (I))

[0125] B# is the ligand that binds to the target.

[0126] n is the average coupling ratio of drug ligands, and n can be an integer or decimal from 1 to 16;

[0127] L represents the connection unit;

[0128] D is a drug with the structure shown in formula (IV):

[0129] in,

[0130] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0131] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0132] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0133] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0134] X is selected from O, S, and NH; and

[0135] The wavy line represents the key connecting L and D.

[0136] In some embodiments of the ligand-drug conjugate shown in formula (I), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It is F or -CH3. In some embodiments of the ligand-drug conjugate shown in formula (I), the R... 1 For F. In some embodiments of the ligand-drug conjugate shown in formula (I), the R 1 It is -CH3.

[0137] In some embodiments of the ligand-drug conjugate shown in formula (I), the R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, F, Cl, and Br. Preferably, the R... 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, F, and Cl. More preferably, the R... 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and F. In some embodiments of the ligand-drug conjugate shown in formula (I), the R... 2 and R 3 All are hydrogen atoms. Alternatively, in some embodiments of the ligand-drug conjugate shown in formula (I), the R... 2 and R 3 One of them is a hydrogen atom, and the other is an F atom.

[0138] In some embodiments of the ligand-drug conjugate shown in formula (I), the R 4 Selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 4The atom is selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 4 It is a hydrogen atom or F. In some embodiments of the ligand-drug conjugate shown in formula (I), the R... 4 It is a hydrogen atom.

[0139] In some embodiments of the ligand-drug conjugate shown in formula (I), the R 5 It is a hydrogen atom. Alternatively, in some embodiments of the ligand-drug conjugate shown in formula (I), the R... 5 It is -C(O)CH2OH.

[0140] In some embodiments of the ligand-drug conjugate shown in Formula (I), X is O or S. In some embodiments of the ligand-drug conjugate shown in Formula (I), X is NH. In some embodiments of the ligand-drug conjugate shown in Formula (I), X is O. In some embodiments of the ligand-drug conjugate shown in Formula (I), X is S.

[0141] In some embodiments of the ligand-drug conjugate shown in formula (I), the R 2 and R 3 The R atoms, whether identical or different and each independently selected from hydrogen, F, and Cl, are... 5 It is a hydrogen atom or -C(O)CH2OH. Preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F, said R 5 It is a hydrogen atom. In some embodiments of the ligand-drug conjugate shown in formula (I), the R... 2 R is a hydrogen atom or F. 3 For hydrogen atoms, the R 5 It is a hydrogen atom. In some embodiments of the ligand-drug conjugate shown in formula (I), the R... 2 R 3 and R 5 All are hydrogen atoms.

[0142] In some embodiments of the ligand-drug conjugate shown in formula (I), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups, the R 4The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups, where X is selected from O, S, and NH. Preferably, R... 1 The R is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups. 4 X is a hydrogen atom or F, and O is an S atom. More preferably, R... 1 The R is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups. 4 X is a hydrogen atom, and O is a hydrogen atom. More preferably, R is a hydrogen atom. 1 For F or -CH3, the R 4 X is a hydrogen atom, and O is a hydrogen atom.

[0143] In some embodiments of the ligand-drug conjugate shown in formula (I), the D has the structure shown in formula (II) or formula (II-S):

[0144] in,

[0145] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0146] R 2 Selected from hydrogen atoms and halogens, and

[0147] The wavy line represents the key connecting L and D.

[0148] The first aspect of this disclosure also relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has the structure shown in formula (I): B#—(L—D)n Formula (I)

[0149] B# is the ligand that binds to the target.

[0150] n is the average coupling ratio of drug ligands, and n can be an integer or decimal from 1 to 16;

[0151] L represents the connection unit;

[0152] D is a drug with the structure shown in formula (II-S):

[0153] in,

[0154] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6Halogenated alkyl groups and vinyl groups;

[0155] R 2 Selected from hydrogen atoms and halogens, and

[0156] The wavy line represents the key connecting L and D.

[0157] In some embodiments of the ligand-drug conjugate shown in formula (I), R 2 Selected from hydrogen atoms, F, Cl, and Br. Preferably, the R... 2 Selected from hydrogen atoms, F, and Cl. More preferably, the R... 2 Selected from hydrogen atoms and F. In some embodiments of the ligand-drug conjugate shown in formula (I), R 2 It is a hydrogen atom.

[0158] In some embodiments of the ligand-drug conjugate shown in formula (I), R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 For F or -CH3. In some embodiments of the ligand-drug conjugate shown in formula (I), R 1 For F. In some embodiments of the ligand-drug conjugate shown in formula (I), R 1 It is -CH3.

[0159] In some embodiments of the ligand-drug conjugate shown in formula (I), D has the structure shown in formula (III) or formula (III-S):

[0160] in,

[0161] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. More preferably, the R... 1The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 For F or -CH3. In some embodiments of the ligand-drug conjugate shown in formula (I), R 1 For F. In some embodiments of the ligand-drug conjugate shown in formula (I), R 1 It is -CH3.

[0162] In some embodiments of the ligand-drug conjugate shown in formula (I), D is selected from the following structures:

[0163] In some embodiments of the ligand-drug conjugate shown in formula (I), L has the following structure: —L4—L3—L2—L1—; wherein, L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4 is a ligand linking unit, and L4 is connected to B#.

[0164] In some embodiments of the ligand-drug conjugate shown in formula (I), the L4 is selected from:

[0165] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer ≥ 1; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or more methylene units of X are independently and arbitrarily coupled to -N(R 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-、 -O-, -S-, -SO-, -SO2-, -N(R 4c SO2-, -SO2N(R) 4c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=S)-, -C(=NR 4c -, -C = C-, -N = N-, -C = N-, or -N = C- are substitutes; m1 is an integer ≥ 1; each R 4a R 4b R 4cEach can be independently represented as hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, or -OR. 4 -SR 4 -(CH2CH2O) m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 -(CH2) m2 N(R 4d (R) 4e -(CH2) m2 C(O)R 4 -(CH2) m2 CO2R 4 -C(O)CH2C(O)R 4 -S(O)R 4 -S(O)2R 4 -C(O)N(R) 4d (R) 4e -SO2N(R) 4d (R) 4e -OC(O)R 4 -N(R)SO2R 4 or C 1-6 Alkyl; wherein each R 4 R 4d R 4e Each of these can be independently identified as 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, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups; m2 is an integer ≥ 0, m3 is an integer ≥ 0, and m4 is an integer ≥ 0;

[0166] The L3 is absent or is -NH-(C(R) 3a (R) 3b )) s -C(=O)-, s is an integer ≥1; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R 3c )C(=O)-、-C(=O)N(R 3c)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, -O-, -S-, -SO-, -SO2-, -N(R 3c SO2-, -SO2N(R) 3c -, -C(=S)-, -C(=NR) 3c -, -C = C-, -N=N-, -C=N-, or -N=C- can be substituted; each R 3a R 3b R 3c Each independently represents hydrogen, protium, deuterium, tritium, halogen, -OR 3 -SR 3 -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 R 3 ; where, each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer ≥ 0, s2 is an integer ≥ 0;

[0167] The L2 is absent or selected from amino acids, peptides or oligosaccharides consisting of 2-10 amino acids; the amino acid residues are selected from natural amino acid residues, non-natural amino acid residues, or their stereoisomers; when the amino acid residue is Lys, the side chain amino group of Lys is optionally surrounded by one or two C atoms. 1-6 Alkyl groups are substituted; preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by one or two C atoms. 1-3 Alkyl groups are substituted; more preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally substituted with two ethyl groups or two n-propyl groups;

[0168] L1 either does not exist or is selected from: Of these, bit 1 is connected to L2, and bit 2 is connected to D.

[0169] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, the L4 is selected from:

[0170] Where X is -(C(R) 4a (R) 4b )) m-, m is an integer from 1 to 10; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or more methylene units of X are independently and arbitrarily coupled to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 12; each R 4a R 4b R 4c Each can be independently classified as hydrogen, protium, deuterium, tritium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group; m2 is an integer from 0 to 20, m3 is an integer from 0 to 20, and m4 is an integer from 0 to 20.

[0171] Preferably, each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 In some implementations, R 4a R 4b Both are hydrogen. In some implementations, R 4a and R 4b One of them is hydrogen, and the other is -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2)m4 R 4 .

[0172] Preferably, each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl group. More preferably, each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -CH3 or -C2H5. In some implementations, R 4c It is hydrogen. In some implementations, R 4c -(CH2CH2O) m2 -R 4 In some implementations, R 4c It is -CH3.

[0173] Preferably, m is an integer from 1 to 8. For example, m is 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m is an integer from 1 to 6. More preferably, m is an integer from 1 to 5.

[0174] Preferably, m1 is an integer from 1 to 8. For example, m1 is 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m1 is an integer from 1 to 6. More preferably, m1 is an integer from 1 to 4. In some embodiments, m1 is 1.

[0175] Preferably, m2 is an integer from 1 to 20. For example, m2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. More preferably, m2 is an integer from 8 to 20. More preferably, m2 is an integer from 12 to 18. In some embodiments, m2 is 16.

[0176] Preferably, m3 is an integer from 0 to 8. For example, m3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m3 is an integer from 1 to 6. More preferably, m3 is an integer from 1 to 3. In some embodiments, m3 is 1.

[0177] Preferably, m4 is an integer from 0 to 8. For example, m3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m4 is an integer from 1 to 6. More preferably, m4 is an integer from 1 to 3. In some embodiments, m4 is 1. In some embodiments, m4 is 2.

[0178] Preferably, each R 4Independently, it is hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3. More preferably, each R... 4 Independently, it can be hydrogen, deuterium, halogen, -CO2H, -CH3, or -OCH3. More preferably, each R 4 Independently -CO2H, -CH3, or -OCH3. In some implementations, R 4 For -CO2H. In some implementations, R 4 For -CH3. In some implementations, R 4 It is -OCH3.

[0179] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, the L4 is selected from:

[0180] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 8; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or 1 methylene units of X are independently and arbitrarily assigned to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 8; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently hydrogen, -CO2H, or C 1-6 Alkyl; m2 is an integer from 1 to 20, m3 is an integer from 0 to 8, and m4 is an integer from 0 to 8.

[0181] In some embodiments of the ligand-drug conjugate shown in formula (I), more preferably, the L4 is selected from:

[0182] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 5; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or 1 methylene units of X are independently and arbitrarily assigned to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 4; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; m2 is an integer from 12 to 18, m3 is an integer from 1 to 3, and m4 is an integer from 1 to 3.

[0183] In some embodiments of the ligand-drug conjugate shown in formula (I), the L4 is selected from:

[0184] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, L3 is s is an integer from 1 to 10; 1 bit is connected to L4, and 2 bits are connected to L2; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c - or -O- substitution; each R 3a R 3b R 3cEach can be independently represented as hydrogen, protium, deuterium, tritium, or -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 24, and s2 is an integer from 0 to 8.

[0185] Preferably, each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 In some implementations, R 3a and R 3b Both are hydrogen. In some implementations, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 Preferably, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 In some implementations, R 3a and R 3b All are -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2)s2 OC(=O)NH(CH2CH2O) s1 -R 3 Preferably, R 3a and R 3b All are -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 .

[0186] Preferably, each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 In some implementations, R 3c It is hydrogen.

[0187] Preferably, s is an integer from 1 to 8. For example, s is 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, s is an integer from 1 to 6. More preferably, s is an integer from 3 to 6. In some embodiments, s is 3. In some embodiments, s is 6.

[0188] Preferably, s1 is an integer from 1 to 20. For example, s1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. More preferably, s1 is an integer from 8 to 20. More preferably, s1 is an integer from 12 to 18. In some embodiments, s1 is 12. In some embodiments, s1 is 16.

[0189] Preferably, s2 is an integer from 0 to 6. For example, s2 is 0, 1, 2, 3, 4, 5, or 6. More preferably, s2 is an integer from 0 to 4. More preferably, s2 is an integer from 1 to 3. In some embodiments, s2 is 1.

[0190] Preferably, each R 3 Independently hydrogen, deuterium, or C 1-6 Alkyl group. More preferably, each R 3 It can be independently hydrogen, deuterium, -CH3, or -C2H5. In some embodiments, R 3 It is -CH3.

[0191] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, L3 is s is an integer from 1 to 8; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 20, and s2 is an integer from 0 to 6.

[0192] In some embodiments of the ligand-drug conjugate shown in formula (I), more preferably, L3 is... s is an integer from 1 to 6; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily converted to -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2)s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently, it can be hydrogen, deuterium, -CH3 or -C2H5; s1 is an integer from 8 to 20, and s2 is an integer from 0 to 4.

[0193] In some embodiments of the ligand-drug conjugate shown in formula (I), the L3 is selected from:

[0194] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, L2 is selected from amino acids, peptides consisting of 2-10 amino acids, and oligosaccharides; the amino acid residues are selected from natural amino acid residues, non-natural amino acid residues, or their stereoisomers; when the amino acid residue is Lys, the distal amino group of Lys is optionally surrounded by 1, 2, or 3 C atoms. 1-6 Alkyl groups are substituted; preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by one or two C atoms. 1-4 Alkyl groups are substituted; more preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally substituted with two methyl groups, two ethyl groups, or two n-propyl groups.

[0195] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, the L2 is selected from -Lys-, -Ala-Lys-, -Gly-Lys-, -Lys-Gly-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Lys-Val-, -Ala-Ala-Asn-, -Ala-Ala-Asn-, -Ala-Ala-Asp-, -Ala-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Lys-Gly-, -Lys-Ala-Asn-, -Val-Lys-Gly-, -Gly-Gly-Phe-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Val-Lys-Gly-Gly- and In this embodiment, the distal amino group of Lys is optionally surrounded by one, two, or three C atoms. 1-6 Alkyl groups are substituted.

[0196] In some embodiments of the ligand-drug conjugate shown in formula (I), the L2 is selected from:

[0197] In some embodiments of the ligand-drug conjugate shown in formula (I), preferably, L1 is selected from:

[0198] In some embodiments of the ligand-drug conjugate shown in formula (I), L is selected from the structures in Table 1 below:

[0199] Table 1

[0200] In some embodiments of the ligand-drug conjugate shown in formula (I), B# can be an antibody or its antigen-binding fragment.

[0201] Preferably, the B# is selected from the group consisting of chimeric antibodies, humanized antibodies, and fully human antibodies.

[0202] In some embodiments of the ligand-drug conjugate shown in formula (I), B# may be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, O772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79 b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD 45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2. c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRv III, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1 , GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL -4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MP F, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6 SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelial peptide receptors, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin α4β7, integrin α5β6, trophoblast cell glycoproteins, and tissue factor.

[0203] In some embodiments of the ligand-drug conjugate shown in Formula (I), B# is an antibody targeting the following targets: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, and EGFR.

[0204] In some embodiments of the ligand-drug conjugate shown in formula (I), B# is an anti-Trop-2 antibody or an antigen-binding fragment thereof; preferably, B# is datopotamab, sacituzumab or an antigen-binding fragment thereof.

[0205] In some embodiments of the ligand-drug conjugate shown in formula (I), B# is an anti-Her 2 antibody or an antigen-binding fragment thereof; preferably, B# is anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, Trastuzumab, Pertuzumab or an antigen-binding fragment thereof.

[0206] More preferably, B# is an anti-Her 2 antibody or its antigen-binding fragment, comprising two heavy chains and two light chains. The heavy chains include a heavy chain variable region, which includes a heavy chain complementarity-determining region 1 (HCDR1) as shown in SEQ ID NO:11, a heavy chain complementarity-determining region 2 (HCDR2) as shown in SEQ ID NO:12, and a heavy chain complementarity-determining region 3 (HCDR3) as shown in SEQ ID NO:13. The light chains include a light chain variable region, which includes a light chain complementarity-determining region 1 (LCDR1) as shown in SEQ ID NO:14, a light chain complementarity-determining region 2 (LCDR2) as shown in SEQ ID NO:15, and a light chain complementarity-determining region 3 (LCDR3) as shown in SEQ ID NO:16.

[0207] More preferably, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:17, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:18;

[0208] More preferably, the heavy chain comprises the amino acid sequence shown in SEQ ID NO:6, and the light chain comprises the amino acid sequence shown in SEQ ID NO:5.

[0209] In some embodiments of the ligand-drug conjugate shown in formula (I), B# is an anti-Her3 antibody or an antigen-binding fragment thereof; preferably, B# is a barecetamab, duligotuzumab, elgemtumab, istiramumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody or an antigen-binding fragment thereof.

[0210] In some embodiments of the ligand-drug conjugate shown in formula (I), B# is an anti-EGFR antibody or an antigen-binding fragment thereof; preferably, B# is demupitamab, depatuxizumab, futuximab, imgatuzumab, lapatuximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomuzotuximab, zalutumumab, Cetuximab or an antigen-binding fragment thereof.

[0211] In some embodiments of the ligand-drug conjugate shown in formula (I), B# is an anti-B7H3 antibody or its antigen-binding fragment; preferably, B# is an antibody such as 1D1, 1D1-01, 2E3, 2E3-02, enoblituzumab, mirzotamab, omburtamab or its antigen-binding fragment.

[0212] In some embodiments of the ligand-drug conjugate shown in formula (I), B# is an anti-LIV1 antibody or an antigen-binding fragment thereof; preferably, B# is Ladiratuzumab or an antigen-binding fragment thereof.

[0213] More preferably, B# is an anti-LIV1 antibody or its antigen-binding fragment; it comprises two heavy chains and two light chains, the heavy chains comprising heavy chain variable regions, the heavy chain variable regions comprising heavy chain complementarity-determining region 1 (HCDR1) as shown in SEQ ID NO:19, heavy chain complementarity-determining region 2 (HCDR2) as shown in SEQ ID NO:20, and heavy chain complementarity-determining region 3 (HCDR3) as shown in SEQ ID NO:21, the light chains comprising light chain variable regions, the light chain variable regions comprising light chain complementarity-determining region 1 (LCDR1) as shown in SEQ ID NO:22, light chain complementarity-determining region 2 (LCDR2) as shown in SEQ ID NO:23, and light chain complementarity-determining region 3 (LCDR3) as shown in SEQ ID NO:24;

[0214] More preferably, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:25, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:26;

[0215] More preferably, the heavy chain comprises the amino acid sequence shown in SEQ ID NO:7, and the light chain comprises the amino acid sequence shown in SEQ ID NO:8.

[0216] In some embodiments of the ligand-drug conjugate shown in formula (I), the average conjugation ratio n of the drug ligand is an integer or decimal from 1 to 10. Preferably, the average conjugation ratio n of the drug ligand is an integer or decimal from 3 to 8. Preferably, the average conjugation ratio n of the drug ligand is an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10. Preferably, the average conjugation ratio n of the drug ligand is 1, 2, 3, 4, 5, 6, 7, or 8.

[0217] In some implementations, the ligand-drug conjugate represented by formula (I) is selected from the structures in Table 2 below:

[0218] Table 2

[0219] In some implementations, the ligand-drug conjugate represented by formula (I) is selected from the structures in Table 3 below:

[0220] Table 3

[0221] In this context, TZB or tzb represents trastuzumab, HLXA represents anti-Her2 antibody, and HLXB represents anti-LIV1 antibody.

[0222] In some embodiments, the ligand-drug conjugate represented by formula (I) is substituted with an isotope. Preferably, in some embodiments, the isotope substitution is deuterium substitution.

[0223] The second aspect of this disclosure relates to a compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IA): L-D Formula (IA);

[0224] Wherein, L is a connecting unit with the following structure: L4'—L3—L2—L1—; wherein, L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4' is a ligand connecting unit, which can be used to connect with a ligand, and L4' is selected from:

[0225] Wherein, G is the leaving group for nucleophilic substitution;

[0226] D is a drug with the structure shown in formula (IV):

[0227] in,

[0228] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0229] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0230] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0231] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0232] X is selected from O, S, and NH; and

[0233] The wavy line represents the key connecting L and D.

[0234] In some embodiments of the compound of formula (IA), the R... 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It is F or -CH3. In some embodiments of compounds of formula (IA), the R... 1 For F. In some embodiments of compounds of formula (IA), the R 1 It is -CH3.

[0235] In some embodiments of the compound of formula (IA), the R... 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, F, Cl, and Br. Preferably, the R... 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, F, and Cl. More preferably, the R... 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and F. In some embodiments of compounds of formula (IA), the R... 2 and R 3 All are hydrogen atoms. Alternatively, in some embodiments of the compound of formula (IA), the R... 2 and R 3 One of them is a hydrogen atom, and the other is an F atom.

[0236] In some embodiments of the compound of formula (IA), the R... 4 Selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 4 The atom is selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 4 It is a hydrogen atom or F. In some embodiments of the compound of formula (IA), the R 4 It is a hydrogen atom.

[0237] In some embodiments of the compound of formula (IA), the R... 5 It is a hydrogen atom. Alternatively, in some embodiments of the compound of formula (IA), the R... 5 It is -C(O)CH2OH.

[0238] In some embodiments of the compound of formula (IA), X is O or S. In some embodiments of the compound of formula (IA), X is NH. In some embodiments of the compound of formula (IA), X is O. In some embodiments of the compound of formula (IA), X is S.

[0239] In some embodiments of the compound of formula (IA), the R... 2 and R 3The R atoms, whether identical or different and each independently selected from hydrogen, F, and Cl, are... 5 It is a hydrogen atom or -C(O)CH2OH. Preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F, said R 5 R is a hydrogen atom. In some embodiments of compounds of formula (IA), the R... 2 R is a hydrogen atom or F. 3 For hydrogen atoms, the R 5 R is a hydrogen atom. In some embodiments of compounds of formula (IA), the R... 2 R 3 and R 5 All are hydrogen atoms.

[0240] In some embodiments of the compound of formula (IA), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups, the R 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups, where X is selected from O, S, and NH. Preferably, R... 1 The R is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups. 4 X is a hydrogen atom or F, and O is an S atom. More preferably, R... 1 The R is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups. 4 X is a hydrogen atom, and O is a hydrogen atom. More preferably, R is a hydrogen atom. 1 For F or -CH3, the R 4 X is a hydrogen atom, and O is a hydrogen atom.

[0241] In some embodiments of the compound of formula (IA), the D has the structure shown in formula (II) or formula (II-S):

[0242] in,

[0243] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0244] R 2 Selected from hydrogen atoms and halogens, and

[0245] The wavy line represents the key connecting L and D.

[0246] A second aspect of this disclosure also relates to a compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound has the structure shown in formula (IA):

[0247] L-D type (IA)

[0248] Wherein, L is a connecting unit with the following structure: L4'—L3—L2—L1—; wherein, L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4' is a ligand connecting unit, which can be used to connect with a ligand, and L4' is selected from:

[0249] Wherein, G is the leaving group for nucleophilic substitution;

[0250] D is a drug with the structure shown in formula (II-S):

[0251] in,

[0252] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0253] R 2 Selected from hydrogen atoms and halogens;

[0254] The wavy line represents the key connecting L and D;

[0255] L3, L2, L1, X, and Y are defined as in equation (I).

[0256] In some embodiments of the compound of formula (IA), G is selected from halogen, sulfonyl, sulfonate, nitro, and optionally substituted with one or more of the following groups: alkyl thioether, aryl thioether, heteroaryl thioether, alkyl sulfoxide, aryl sulfoxide, heteroaryl sulfoxide, alkyl sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, wherein each substituent is independently selected from hydrogen, deuterium, halogen, CN, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, 6-10 aryl, and 5-16 heteroaryl. Preferably, G is selected from F, Cl, Br, I, OMs (methanesulfonate), Ots (p-toluenesulfonate), OTf (trifluoromethanesulfonate), methanesulfonyl, ethanesulfonyl, p-toluenesulfonyl, and naphthalenesulfonyl. More preferably, the G is selected from F, Cl, Br, OMs, OTs, methanesulfonyl, and p-toluenesulfonyl. More preferably, the G is selected from Cl and methanesulfonyl.

[0257] In some embodiments of the compound of formula (IA), the R... 2 Selected from hydrogen atoms, F, C11, and Br. Preferably, the R... 2 Selected from hydrogen atoms, F, and Cl. More preferably, the R... 2 Selected from hydrogen atoms and F. In some embodiments of the compound of formula (IA), the R... 2 It is a hydrogen atom.

[0258] In some embodiments of the compound of formula (IA), the R... 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It is F or -CH3. In some embodiments of compounds of formula (IA), the R... 1 For F. In some embodiments of compounds of formula (IA), the R 1 It is -CH3.

[0259] In some embodiments of the compound of formula (IA), D has the structure shown in formula (III) or formula (III-S):

[0260] Among them, R 1 Selected from halogens, C 1-6Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups. In some embodiments of compounds of formula (IA), the R... 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. More preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It is F or -CH3. In some embodiments of compounds of formula (IA), the R... 1 For F. In some embodiments of compounds of formula (IA), the R 1 It is -CH3.

[0261] In some embodiments of the compound of formula (IA), D is selected from the following structures:

[0262] In some embodiments of the compound of formula (IA), in L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer ≥ 1; Y is -C(=O)-; 0 or more methylene units of X are each independently and arbitrarily selected by -N(R 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-、 -O-, -S-, -SO-, -SO2-, -N(R 4c SO2-, -SO2N(R) 4c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=S)-, -C(=NR 4c -, -C = C-, -N = N-, -C = N-, or -N = C- are substitutes; m1 is an integer ≥ 1; each R 4a R 4b R 4c Each can be independently represented as hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, or -OR. 4 -SR 4 -(CH2CH2O) m2 -R 4 -(CH2)m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 -(CH2) m2 N(R 4d (R) 4e -(CH2) m2 C(O)R 4 -(CH2) m2 CO2R 4 -C(O)CH2C(O)R 4 -S(O)R 4 -S(O)2R 4 -C(O)N(R) 4d (R) 4e -SO2N(R) 4d (R) 4e -OC(O)R 4 -N(R)SO2R 4 or C 1-6 Alkyl; wherein each R 4 R 4d R 4e Each of these can be independently identified as 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, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups; m2 is an integer ≥ 0, m3 is an integer ≥ 0, and m4 is an integer ≥ 0;

[0263] The L3 is absent or is -NH-(C(R) 3a (R) 3b )) s -C(=O)-, s is an integer ≥1; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, -O-, -S-, -SO-, -SO2-, -N(R 3c SO2-, -SO2N(R) 3c-, -C(=S)-, -C(=NR) 3c -, -C = C-, -N=N-, -C=N-, or -N=C- can be substituted; each R 3a R 3b R 3c Each independently represents hydrogen, protium, deuterium, tritium, halogen, -OR 3 -SR 3 -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 R 3 ; where, each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer ≥ 0, s2 is an integer ≥ 0;

[0264] The L2 is absent or selected from amino acids, peptides or oligosaccharides consisting of 2-10 amino acids; the amino acid residues are selected from natural amino acid residues, non-natural amino acid residues, or their stereoisomers; when the amino acid residue is Lys, the side chain amino group of Lys is optionally surrounded by one or two C atoms. 1-6 Alkyl groups are substituted; preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by one or two C atoms. 1-3 Alkyl groups are substituted; more preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally substituted with two ethyl groups or two n-propyl groups;

[0265] L1 either does not exist or is selected from: Of these, bit 1 is connected to L2, and bit 2 is connected to D.

[0266] In some embodiments of the compound of formula (IA), preferably, in L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 10; Y is -C(=O)-; 0 or more methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 12; each R 4a R 4b R 4c Each can be independently classified as hydrogen, protium, deuterium, tritium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 Or C 1-6 Alkyl; wherein, each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group; m2 is an integer from 0 to 20, m3 is an integer from 0 to 20, and m4 is an integer from 0 to 20.

[0267] Preferably, each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 In some implementations, R 4a R 4b Both are hydrogen. In some implementations, R 4a and R 4b One of them is hydrogen, and the other is -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 .

[0268] Preferably, each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl group. More preferably, each R 4cEach can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -CH3 or -C2H5. In some implementations, R 4c It is hydrogen. In some implementations, R 4c -(CH2CH2O) m2 -R 4 In some implementations, R 4c It is -CH3.

[0269] Preferably, m is an integer from 1 to 8. For example, m is 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m is an integer from 1 to 6. More preferably, m is an integer from 1 to 5.

[0270] Preferably, m1 is an integer from 1 to 8. For example, m1 is 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m1 is an integer from 1 to 6. More preferably, m1 is an integer from 1 to 4. In some embodiments, m1 is 1.

[0271] Preferably, m2 is an integer from 1 to 20. For example, m2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. More preferably, m2 is an integer from 8 to 20. More preferably, m2 is an integer from 12 to 18. In some embodiments, m2 is 16.

[0272] Preferably, m3 is an integer from 0 to 8. For example, m3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m3 is an integer from 1 to 6. More preferably, m3 is an integer from 1 to 3. In some embodiments, m3 is 1.

[0273] Preferably, m4 is an integer from 0 to 8. For example, m3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, m4 is an integer from 1 to 6. More preferably, m4 is an integer from 1 to 3. In some embodiments, m4 is 1. In some embodiments, m4 is 2.

[0274] Preferably, each R 4 Independently, it is hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3. More preferably, each R... 4 Independently, it can be hydrogen, deuterium, halogen, -CO2H, -CH3, or -OCH3. More preferably, each R 4 Independently -CO2H, -CH3, or -OCH3. In some implementations, R 4 For -CO2H. In some implementations, R 4For -CH3. In some implementations, R 4 It is -OCH3.

[0275] In some embodiments of the compound of formula (IA), more preferably, in L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 8; Y is -C(=O)-; 0 or 1 methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 8; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently hydrogen, -CO2H, or C 1-6 Alkyl; m2 is an integer from 1 to 20, m3 is an integer from 0 to 8, and m4 is an integer from 0 to 8.

[0276] In some embodiments of the compound of formula (IA), more preferably, in L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 5; Y is -C(=O)-; 0 or 1 methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 4; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; m2 is an integer from 12 to 18, m3 is an integer from 1 to 3, and m4 is an integer from 1 to 3.

[0277] In some embodiments of the compound of formula (IA), preferably, the L3 is s is an integer from 1 to 10; 1 bit is connected to L4, and 2 bits are connected to L2; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c - or -O- substitution; each R 3a R 3b R 3c Each can be independently represented as hydrogen, protium, deuterium, tritium, or -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 24, and s2 is an integer from 0 to 8.

[0278] Preferably, each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 In some implementations, R 3a and R 3b Both are hydrogen. In some implementations, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 Preferably, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 In some implementations, R 3a and R 3b All are -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 Preferably, R 3a and R 3b All are -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 .

[0279] Preferably, each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1-R 3 In some implementations, R 3c It is hydrogen.

[0280] Preferably, s is an integer from 1 to 8. For example, s is 1, 2, 3, 4, 5, 6, 7, or 8. More preferably, s is an integer from 1 to 6. More preferably, s is an integer from 3 to 6. In some embodiments, s is 3. In some embodiments, s is 6.

[0281] Preferably, s1 is an integer from 1 to 20. For example, s1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. More preferably, s1 is an integer from 8 to 20. More preferably, s1 is an integer from 12 to 18. In some embodiments, s1 is 12. In some embodiments, s1 is 16.

[0282] Preferably, s2 is an integer from 0 to 6. For example, s2 is 0, 1, 2, 3, 4, 5, or 6. More preferably, s2 is an integer from 0 to 4. More preferably, s2 is an integer from 1 to 3. In some embodiments, s2 is 1.

[0283] Preferably, each R 3 Independently hydrogen, deuterium, or C 1-6 Alkyl group. More preferably, each R 3 It can be independently hydrogen, deuterium, -CH3, or -C2H5. In some embodiments, R 3 It is -CH3.

[0284] In some embodiments of the compound of formula (IA), more preferably, the L3 is s is an integer from 1 to 8; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O)s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 or-

[0285] (CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 20, and s2 is an integer from 0 to 6.

[0286] In some embodiments of the compound of formula (IA), more preferably, the L3 is s is an integer from 1 to 6; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily converted to -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently, it can be hydrogen, deuterium, -CH3 or -C2H5; s1 is an integer from 8 to 20, and s2 is an integer from 0 to 4.

[0287] In some embodiments of the compound of formula (IA), the L3 is selected from:

[0288] In some embodiments of the compound of formula (IA), preferably, the L2 is selected from amino acids, peptides consisting of 2-10 amino acids, and oligosaccharides; the amino acid residue is selected from natural amino acid residues, non-natural amino acid residues, or stereoisomers thereof; when the amino acid residue is Lys, the distal amino group of the Lys is optionally surrounded by 1, 2, or 3 C atoms. 1-6 Alkyl groups are substituted; preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by one or two C atoms. 1-4 Alkyl groups are substituted; more preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally substituted with two methyl groups, two ethyl groups, or two n-propyl groups.

[0289] In some embodiments of the compound of formula (IA), preferably, the L2 is selected from -Lys-, -Ala-Lys-, -Gly-Lys-, -Lys-Gly-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Lys-Val-, -Ala-Ala-Asn-, -Ala-Ala-Asn-, -Ala-Ala-Asp-, -Ala-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Lys-Gly-, -Lys-Ala-Asn-, -Val-Lys-Gly-, -Gly-Gly-Phe-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Val-Lys-Gly-Gly- and In this embodiment, the distal amino group of Lys is optionally surrounded by one, two, or three C atoms. 1-6 Alkyl groups are substituted.

[0290] In some embodiments of the compound of formula (IA), the L2 is selected from:

[0291] In some embodiments of the compound of formula (IA), preferably, the L1 is selected from:

[0292] In some embodiments of the compound of formula (IA), the compound of formula (IA) is selected from the structures in Table 4 below:

[0293] Table 4

[0294] In some embodiments, the above-mentioned compound is substituted with an isotope. Preferably, in some embodiments, the isotope substitution is deuterium substitution.

[0295] The third aspect of this application relates to a compound of formula (IVA) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof:

[0296] R is selected from 1: autohalogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0297] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0298] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0299] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0300] X is selected from -OH, -SH, and -NH2.

[0301] In some embodiments of the compound of formula (IVA), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It is F or -CH3. In some embodiments of the compound of formula (IVA), the R... 1 For F. In some embodiments of the compound of formula (IVA), the R 1 It is -CH3.

[0302] In some embodiments of the compound of formula (IVA), the R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, F, Cl, and Br. Preferably, the R... 2and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, F, and Cl. More preferably, the R... 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and F. In some embodiments of the compound of formula (IVA), the R... 2 and R 3 All are hydrogen atoms. Alternatively, in some embodiments of the compound of formula (IVA), the R... 2 and R 3 One of them is a hydrogen atom, and the other is an F atom.

[0303] In some embodiments of the compound of formula (IVA), the R 4 Selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 4 The atom is selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 4 It is a hydrogen atom or F. In some embodiments of the compound of formula (IVA), the R... 4 It is a hydrogen atom.

[0304] In some embodiments of the compound of formula (IVA), the R 5 It is a hydrogen atom. Alternatively, in some embodiments of the compound of formula (IVA), the R... 5 It is -C(O)CH2OH.

[0305] In some embodiments of the compound of formula (IVA), X is -OH or -SH. In some embodiments of the compound of formula (IVA), X is -NH2. In some embodiments of the compound of formula (IVA), X is -OH. In some embodiments of the compound of formula (IVA), X is -SH.

[0306] In some embodiments of the compound of formula (IVA), the R 2 and R 3 The R atoms, whether identical or different and each independently selected from hydrogen, F, and Cl, are... 5 It is a hydrogen atom or -C(O)CH2OH. Preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F, said R5 It is a hydrogen atom. In some embodiments of the compound of formula (IVA), the R... 2 R is a hydrogen atom or F. 3 For hydrogen atoms, the R 5 It is a hydrogen atom. In some embodiments of the compound of formula (IVA), the R... 2 R 3 and R 5 All are hydrogen atoms.

[0307] In some embodiments of the compound of formula (IVA), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups, the R 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups, and X is selected from -OH, -SH, and -NH2. Preferably, R... 1 The R is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups. 4 X is a hydrogen atom or F, and X is -OH or -SH. More preferably, R... 1 The R is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups. 4 X is a hydrogen atom, and X is -OH. More preferably, R... 1 For F or -CH3, the R 4 X is a hydrogen atom, and X is -OH.

[0308] A third aspect of this disclosure also relates to a compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IIA):

[0309] Among them, R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups; R 2 Selected from hydrogen atoms and halogens.

[0310] In some embodiments of the structure shown in formula (IIA), the R 2 Selected from hydrogen atoms, F, Cl, and Br. Preferably, the R... 2 Selected from hydrogen atoms, F, and Cl. More preferably, the R... 2Selected from hydrogen atoms and F. In some embodiments of the structure shown in formula (IIA), the R 2 It is a hydrogen atom.

[0311] In some embodiments of the structure shown in formula (IIA), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. Preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R... 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It can be F or -CH3.

[0312] In some embodiments of the structure shown in formula (IIA), the R 1 It is F.

[0313] In some embodiments of the structure shown in formula (IIA), the R 1 It is -CH3.

[0314] In some embodiments, the compound is selected from the structures in Table 5 of this specification.

[0315] In some embodiments, the compound has the structure shown in formula (IIA-S):

[0316] Among them, R 1 and R 2 As defined by equation (IIA).

[0317] In some embodiments, the compound has the structure shown in formula (IIIA):

[0318] Among them, R 1 As defined in equation (III).

[0319] In some embodiments of the structure shown in equation (IIIA), the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups. More preferably, the R... 1 The derivative is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups. More preferably, the R...1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups. More preferably, the R... 1 It can be F or -CH3.

[0320] In some embodiments of the structure shown in equation (IIIA), the R 1 It is F.

[0321] In some embodiments of the structure shown in equation (IIIA), the R 1 It is -CH3.

[0322] In some embodiments, preferably, the compound has the structure shown in formula (IIIA-S):

[0323] Among them, R 1 As defined by equation (IIIA).

[0324] In some embodiments, the compound is selected from:

[0325] In some embodiments, the above-mentioned compound is substituted with an isotope. Preferably, in some embodiments, the isotope substitution is deuterium substitution.

[0326] The 2-indole ketone compounds disclosed herein possess excellent antitumor activity. This disclosure describes the conjugation of these 2-indole ketone compounds as a payload to antibodies that bind to tumor cell surface antigens. This fully utilizes the specificity of antibody binding to tumor cell surface antigens and the antitumor activity and excellent safety of these compounds, potentially overcoming the problems of insufficient antitumor activity, drug resistance, and excessive toxic side effects of existing ADC drugs.

[0327] Preparation method

[0328] The fourth aspect of this disclosure relates to a method for preparing a compound of formula (I) of this disclosure or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising contacting ligand B# with the structure shown in formula (IA) of this disclosure.

[0329] This disclosure also relates to a method for preparing compounds of formula (IVA) and formula (IIA) or pharmaceutically acceptable salts thereof in its fourth aspect. Formulas (IVA) and (IIA) can be prepared by the same method. Taking formula (IIA) as an example, the method for preparing compounds of formula (IIA) or pharmaceutically acceptable salts thereof includes the following steps:

[0330] The compound of formula (IIA-1) or its salt reacts with an alcohol reagent in the presence of a metal catalyst to give the compound of formula (IIA) or its pharmaceutically acceptable salt.

[0331] Among them, R 1 R 2 As defined in this article, X is a halogen.

[0332] In some embodiments, the metal catalyst is a palladium catalyst.

[0333] In some embodiments, the alcohol reagent is tributyltin-methanol.

[0334] In some embodiments, X is Cl or Br. Preferably, X is Br.

[0335] In some embodiments, the reaction solvent is selected from: ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, toluene, pyridine, and mixtures thereof.

[0336] It will be apparent to those skilled in the art that conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in “Protective Groups in Organic Synthesis,” 4th ed. PGMUTS; TW Greene, John Wiley, 2007, and the references cited therein. The reagents used in the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. Furthermore, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others can be prepared by the processes described in standard reference books or by obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (Wiley, 7th edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any available updates up to this application.

[0337] Composition

[0338] This disclosure relates in a fifth aspect to a pharmaceutical composition comprising, for example, a ligand-drug conjugate of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (IIA), (IIIA), or (IVA) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The carrier may be selected from the group consisting of fillers (diluents), binders, wetting agents, disintegrants, and excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0339] Pharmaceutical compositions containing active ingredients may be in oral forms, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and may contain binders, fillers, lubricants, disintegrants, or pharmaceutically acceptable wetting agents, and may also contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives.

[0340] Aqueous suspensions may contain active substances and excipients suitable for mixing. Aqueous suspensions may also contain one or more preservatives, such as one or more colorants, one or more flavoring agents, and one or more sweeteners. Oil suspensions can be prepared by suspending the active ingredient in vegetable oil. Oil suspensions may contain thickeners. The aforementioned sweeteners and flavoring agents may also be added.

[0341] The pharmaceutical composition may also provide the active ingredient as a dispersible powder or granules for preparing an aqueous suspension, by adding one or more of a water-mixing dispersant, wetting agent, suspending agent, or preservative. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid. The pharmaceutical compositions of this application may also be in the form of an oil-in-water emulsion.

[0342] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or media that can 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 the oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution may then be treated with a mixture of water and glycerol to form a microemulsion. The injection solution or microemulsion may be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of this application. To maintain such a constant concentration, a continuous intravenous delivery device may be used. For example, the device may be a Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0343] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. This suspension may be formulated using suitable dispersants or wetting agents and suspending agents described above, according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension prepared in a parenteral-acceptable, non-toxic diluent or solvent. Alternatively, a sterile fixative oil may be conveniently used as a solvent or suspension medium.

[0344] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug. Such substances include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycol of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0345] 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 activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and the combination of drugs; in addition, the optimal mode of treatment, such as the treatment regimen, the compound described in this disclosure or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and / or the daily dosage or type of pharmaceutically acceptable salt of the compound or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, can be verified based on conventional treatment protocols.

[0346] Treatment and / or prevention

[0347] The sixth aspect of this disclosure relates to the use of a ligand-drug conjugate containing, for example, a ligand-drug conjugate of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof, or a compound of formula (IIA), formula (IIIA), formula (IVA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition of this disclosure in the preparation of a medicament for treating and / or preventing tumors.

[0348] This disclosure also provides a method for treating and / or preventing tumors, comprising administering to a subject in need the ligand-drug conjugate described herein or a pharmaceutically acceptable salt thereof, or the compound described herein or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition thereof.

[0349] This disclosure also provides a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, or the compound thereof or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition thereof, for the treatment and / or prevention of tumors.

[0350] In some embodiments, the tumor may be selected from tumors associated with the expression of the following groups: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, O772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5. , CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2. c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRv III, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1 , GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL -4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MP F, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6 SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelial peptide receptors, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin α4β7, integrin α5β6, trophoblast cell glycoproteins, and tissue factor.

[0351] In some implementations, the tumor may be selected from tumors associated with the expression of the following groups: HER2, HER3, B7H3, TROP2, LIV-1, Claudin 18.2, CD30, CD33, CD70, or EGFR.

[0352] In some implementations, the tumor is a tumor associated with HER2 expression.

[0353] In some implementations, the tumor is a tumor associated with HER3 expression.

[0354] In some implementations, the tumor is a tumor associated with B7H3 expression.

[0355] In some implementations, the tumor is a tumor associated with TROP2 expression.

[0356] In some implementations, the tumor is a tumor associated with LIV-1 expression.

[0357] In some implementations, the tumor is a tumor associated with Claudin 18.2 expression.

[0358] In some implementations, the tumor is a tumor associated with CD30 expression.

[0359] In some implementations, the tumor is a tumor associated with CD33 expression.

[0360] In some implementations, the tumor is a tumor associated with CD70 expression.

[0361] In some implementations, the tumor is a tumor associated with EGFR expression.

[0362] In some embodiments, the tumor may be selected from the group consisting of: lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial carcinoma, head and neck cancer, nasopharyngeal carcinoma, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric mucinoma, lymphoma, leukemia, plasmacytoma, sinoatrial node cell tumor, giant cell tumor of the tendon sheath, brain cancer, squamous cell carcinoma, epidermal carcinoma, and non-Hodgkin's lymphoma; more preferably, the cancer is selected from breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, malignant lymphoma, liver cancer, and leukemia;

[0363] Preferably, the cancer is ER-positive and / or TRPM4-positive; or

[0364] Preferably, the breast cancer is ER+ breast cancer or ER+ / HER2- breast cancer; or

[0365] Preferably, the lung cancer is non-small cell lung cancer; or

[0366] Preferably, the prostate cancer is castration-resistant prostate cancer.

[0367] The compounds described in this application can possess inhibitory activity against the in vitro proliferation of tumor cells. This inhibitory activity can be defined as a decrease in the proliferation capacity of tumor cells by more than 1%, 2%, 4%, 5%, 8%, 10%, 15%, 18%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% when the compound is added to a culture medium containing tumor cells, compared to the addition of a negative control or control drug. For example, the inhibitory activity can be defined as an effect on the IC50 of tumor cells. 50 The value (nM) can be below 10000, below 5000, below 4000, below 3000, below 2000, below 1000, below 500, below 400, below 300, below 200, below 150, below 120, below 110, below 100, below 99, below 98, below 97, below 95, below 90, below 80, below 75, below 70, below 65, below 62, below 60, below 50, below 40, below 30, below 25, below 23, below 22, below 20, below 19, below 18, below 18.5, below 17, below 15, below 12, below 10, below 9. Below 8.5, below 7, below 6.7, below 6, below 5.9, below 5.5, below 5.0, below 4.8, below 4.5, below 4.4, below 4, below 3.5, below 3, below 2.5, below 2, below 1.5, below 1.0, below 0.5, below 0.3, below 0.29, below 0.25, below 0.21, below 0.20, below 0.18, below 0.17, below 0.15, below 0.12, below 0.10, below 0.09, below 0.08, below 0.07, below 0.06, below 0.05, below 0.04, below 0.03, below 0.02, or below 0.01. For example, the tumor cells may include, but are not limited to, solid tumor cells, such as gastric cancer cells or breast cancer cells, such as MCF-7 cells, MCF7... Y537S Cells, PC-3 cells, DA-MB-361 cells, BT-20 cells, AGS cells, MDA-MB-468 cells, BT474 cells, T47D cells, MCF7-LIV1 cells, NCI-N87 cells, JIMT-1 cells, or MBA-MB-231 cells.

[0368] The compounds described in this application may possess targeted inhibitory properties. This targeted inhibitory property can be defined as the reduction in the proliferation capacity of tumor cells highly expressing a specific target by more than 1%, 2%, 4%, 5%, 8%, 10%, 15%, 18%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% when the compound is added to a culture medium containing a negative control or control drug, compared to the addition of a negative control or control drug. For example, the targeted inhibitory property can be defined as an IC50 effect on tumor cells highly expressing a specific target. 50 The value (nM) can be below 10000, below 5000, below 4000, below 3000, below 2000, below 1000, below 500, below 400, below 300, below 200, below 185, below 150, below 120, below 110, below 100, below 99, below 98, below 97, below 95, below 91, below 80, below 74, below 70, below 65, below 62, below 60, below 50, below 40, below 30, below 25, below 23, below 22, below 20, below 19, below 18, below 18.5, below 17, below 15, below 12, below 10, 9 Below, below 8.5, below 7, below 6.7, below 6, below 5.9, below 5.5, below 5.0, below 4.8, below 4.5, below 4.4, below 4, below 3.5, below 3, below 2.5, below 2, below 1.5, below 1.0, below 0.5, below 0.3, below 0.29, below 0.25, below 0.21, below 0.20, below 0.18, below 0.17, below 0.15, below 0.12, below 0.10, below 0.09, below 0.08, below 0.07, below 0.06, below 0.05, below 0.04, below 0.03, below 0.02, or below 0.01. For example, tumor cells that highly express the specific target may include, but are not limited to, solid tumor cells. For instance, tumor cells that highly express the specific target may include, but are not limited to, gastric cancer cells or breast cancer cells. For example, tumor cells that highly express the specific target may include, but are not limited to, BT474 cells, T47D cells, or MCF7-LIV1 cells. The specific target may include, but is not limited to, HER2, TROP2, or LIV1.

[0369] The compounds described in this application may possess plasma stability. This plasma stability means that when the compound is added to plasma, the release rate of the cytotoxic drug released by the compound does not exceed 50%, 40%, 30%, 20%, 10%, 7%, 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0370] The compounds described in this application can have an in vivo tumor-suppressing effect. This tumor-suppressing effect can be demonstrated by the following: when the compounds of this application are administered to animals, compared to the addition of a negative control or control drug, the tumor volume of the animals is reduced by more than 1%, 2%, 4%, 5%, 8%, 10%, 15%, 18%, 20%, 25%, 40%, 50%, 55%, 60%, 70%, 73%, or 75% at 1, 3, 5, 7, 14, 20, 21, or 30 days, respectively. The tumor volume of the animal decreased by more than 1.1 times, 1.3 times, 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 22 times, 30 times, 50 times, 100 times, 500 times, 1000 times, or 1500 times or more at 1 day, 3 days, 5 days, 7 days, 14 days, 20 days, 21 days, or 30 days, or compared to the administration of a negative control or control drug. The animal may include, but is not limited to, mammals, such as cats, dogs, horses, pigs, cows, sheep, rabbits, mice, rats, monkeys, or humans. The administration may include, but is not limited to, oral administration, intravenous injection, intravenous infusion, intraperitoneal injection, or local administration.

[0371] The compounds described in this application may exhibit a bystander effect. This bystander effect can mean that the compounds of this application have no significant inhibitory effect on the cell proliferation of tumor cells with low expression of a specific target, but in co-culture of tumor cells with low expression of a specific target and tumor cells with high expression of a specific target, the compounds of this application can simultaneously inhibit the cell proliferation of both types of tumor cells. For example, in co-culture of tumor cells with low expression of a specific target and tumor cells with high expression of a specific target, the inhibitory activity can be defined as an IC50 value against tumor cells with low expression of a specific target. 50The value (nM) can be below 10000, below 5000, below 4000, below 3000, below 2000, below 1000, below 500, below 400, below 300, below 200, below 185, below 150, below 120, below 110, below 100, below 99, below 98, below 97, below 95, below 91, below 80, below 74, below 70, below 65, below 62, below 60, below 50, below 40, below 30, below 25, below 23, below 22, below 20, below 19, below 18, below 18.5, below 17, below 15, below 12, below 10, 9 Below, below 8.5, below 7, below 6.7, below 6, below 5.9, below 5.5, below 5.0, below 4.8, below 4.5, below 4.4, below 4, below 3.5, below 3, below 2.5, below 2, below 1.5, below 1.0, below 0.5, below 0.3, below 0.29, below 0.25, below 0.21, below 0.20, below 0.18, below 0.17, below 0.15, below 0.12, below 0.10, below 0.09, below 0.08, below 0.07, below 0.06, below 0.05, below 0.04, below 0.03, below 0.02, or below 0.01. Compared to tumor cells that highly express a specific target, tumor cells with low expression of that target may exhibit a reduction in the expression of that specific target by more than 1%, 2%, 4%, 5%, 8%, 10%, 15%, 18%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. For example, tumor cells with high expression of the specific target may include, but are not limited to, solid tumor cells, such as gastric cancer cells or breast cancer cells, including but not limited to BT474 cells, T47D cells, or MCF7-LIV1 cells. Similarly, tumor cells with low expression of the specific target may include, but are not limited to, solid tumor cells, such as breast cancer cells, including but not limited to HCC1187 cells.

[0372] The compounds described in this application may possess antitransporter transport capabilities. This antitransporter capability can be defined as a reduction in the efflux ratio of the compound compared to a standard of the transport substrate, which is more than 1%, 2%, 4%, 5%, 8%, 10%, 15%, 18%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. For example, the efflux ratio test can be a method commonly used by those skilled in the art, or it can be described in the embodiments of this application.

[0373] The compounds described in this application may possess in vivo tumor-targeting capability. This in vivo targeting capability can refer to the distribution of the labeled compound in the tumor tissue of an animal, compared to other tissues and organs, being increased by more than 1%, 2%, 4%, 5%, 8%, 10%, 15%, 18%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or by more than 1.1 times, 1.3 times, 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 22 times, 30 times, 50 times, 100 times, 500 times, 1000 times, or 1500 times. The signaling substance may be a radioactive substance, and for example, the signaling substance includes, but is not limited to, radioactive substances. 125 I. The animal may include, but is not limited to, mammals, such as cats, dogs, horses, pigs, cows, sheep, rabbits, mice, rats, monkeys, or humans. The administration may include, but is not limited to, oral administration, intravenous injection, intravenous infusion, intraperitoneal injection, or local administration. The tissue or organ may include, but is not limited to, the heart, liver, spleen, lungs, kidneys, brain, or bone marrow.

[0374] The compounds described in this application can exhibit good in vivo safety. This in vivo safety can be defined as the release rate of free toxins in animals after administration of the compounds to animals not exceeding 50%, 40%, 30%, 20%, 10%, 7%, 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. For example, the in vivo safety can be defined as the absence of toxic effects in animals. The application concentration of the compound described in this application can be 0.5 mg / kg or higher, 1 mg / kg or higher, 2 mg / kg or higher, 3 mg / kg or higher, 4 mg / kg or higher, 5 mg / kg or higher, 10 mg / kg or higher, 20 mg / kg or higher, 30 mg / kg or higher, 50 mg / kg or higher, 70 mg / kg or higher, 100 mg / kg or higher, 200 mg / kg or higher, 500 mg / kg or higher, or 1000 mg / kg or higher. For example, the animals may include, but are not limited to, cats, dogs, horses, pigs, dairy cows, sheep, rabbits, mice, rats, monkeys, or humans. The application may include, but is not limited to, oral administration, intravenous injection, intravenous infusion, intraperitoneal injection, or local administration.

[0375] Reagent test kit

[0376] A seventh aspect of this disclosure relates to a kit containing, for example, a ligand-drug conjugate of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof, or a compound of formula (IIA), formula (IIIA), formula (IVA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition of this disclosure.

[0377] Other aspects and advantages of this disclosure will readily become apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this disclosure are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this disclosure enables them to make modifications to the specific embodiments disclosed without departing from the spirit and scope of the invention to which this disclosure pertains. Accordingly, the descriptions in the accompanying drawings and specification of this disclosure are merely exemplary and not restrictive.

[0378] In addition, this disclosure also provides the following implementation schemes:

[0379] 1. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has the structure shown in formula (I): B#—(L—D)n Formula (I)

[0380] B# is the ligand that binds to the target.

[0381] n is the average coupling ratio of drug ligands, and n is an integer or decimal from 1 to 16;

[0382] L represents the connection unit;

[0383] D is a drug with the structure shown in formula (IV):

[0384] in,

[0385] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0386] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0387] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0388] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0389] X is selected from O, S, and NH; and

[0390] The wavy line represents the key connecting L and D.

[0391] 2. The ligand-drug conjugate or its pharmaceutically acceptable salt according to embodiment 1, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups; preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups; more preferably, R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl; more preferably, the R 1 It is F or -CH3; more preferably, the R 1For F; or, more preferably, for R 1 It is -CH3.

[0392] 3. The ligand-drug conjugate or its pharmaceutically acceptable salt according to embodiment 1 or 2, characterized in that the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms, F, Cl and Br; preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms, F and Cl; more preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F; more preferably, the R 2 and R 3 All are hydrogen atoms; or, more preferably, the R 2 and R 3 One of them is a hydrogen atom, and the other is an F atom.

[0393] 4. The ligand-drug conjugate or its pharmaceutically acceptable salt according to any one of embodiments 1-3, characterized in that the R 4 Selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups; preferably, the R 4 Selected from hydrogen atoms, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups; more preferably, the R... 4 Selected from hydrogen atoms, F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups; more preferably, the R... 4 It is a hydrogen atom or F; more preferably, the R 4 It is a hydrogen atom.

[0394] 5. The ligand-drug conjugate or its pharmaceutically acceptable salt according to any one of embodiments 1-4, characterized in that the R 5 It is a hydrogen atom; or, in some other embodiments of the compound of formula (I), the R... 5 It is -C(O)CH2OH.

[0395] 6. The ligand-drug conjugate or its pharmaceutically acceptable salt according to any one of embodiments 1-5, characterized in that X is -OH or -SH; or, preferably, X is -NH2; or, preferably, X is -OH; or, preferably, X is -SH.

[0396] 7. The ligand-drug conjugate or its pharmaceutically acceptable salt according to any one of embodiments 1-6, characterized in that the R 2 and R 3 The R atoms, whether identical or different and each independently selected from hydrogen, F, and Cl, are... 5 It is a hydrogen atom or -C(O)CH2OH; preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F, said R 5 It is a hydrogen atom; or, preferably, the R 2 R is a hydrogen atom or F. 3 For hydrogen atoms, the R 5 It is a hydrogen atom; or, preferably, the R 2 R 3 and R 5 All are hydrogen atoms.

[0397] 8. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-7, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups, the R 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups, wherein X is selected from -OH, -SH, and -NH2; preferably, R... 1 The R is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups. 4 X is a hydrogen atom or F, and X is -OH or -SH; more preferably, R 1 The R is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups. 4 X is a hydrogen atom, and X is -OH; more preferably, R is a hydrogen atom. 1 For F or -CH3, the R 4 X is a hydrogen atom, and X is -OH.

[0398] 9. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has the structure shown in formula (I): B#—(L—D)n Formula (I)

[0399] B# is the ligand that binds to the target.

[0400] n is the average coupling ratio of drug ligands, and n is an integer or decimal from 1 to 16;

[0401] L represents the connection unit;

[0402] D is a drug having the structure shown in formula (II) or formula (II-S):

[0403] in,

[0404] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0405] R 2 Selected from hydrogen atoms and halogens; and

[0406] The wavy line represents the key connecting L and D.

[0407] 10. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to embodiment 9, characterized in that the R 2 Selected from hydrogen atoms, F, Cl, and Br;

[0408] Preferably, the R 2 Selected from hydrogen atoms, F and Cl;

[0409] More preferably, the R 2 Selected from hydrogen atoms and F;

[0410] More preferably, the R 2 It is a hydrogen atom.

[0411] 11. The ligand-drug conjugate or its pharmaceutically acceptable salt according to embodiment 9 or 10, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups;

[0412] Preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups;

[0413] More preferably, the R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl;

[0414] More preferably, the R 1 For F or -CH3;

[0415] More preferably, the R 1 For F;

[0416] More preferably, the R 1 It is -CH3.

[0417] 12. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 9-11, characterized in that D has the structure shown in formula (III) or formula (III-S):

[0418] in,

[0419] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups.

[0420] 13. The ligand-drug conjugate or its pharmaceutically acceptable salt according to embodiment 12 above, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups;

[0421] Preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups;

[0422] More preferably, the R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl;

[0423] More preferably, the R 1 For F or -CH3;

[0424] More preferably, the R 1 For F;

[0425] More preferably, the R 1 It is -CH3.

[0426] 14. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-13, characterized in that D is selected from the following structures:

[0427] 15. The ligand-drug conjugate or its pharmaceutically acceptable salt according to any one of embodiments 1-14, characterized in that the L has the following structure: —L4—L3—L2—L1—; wherein L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4 is a ligand linking unit, and L4 is connected to B#.

[0428] 16. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to embodiment 15, characterized in that the L4 is selected from:

[0429] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer ≥ 1; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or more methylene units of X are independently and arbitrarily coupled to -N(R 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-、 -O-, -S-, -SO-, -SO2-, -N(R 4c SO2-, -SO2N(R) 4c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=S)-, -C(=NR 4c -, -C = C-, -N = N-, -C = N-, or -N = C- are substitutes; m1 is an integer ≥ 1; each R 4a R 4b R 4c Each can be independently represented as hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, or -OR. 4 -SR 4 -(CH2CH2O) m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 -(CH2) m2 N(R 4d (R) 4e -(CH2) m2 C(O)R 4 -(CH2) m2CO2R 4 -C(O)CH2C(O)R 4 -S(O)R 4 -S(O)2R 4 -C(O)N(R) 4d (R) 4e -SO2N(R) 4d (R) 4e -OC(O)R 4 -N(R)SO2R 4 or C 1-6 Alkyl; wherein each R 4 R 4d R 4e Each of these can be independently identified as 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, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups; m2 is an integer ≥ 0, m3 is an integer ≥ 0, and m4 is an integer ≥ 0;

[0430] The L3 is absent or is s is an integer ≥ 1, with 1 bit connected to L4 and 2 bits connected to L2; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, -O-, -S-, -SO-, -SO2-, -N(R 3c SO2-, -SO2N(R) 3c -, -C(=S)-, -C(=NR) 3c -, -C = C-, -N=N-, -C=N-, or -N=C- can be substituted; each R 3a R 3b R 3c Each independently represents hydrogen, protium, deuterium, tritium, halogen, -OR 3 -SR 3 -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O)s1 R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 R 3 ; where, each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer ≥ 0, s2 is an integer ≥ 0;

[0431] The L2 is absent or selected from amino acids, peptides or oligosaccharides consisting of 2-10 amino acids; the amino acids are selected from natural amino acid residues, non-natural amino acid residues, or their stereoisomers; when the amino acid residue is Lys, the side chain amino group of Lys is optionally surrounded by one or two C atoms. 1-6 Alkyl groups are substituted; preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by one or two C atoms. 1-3 Alkyl groups are substituted; more preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally substituted with two ethyl groups or two n-propyl groups;

[0432] L1 either does not exist or is selected from: Of these, bit 1 is connected to L2, and bit 2 is connected to D.

[0433] 17. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to embodiment 15 or 16, characterized in that the L4 is selected from:

[0434] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 10; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or more methylene units of X are independently and arbitrarily coupled to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 12; each R 4a R 4b R 4c Each can be independently classified as hydrogen, protium, deuterium, tritium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4-(CH2) m3 NH(CH2) m4 R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group; m2 is an integer from 0 to 20, m3 is an integer from 0 to 20, and m4 is an integer from 0 to 20.

[0435] 18. The ligand-drug conjugate or its pharmaceutically acceptable salt according to embodiment 16 or 17, characterized in that each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ;

[0436] Preferably, R 4a R 4b All are hydrogen; or

[0437] Preferably, R 4a and R 4b One of them is hydrogen, and the other is -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 .

[0438] 19. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-18, characterized in that each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 alkyl;

[0439] Preferably, each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R4 -CH3 or -C2H5;

[0440] More preferably, R 4c It is hydrogen;

[0441] More preferably, R 4c -(CH2CH2O) m2 -R 4 ;

[0442] More preferably, R 4c It is -CH3.

[0443] 20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-19, characterized in that m is an integer from 1 to 8;

[0444] Preferably, m is an integer from 1 to 6;

[0445] Preferably, m is an integer from 1 to 5.

[0446] 21. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-20, characterized in that m1 is an integer from 1 to 8;

[0447] Preferably, m1 is an integer from 1 to 6;

[0448] Preferably, m1 is an integer from 1 to 4;

[0449] More preferably, m1 is 1.

[0450] 22. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-21, characterized in that m2 is an integer from 1 to 20;

[0451] Preferably, m2 is an integer between 8 and 20;

[0452] Preferably, m2 is an integer between 12 and 18;

[0453] More preferably, m2 is 16.

[0454] 23. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-22, wherein m3 is an integer from 0 to 8;

[0455] Preferably, m3 is an integer from 1 to 6;

[0456] Preferably, m3 is an integer from 1 to 3;

[0457] More preferably, m3 is 1.

[0458] 24. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-23, characterized in that m4 is an integer from 0 to 8;

[0459] Preferably, m4 is an integer from 1 to 6;

[0460] Preferably, m4 is an integer from 1 to 3;

[0461] More preferably, m4 is 1;

[0462] More preferably, m4 is 2.

[0463] 25. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-24, characterized in that each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3;

[0464] Preferably, each R 4 It can be independently hydrogen, deuterium, halogen, -CO2H, -CH3, or -OCH3;

[0465] More preferably, each R 4 Independently -CO2H, -CH3, or -OCH3;

[0466] More preferably, R 4 It is -CO2H;

[0467] More preferably, R 4 -CH3;

[0468] More preferably, R 4 It is -OCH3.

[0469] 26. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-25, characterized in that the L4 is selected from:

[0470] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 8; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or 1 methylene units of X are independently and arbitrarily assigned to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 8; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently hydrogen, -CO2H, or C 1-6 Alkyl; m2 is an integer from 1 to 20, m3 is an integer from 0 to 8, and m4 is an integer from 0 to 8.

[0471] 27. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-26, characterized in that the L4 is selected from:

[0472] Where X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 5; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or 1 methylene units of X are independently and arbitrarily assigned to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 4; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; m2 is an integer from 12 to 18, m3 is an integer from 1 to 3, and m4 is an integer from 1 to 3.

[0473] 28. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-27, characterized in that the L4 is selected from:

[0474] 29. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-28, characterized in that L3 is s is an integer from 1 to 10; 1 bit is connected to L4, and 2 bits are connected to L2; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c - or -O- substitution; each R 3a R 3b R 3c Each can be independently represented as hydrogen, protium, deuterium, tritium, or -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 24, and s2 is an integer from 0 to 8.

[0475] 30. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-29, characterized in that each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2OC(=O)NH(CH2CH2O) s1 -R 3 ;

[0476] Preferably, R 3a and R 3b All are hydrogen;

[0477] Preferably, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 More preferably, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 ;

[0478] Preferably, R 3a and R 3b All are -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 More preferably, R 3a and R 3b All are -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 .

[0479] 31. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-30, characterized in that each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ;

[0480] Preferably, R 3c It is hydrogen.

[0481] 32. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-31, characterized in that s is an integer from 1 to 8;

[0482] Preferably, s is an integer from 1 to 6;

[0483] Preferably, s is an integer between 3 and 6;

[0484] More preferably, s is 3; or

[0485] More preferably, s is 6.

[0486] 33. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-32, characterized in that s1 is an integer from 1 to 20;

[0487] Preferably, s1 is an integer between 8 and 20;

[0488] Preferably, s1 is an integer between 12 and 18;

[0489] More preferably, s1 is 12; or

[0490] More preferably, s1 is 16.

[0491] 34. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-33, characterized in that s2 is an integer from 0 to 6;

[0492] Preferably, s2 is an integer between 0 and 4;

[0493] Preferably, s2 is an integer from 1 to 3;

[0494] More preferably, s2 is 1.

[0495] 35. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-34, characterized in that each R 3 Independently hydrogen, deuterium, or C 1-6 alkyl;

[0496] Preferably, each R 3It can be independently hydrogen, deuterium, -CH3, or -C2H5;

[0497] More preferably, R 3 It is -CH3.

[0498] 36. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-35, characterized in that L3 is s is an integer from 1 to 8; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 20, and s2 is an integer from 0 to 6.

[0499] 37. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-36, characterized in that L3 is s is an integer from 1 to 6; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily converted to -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3bEach can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently, it can be hydrogen, deuterium, -CH3 or -C2H5; s1 is an integer from 8 to 20, and s2 is an integer from 0 to 4.

[0500] 38. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-37, characterized in that the L3 is selected from:

[0501] 39. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-38, characterized in that the L2 is selected from amino acids, peptides consisting of 2-10 amino acids, and oligosaccharides; the amino acid residue is selected from natural amino acid residues, non-natural amino acid residues, or stereoisomers thereof; when the amino acid residue is Lys, the distal amino group of the Lys is optionally surrounded by 1, 2, or 3 C atoms. 1-6 Alkyl groups are substituted;

[0502] Preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally surrounded by one or two C atoms. 1-4 Alkyl groups are substituted;

[0503] More preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by two methyl groups, two ethyl groups, or two n-propyl groups.

[0504] 40. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-39, wherein the L2 is selected from -Lys-, -Ala-Lys-, -Gly-Lys-, -Lys-Gly-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Lys-Val-, -Ala-Ala-Asn-, -Ala-Ala-Asn-, -Al a-Ala-Asp-, -Ala-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Lys-Gly-, -Lys-Ala-Asn-, -Val-Ly s-Gly-, -Gly-Gly-Phe-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Val-Lys-Gly-Gly-, and In this embodiment, the distal amino group of Lys is optionally surrounded by one, two, or three C atoms. 1-6 Alkyl groups are substituted.

[0505] 41. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-40, characterized in that the L2 is selected from:

[0506] 42. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-41, characterized in that L1 is selected from:

[0507] 43. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 16-42, characterized in that L is selected from the structures in Table 1.

[0508] 44. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-43, characterized in that B# can be an antibody or an antigen-binding fragment thereof.

[0509] 45. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-44, characterized in that the B# is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human antibodies.

[0510] 46. ​​The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-45, characterized in that B# is an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, O772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, C ADM1, CCD79b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD 40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2. c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRv III, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1 , GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL -4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MP F, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6 SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelial peptide receptors, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin α4β7, integrin α5β6, trophoblast cell glycoproteins, and tissue factor.

[0511] 47. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-46, characterized in that B# is an antibody targeting the following targets: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 and EGFR.

[0512] 48. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-47, characterized in that B# is an anti-Trop-2 antibody or an antigen-binding fragment thereof;

[0513] Preferably, B# is datopotamab, sacituzumab, or an antigen-binding fragment thereof.

[0514] 49. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-47, characterized in that B# is an anti-Her 2 antibody or an antigen-binding fragment thereof;

[0515] Preferably, B# is anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, timigutuzumab, zanidatamab, trastuzumab, pertuzumab, or an antigen-binding fragment thereof.

[0516] More preferably, B# is an anti-Her 2 antibody or its antigen-binding fragment; it comprises two heavy chains and two light chains, the heavy chains comprising a heavy chain variable region, the heavy chain variable region comprising heavy chain complementarity-determining region 1 (HCDR1) as shown in SEQ ID NO:11, heavy chain complementarity-determining region 2 (HCDR2) as shown in SEQ ID NO:12, and heavy chain complementarity-determining region 3 (HCDR3) as shown in SEQ ID NO:13, the light chains comprising a light chain variable region, the light chain variable region comprising light chain complementarity-determining region 1 (LCDR1) as shown in SEQ ID NO:14, light chain complementarity-determining region 2 (LCDR2) as shown in SEQ ID NO:15, and light chain complementarity-determining region 3 (LCDR3) as shown in SEQ ID NO:16;

[0517] More preferably, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:17, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:18;

[0518] More preferably, the heavy chain comprises the amino acid sequence shown in SEQ ID NO:6, and the light chain comprises the amino acid sequence shown in SEQ ID NO:5.

[0519] 50. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-47, characterized in that B# is an anti-Her3 antibody or an antigen-binding fragment thereof;

[0520] Preferably, B# is a barecetamab, duligotuzumab, elgemtumab, istiramumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody or its antigen-binding fragment.

[0521] 51. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-47, characterized in that B# is an anti-EGFR antibody or an antigen-binding fragment thereof;

[0522] Preferably, B# is demupitamab, depatuxizumab, futuximab, imgatuzumab, lapatuximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomuzotuximab, zalutumumab, Cetuximab, or an antigen-binding fragment thereof.

[0523] 52. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-47, characterized in that B# is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0524] Preferably, B# is 1D1, 1D1-01, 2E3, 2E3-02 antibody, enoblituzumab, mirzotamab, omburtamab, or an antigen-binding fragment thereof.

[0525] 53. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-47, characterized in that B# is an anti-LIV1 antibody or an antigen-binding fragment thereof;

[0526] Preferably, B# is Ladiratuzumab or its antigen-binding fragment;

[0527] More preferably, B# is an anti-LIV1 antibody or its antigen-binding fragment; it comprises two heavy chains and two light chains, the heavy chains comprising heavy chain variable regions, the heavy chain variable regions comprising heavy chain complementarity-determining region 1 (HCDR1) as shown in SEQ ID NO:19, heavy chain complementarity-determining region 2 (HCDR2) as shown in SEQ ID NO:20, and heavy chain complementarity-determining region 3 (HCDR3) as shown in SEQ ID NO:21, the light chains comprising light chain variable regions, the light chain variable regions comprising light chain complementarity-determining region 1 (LCDR1) as shown in SEQ ID NO:22, light chain complementarity-determining region 2 (LCDR2) as shown in SEQ ID NO:23, and light chain complementarity-determining region 3 (LCDR3) as shown in SEQ ID NO:24;

[0528] More preferably, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:25, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:26;

[0529] More preferably, the heavy chain comprises the amino acid sequence shown in SEQ ID NO:7, and the light chain comprises the amino acid sequence shown in SEQ ID NO:8.

[0530] 54. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-53, characterized in that the average conjugation ratio n of the drug ligand is an integer or decimal from 1 to 10;

[0531] Preferably, the average conjugation ratio n of the drug ligand is an integer or a decimal of 3 to 8; or

[0532] Preferably, the average conjugation ratio n of the drug ligand is an integer or decimal of 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10; or

[0533] Preferably, the average conjugation ratio n of the drug ligand is 1, 2, 3, 4, 5, 6, 7 or 8.

[0534] 55. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-54, characterized in that the ligand-drug conjugate is selected from the structures in Table 2.

[0535] 56. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-54, characterized in that the ligand-drug conjugate is selected from the structures in Table 3.

[0536] 57. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-56, wherein the ligand-drug conjugate is substituted with an isotope;

[0537] Preferably, the isotope substitution is deuterium atom substitution.

[0538] 58. A compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound has the structure shown in formula (IA):

[0539] L-D formula (IA);

[0540] Wherein, L is a connecting unit with the following structure: L4'—L3—L2—L1—; wherein, L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4' is a ligand connecting unit, which can be used to connect with a ligand, and L4' is selected from:

[0541] Wherein, G is the leaving group for nucleophilic substitution;

[0542] D is a drug with the structure shown in formula (IV):

[0543] in,

[0544] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0545] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0546] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0547] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0548] X is selected from O, S, and NH; and

[0549] The wavy line represents the key connecting L and D.

[0550] 59. The compound according to embodiment 58, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups; preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups; more preferably, R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl; more preferably, the R 1 It is F or -CH3; more preferably, the R 1 For F; or, more preferably, for R 1 It is -CH3.

[0551] 60. The compound according to embodiment 58 or 59, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms, F, Cl and Br; preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms, F and Cl; more preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F; more preferably, the R 2 and R 3 All are hydrogen atoms; or, more preferably, the R 2 and R 3 One of them is a hydrogen atom, and the other is an F atom.

[0552] 61. The compound according to any one of embodiments 58-60, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the R 4 Selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups; preferably, the R 4Selected from hydrogen atoms, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups; more preferably, the R... 4 Selected from hydrogen atoms, F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups; more preferably, the R... 4 It is a hydrogen atom or F; more preferably, the R 4 It is a hydrogen atom.

[0553] 62. The compound according to any one of embodiments 58-61, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the R 5 It is a hydrogen atom; or, in some other embodiments of the compound of formula (I), the R... 5 It is -C(O)CH2OH.

[0554] 63. The compound according to any one of embodiments 58-62, or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that X is -OH or -SH; or, preferably, X is -NH2; or, preferably, X is -OH; or, preferably, X is -SH.

[0555] 64. The compound according to any one of embodiments 58-63, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the R 2 and R 3 The R atoms, whether identical or different and each independently selected from hydrogen, F, and Cl, are... 5 It is a hydrogen atom or -C(O)CH2OH; preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F, said R 5 It is a hydrogen atom; or, preferably, the R 2 R is a hydrogen atom or F. 3 For hydrogen atoms, the R 5 It is a hydrogen atom; or, preferably, the R 2 R 3 and R 5 All are hydrogen atoms.

[0556] 65. The compound according to any one of embodiments 58-64, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups, the R 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups, wherein X is selected from -OH, -SH, and -NH2; preferably, R... 1 The R is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups. 4 X is a hydrogen atom or F, and X is -OH or -SH; more preferably, R 1 The R is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups. 4 X is a hydrogen atom, and X is -OH; more preferably, R is a hydrogen atom. 1 For F or -CH3, the R 4 X is a hydrogen atom, and X is -OH.

[0557] 66. A compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IA): L-D Formula (IA);

[0558] Wherein, L is a connecting unit with the following structure: L4'—L3—L2—L1—; wherein, L1 is absent or is a self-cleaving unit, and L1 is connected to D; L2 is absent or is a conditionally cleaving unit; L3 is absent or is a hydrophilic unit; L4' is a ligand connecting unit used to connect with a ligand, and L4' is selected from:

[0559] Wherein, G is the leaving group for nucleophilic substitution;

[0560] D is a drug having the structure shown in formula (II) or formula (II-S):

[0561] in,

[0562] R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0563] R 2 Selected from hydrogen atoms and halogens;

[0564] The wavy line represents the key connecting L and D.

[0565] 67. The compound according to embodiment 66, or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the G is selected from halogen, sulfonyl, sulfonate, nitro, and optionally substituted with one or more of the following groups: alkyl thioether, aryl thioether, heteroaryl thioether, alkyl sulfoxide, aryl sulfoxide, heteroaryl sulfoxide, alkyl sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, wherein each substituent is independently selected from hydrogen, deuterium, halogen, CN, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, 6-10 aryl, and 5-16 heteroaryl;

[0566] Preferably, G is selected from F, Cl, Br, I, OMs, Ots, OTf, methanesulfonyl, ethanesulfonyl, p-toluenesulfonyl, and naphthalenesulfonyl.

[0567] More preferably, the G is selected from F, Cl, Br, OMs, OTs, methanesulfonyl and p-toluenesulfonyl;

[0568] More preferably, the G is selected from Cl and methanesulfonyl.

[0569] 68. The compound according to embodiment 66 or 67, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the R 2 Selected from hydrogen atoms, F, Cl, and Br;

[0570] Preferably, the R 2 Selected from hydrogen atoms, F and Cl;

[0571] More preferably, the R 2 Selected from hydrogen atoms and F;

[0572] More preferably, the R 2 It is a hydrogen atom.

[0573] 69. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 66-68, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups;

[0574] Preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups;

[0575] More preferably, the R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl;

[0576] More preferably, the R 1 For F or -CH3;

[0577] More preferably, the R 1 For F;

[0578] Or, more preferably, the R 1 It is -CH3.

[0579] 70. The compound according to any one of embodiments 66-69, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that D has the structure shown in formula (III) or formula (III-S):

[0580] Among them, R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups.

[0581] 71. The compound according to embodiment 70, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups;

[0582] Preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups;

[0583] More preferably, the R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl;

[0584] More preferably, the R 1For F or -CH3;

[0585] More preferably, the R 1 For F;

[0586] More preferably, the R 1 It is -CH3.

[0587] 72. The compound according to any one of embodiments 58-71, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that D is selected from the following structures:

[0588] 73. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-72, characterized in that, in L4', X is -(C(R 4a (R) 4b )) m -, m is an integer ≥ 1; Y is -C(=O)-; 0 or more methylene units of X are each independently and arbitrarily selected by -N(R 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-、 -O-, -S-, -SO-, -SO2-, -N(R 4c SO2-, -SO2N(R) 4c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=S)-, -C(=NR 4c -, -C = C-, -N = N-, -C = N-, or -N = C- are substitutes; m1 is an integer ≥ 1; each R 4a R 4b R 4c Each can be independently represented as hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, or -OR. 4 -SR 4 -(CH2CH2O) m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 -(CH2) m2 N(R4d (R) 4e -(CH2) m2 C(O)R 4 -(CH2) m2 CO2R 4 -C(O)CH2C(O)R 4 -S(O)R 4 -S(O)2R 4 -C(O)N(R) 4d (R) 4e -SO2N(R) 4d (R) 4e -OC(O)R 4 -N(R)SO2R 4 or C 1-6 Alkyl; wherein each R 4 R 4d R 4e Each of these can be independently identified as 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, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl groups; m2 is an integer ≥ 0, m3 is an integer ≥ 0, and m4 is an integer ≥ 0;

[0589] The L3 is absent or is -NH-(C(R) 3a (R) 3b )) s -C(=O)-, s is an integer ≥1; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, -O-, -S-, -SO-, -SO2-, -N(R 3c SO2-, -SO2N(R) 3c -, -C(=S)-, -C(=NR) 3c -, -C = C-, -N=N-, -C=N-, or -N=C- can be substituted; each R 3a R 3b R 3cEach independently represents hydrogen, protium, deuterium, tritium, halogen, -OR 3 -SR 3 -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 R 3 ; where, each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer ≥ 0, s2 is an integer ≥ 0;

[0590] The L2 is absent or selected from amino acids, peptides or oligosaccharides consisting of 2-10 amino acids; the amino acid residues are selected from natural amino acid residues, non-natural amino acid residues, or their stereoisomers; when the amino acid residue is Lys, the side chain amino group of Lys is optionally surrounded by one or two C atoms. 1-6 Alkyl groups are substituted; preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by one or two C atoms. 1-3 Alkyl groups are substituted; more preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally substituted with two ethyl groups or two n-propyl groups;

[0591] L1 either does not exist or is selected from: Of these, bit 1 is connected to L2, and bit 2 is connected to D.

[0592] 74. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-73, characterized in that, in L4', X is -(C(R 4a (R) 4b )) m -, m is an integer from 1 to 10; Y is -C(=O)-; 0 or more methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 12; each R 4a R 4b R 4cEach can be independently classified as hydrogen, protium, deuterium, tritium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group; m2 is an integer from 0 to 20, m3 is an integer from 0 to 20, and m4 is an integer from 0 to 20.

[0593] 75. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-74, characterized in that each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ;

[0594] Preferably, R 4a R 4b All are hydrogen; or

[0595] Preferably, R 4a and R 4b One of them is hydrogen, and the other is -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 .

[0596] 76. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-75, characterized in that each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 alkyl;

[0597] Preferably, each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -CH3 or -C2H5;

[0598] More preferably, R 4c It is hydrogen;

[0599] More preferably, R 4c -(CH2CH2O) m2 -R 4 ;

[0600] More preferably, R 4c It is -CH3.

[0601] 77. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-76, characterized in that m is an integer from 1 to 8;

[0602] Preferably, m is an integer from 1 to 6;

[0603] Preferably, m is an integer from 1 to 5.

[0604] 78. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-77, characterized in that m1 is an integer from 1 to 8;

[0605] Preferably, m1 is an integer from 1 to 6;

[0606] Preferably, m1 is an integer from 1 to 4;

[0607] More preferably, m1 is 1.

[0608] 79. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-78, characterized in that m2 is an integer from 1 to 20;

[0609] Preferably, m2 is an integer between 8 and 20;

[0610] Preferably, m2 is an integer between 12 and 18;

[0611] More preferably, m2 is 16.

[0612] 80. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-79, characterized in that m3 is an integer from 0 to 8;

[0613] Preferably, m3 is an integer from 1 to 6;

[0614] Preferably, m3 is an integer from 1 to 3;

[0615] More preferably, m3 is 1.

[0616] 81. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-80, characterized in that m4 is an integer from 0 to 8;

[0617] Preferably, m4 is an integer from 1 to 6;

[0618] Preferably, m4 is an integer from 1 to 3;

[0619] More preferably, m4 is 1; or,

[0620] More preferably, m4 is 2.

[0621] 82. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-81, characterized in that each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3;

[0622] Preferably, each R 4 It can be independently hydrogen, deuterium, halogen, -CO2H, -CH3, or -OCH3;

[0623] More preferably, each R 4 Independently -CO2H, -CH3, or -OCH3;

[0624] More preferably, R 4-CO2H; or

[0625] More preferably, R 4 -CH3; or

[0626] More preferably, R 4 It is -OCH3.

[0627] 83. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-82, characterized in that, in L4', X is -(C(R 4a (R) 4b )) m -, m is an integer from 1 to 8; Y is -C(=O)-; 0 or 1 methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 8; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently hydrogen, -CO2H, or C 1-6 Alkyl; m2 is an integer from 1 to 20, m3 is an integer from 0 to 8, and m4 is an integer from 0 to 8.

[0628] 84. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-83, characterized in that, in L4', X is -(C(R 4a (R) 4b )) m-, m is an integer from 1 to 5; Y is -C(=O)-; 0 or 1 methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 4; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; m2 is an integer from 12 to 18, m3 is an integer from 1 to 3, and m4 is an integer from 1 to 3.

[0629] 85. The compound according to any one of embodiments 58-84, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that L3 is s is an integer from 1 to 10; 1 bit is connected to L4, and 2 bits are connected to L2; 0 or more methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c - or -O- substitution; each R 3a R 3b R 3c Each can be independently represented as hydrogen, protium, deuterium, tritium, or -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2)s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 24, and s2 is an integer from 0 to 8.

[0630] 86. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-85, characterized in that each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ;

[0631] Preferably, R 3a and R 3b All are hydrogen;

[0632] Preferably, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 More preferably, R 3a and R 3b One of them is hydrogen, and the other is -C(=O)NH(CH2CH2O). s1 -R 3 ;

[0633] Preferably, R 3a and R 3b All are -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 More preferably, R 3a and R 3b All are -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 .

[0634] 87. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-86, characterized in that each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ;

[0635] Preferably, R 3c It is hydrogen.

[0636] 88. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-87, characterized in that s is an integer from 1 to 8;

[0637] Preferably, s is an integer from 1 to 6;

[0638] Preferably, s is an integer between 3 and 6;

[0639] More preferably, s is 3; or

[0640] More preferably, s is 6.

[0641] 89. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-88, characterized in that s1 is an integer from 1 to 20;

[0642] Preferably, s1 is an integer between 8 and 20;

[0643] Preferably, s1 is an integer between 12 and 18;

[0644] More preferably, s1 is 12; or

[0645] More preferably, s1 is 16.

[0646] 90. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 55-89, characterized in that s2 is an integer from 0 to 6;

[0647] Preferably, s2 is an integer between 0 and 4;

[0648] Preferably, s2 is an integer from 1 to 3;

[0649] More preferably, s2 is 1.

[0650] 91. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-90, characterized in that each R 3 Independently hydrogen, deuterium, or C 1-6 alkyl;

[0651] Preferably, each R 3 It can be independently hydrogen, deuterium, -CH3, or -C2H5;

[0652] More preferably, R 3 It is -CH3.

[0653] 92. The compound according to any one of embodiments 58-91, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that L3 is s is an integer from 1 to 8; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily selected by -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3 Independently hydrogen, protium, deuterium, tritium, or C 1-6 Alkyl group; s1 is an integer from 1 to 20, and s2 is an integer from 0 to 6.

[0654] 93. The compound according to any one of embodiments 58-92, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that L3 is s is an integer from 1 to 6; the 0, 1, or 2 methylene units of L3 are each independently and arbitrarily converted to -N(R) 3c )C(=O)-、-C(=O)N(R 3c -, -C(=O)-, -NR 3c - or -O- substitution; each R 3a and R 3b Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Each R 3c Each can be independently hydrogen, deuterium, or -C(=O)NH(CH2CH2O) s1 -R 3 -(CH2) s2 O(CH2CH2O) s1 -R 3 Or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; where each R 3Independently, it can be hydrogen, deuterium, -CH3 or -C2H5; s1 is an integer from 8 to 20, and s2 is an integer from 0 to 4.

[0655] 94. The compound according to any one of embodiments 58-93, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the L3 is selected from:

[0656] 95. The compound according to any one of embodiments 58-92, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the L2 is selected from amino acids, peptides consisting of 2-10 amino acids, and oligosaccharides; the amino acids are selected from natural amino acid residues, non-natural amino acid residues, or their stereoisomers; and when the amino acid residue is Lys, the distal amino group of the Lys is optionally surrounded by one, two, or three C atoms. 1-6 Alkyl groups are substituted;

[0657] Preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally surrounded by one or two C atoms. 1-4 Alkyl groups are substituted;

[0658] More preferably, when the amino acid residue is Lys, the side chain amino group of Lys is optionally replaced by two methyl groups, two ethyl groups, or two n-propyl groups.

[0659] 96. The compound according to any one of embodiments 58-95, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the L2 is selected from -Lys-, -Ala-Lys-, -Gly-Lys-, -Lys-Gly-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Lys-Val-, -Ala-Ala-Asn -, -Ala-Ala-Asn-, -Ala-Ala-Asp-, -Ala-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Lys-Gly-, -Lys-Ala-Asn -, -Val-Lys-Gly-, -Gly-Gly-Phe-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Val-Lys-Gly-Gly-, and In this embodiment, the distal amino group of Lys is optionally surrounded by one, two, or three C atoms. 1-6 Alkyl groups are substituted.

[0660] 97. The compound according to any one of embodiments 58-96, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the L2 is selected from:

[0661] 98. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-97, characterized in that L1 is selected from:

[0662] 99. The compound according to any one of embodiments 58-98, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (IA) is selected from the structures in Table 4.

[0663] 100. The compound or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 58-99, characterized in that the ligand-drug conjugate is substituted with an isotope;

[0664] Preferably, the isotope substitution is deuterium atom substitution.

[0665] 101. A compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the compound has a structure represented by formula (IVA):

[0666] R is selected from 1: autohalogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0667] R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens;

[0668] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups;

[0669] R 5 Selected from hydrogen atoms and -C(O)CH2OH;

[0670] X is selected from -OH, -SH, and -NH2.

[0671] 102. The compound according to embodiment 101, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups; preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups; more preferably, R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl; more preferably, the R 1 It is F or -CH3; more preferably, the R 1 For F; or, more preferably, for R 1 It is -CH3.

[0672] 103. The compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, according to embodiments 101 or 102, characterized in that the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms, F, Cl and Br; preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms, F and Cl; more preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F; more preferably, the R 2 and R 3 All are hydrogen atoms; or, more preferably, the R 2 and R 3 One of them is a hydrogen atom, and the other is an F atom.

[0673] 104. The compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, according to any one of embodiments 101-103, characterized in that the R 4 Selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups; preferably, the R 4Selected from hydrogen atoms, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl groups; more preferably, the R... 4 Selected from hydrogen atoms, F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups; more preferably, the R... 4 It is a hydrogen atom or F; more preferably, the R 4 It is a hydrogen atom.

[0674] 105. The compound according to any one of embodiments 101-104, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the R 5 It is a hydrogen atom; or, in some other embodiments of the compound of formula (I), the R... 5 It is -C(O)CH2OH.

[0675] 106. The compound according to any one of embodiments 101-105, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that X is -OH or -SH; or, preferably, X is -NH2; or, preferably, X is -OH; or, preferably, X is -SH.

[0676] 107. The compound according to any one of embodiments 101-106, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the R 2 and R 3 The R atoms, whether identical or different and each independently selected from hydrogen, F, and Cl, are... 5 It is a hydrogen atom or -C(O)CH2OH; preferably, the R 2 and R 3 The same or different, and each independently selected from hydrogen atoms and F, said R 5 It is a hydrogen atom; or, preferably, the R 2 R is a hydrogen atom or F. 3 For hydrogen atoms, the R 5 It is a hydrogen atom; or, preferably, the R 2 R 3 and R 5 All are hydrogen atoms.

[0677] 108. The compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, according to any one of embodiments 102-107, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups, the R 4 The atom is selected from hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, and vinyl groups, wherein X is selected from -OH, -SH, and -NH2; preferably, R... 1 The R is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups. 4 X is a hydrogen atom or F, and X is -OH or -SH; more preferably, R 1 The R is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl groups. 4 X is a hydrogen atom, and X is -OH; more preferably, R is a hydrogen atom. 1 For F or -CH3, the R 4 X is a hydrogen atom, and X is -OH.

[0678] 109. A compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound has the structure shown in formula (IIA):

[0679] Among them, R 1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and vinyl groups; R 2 Selected from hydrogen atoms and halogens.

[0680] 110. The compound according to embodiment 109, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that the R 2 Selected from hydrogen atoms, F, Cl, and Br;

[0681] Preferably, the R 2 Selected from hydrogen atoms, F and Cl;

[0682] More preferably, the R 2 Selected from hydrogen atoms and F;

[0683] More preferably, the R 2 It is a hydrogen atom.

[0684] 111. The compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, according to embodiments 109 or 110, characterized in that the R 1 Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and vinyl groups;

[0685] Preferably, the R 1 Selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl groups;

[0686] More preferably, the R 1 Selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl;

[0687] More preferably, the R 1 For F or -CH3;

[0688] More preferably, the R 1 For F;

[0689] Or, more preferably, the R 1 It is -CH3.

[0690] 112. The compound according to any one of embodiments 109-111, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound has a structure represented by formula (IIA-S):

[0691] 113. The compound according to any one of embodiments 101-111, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IIIA):

[0692] 114. The compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, as described in embodiments 101-113, wherein the compound has a structure represented by formula (IIIA-S):

[0693] 115. The compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, as described in embodiments 101-114, wherein the compound is selected from:

[0694] 116. The compound according to any one of embodiments 101-115, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with an isotope;

[0695] Preferably, the isotope substitution is deuterium atom substitution.

[0696] 117. A method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof of formula (I) as described in any one of embodiments 1-57, characterized in that the method comprises contacting ligand B# with the structure of formula (IA) as described in any one of embodiments 58-100.

[0697] 118. A pharmaceutical composition, characterized in that the pharmaceutical composition contains a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-57, and a pharmaceutically acceptable carrier.

[0698] 119. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises a compound as described in any one of embodiments 58-100, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0699] 120. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises a compound as described in any one of embodiments 101-116, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0700] 121. Use of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-57, or a pharmaceutical composition according to embodiment 118, in the preparation of a medicament for treating and / or preventing tumors.

[0701] 122. Use of a compound according to any one of embodiments 58-100, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing tumors;

[0702] Preferably, the drug is a ligand-drug conjugate.

[0703] 123. Use of a compound according to embodiments 101-116 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 120, in the preparation of a medicament for treating and / or preventing tumors.

[0704] 124. A method of treating and / or preventing tumors, comprising administering to a subject in need the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-57, or the pharmaceutical composition described in embodiment 118.

[0705] 125. A method of treating and / or preventing tumors, comprising administering to a subject in need a compound or tautomer of any one of embodiments 101-116, or a racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 120.

[0706] 126. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-57, or a pharmaceutical composition according to embodiment 118, for the treatment and / or prevention of tumors.

[0707] 127. A compound according to any one of embodiments 101-116, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 120, for the treatment and / or prevention of tumors.

[0708] 128. The use according to any one of embodiments 121-123, the method of embodiment 124 or 125, the ligand-drug conjugate of embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound of embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is selected from tumors associated with expression of the following group: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, O772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASL G659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, C CR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD 66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2. c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRv III, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1 , GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL -4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MP F, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6 SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelial peptide receptors, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin α4β7, integrin α5β6, trophoblast cell glycoproteins, and tissue factor.

[0709] 128. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is selected from tumors associated with expression of the following group: HER2, HER3, B7H3, TROP2, LIV-1, Claudin 18.2, CD30, CD33, CD70, or EGFR.

[0710] 129. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with HER2 expression.

[0711] 130. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with HER3 expression.

[0712] 131. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with B7H3 expression.

[0713] 132. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with TROP2 expression.

[0714] 133. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with LIV-1 expression.

[0715] 134. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with Claudin 18.2 expression.

[0716] 135. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with CD30 expression.

[0717] 136. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with CD33 expression.

[0718] 137. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with CD70 expression.

[0719] 138. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is a tumor associated with EGFR expression.

[0720] 139. The use according to any one of embodiments 121-123, the method according to embodiment 124 or 125, the ligand-drug conjugate according to embodiment 126 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, the compound according to embodiment 127 or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, characterized in that the tumor is selected from the group consisting of: lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, and urothelial carcinoma. Cancer, head and neck cancer, nasopharyngeal carcinoma, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric mucinous tumor, lymphoma, leukemia, plasmacytoma, sinoatrial node cell tumor, tenosynovial giant cell tumor, brain cancer, squamous cell carcinoma, epidermal cancer, non-Hodgkin's lymphoma; preferably, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, malignant lymphoma, liver cancer, and leukemia;

[0721] Preferably, the cancer is ER-positive and / or TRPM4-positive; or

[0722] Preferably, the breast cancer is ER+ breast cancer or ER+ / HER2- breast cancer; or

[0723] Preferably, the lung cancer is non-small cell lung cancer; or

[0724] Preferably, the prostate cancer is castration-resistant prostate cancer.

[0725] 140. A kit comprising a ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-57, a compound or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition according to embodiment 118 or 120.

[0726] Example

[0727] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0728] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. - 6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0729] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0730] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0731] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0732] High-performance liquid chromatography (HPLC) preparative chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0733] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0734] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0735] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0736] Silica gel column chromatography typically uses 200–300 mesh or 300–400 mesh silica gel as the carrier.

[0737] The known starting materials disclosed herein can be synthesized using methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

[0738] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0739] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0740] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0741] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0742] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0743] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0744] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0745] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0746] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included, but were not limited to: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0747] The specific enantiomers in the examples can be obtained by separation using chiral HPLC. When a specific geometrical isomer is desired, chromatography, recrystallization, and other conventional separation operations can also be used. Alternatively, undesirable enantiomers can be racemiced to desired enantiomers in the presence of an acid or base, according to methods known to those skilled in the art or as described in the accompanying examples.

[0748] To determine the aggregation of the antibody-drug conjugates obtained in the examples, the prepared ADCs were subsequently characterized by size exclusion chromatography. (The sentence fragment about equipment appears to be incomplete and lacks context. It has been left as is.) Size exclusion chromatography was performed on an Agilent 1260 HPLC system with a G3000SWxL column (Tosoh Bioscience LLC, 7.8 mm × 30 cm, 5 μm pore size). Naked antibody or conjugate samples were eluted from the column for 30 minutes at a flow rate of 0.5–1.0 mL / min with 0.1 M sodium phosphate containing 0.15 M sodium chloride and 10–15% isopropanol (pH 7.4). All data were analyzed using Agilent ChemStation software. The aggregation percentage of the naked antibody or antibody-conjugate was calculated as follows:

[0749] Where: PA = peak area of ​​the integral

[0750] To determine the drug-antibody ratio (i.e., the average drug-ligand conjugation ratio n) of the antibody-drug conjugates obtained in the examples, the prepared ADCs were subsequently analyzed by liquid chromatography-mass spectrometry (LC-MS). LC-MS analysis of the drug loading value of the conjugates was initiated after the antibody-drug conjugate sample was reduced with DTT at 37°C for 10 minutes. The reduced sample was then injected into an Acquity UPLC BEH C4 reversed-phase column (Waters Corporation, 2.1 mm × 50 mm, 1.7 μm). The LC-MS system (Agilent 1290 Infinity II LC system and Agilent 6545XT AdvanceBio Q-TOF) provides deconvolutioned LC-MS results for DAR computation.

[0751] Example 1: Preparation of drug D

[0752] Example 1-1: Synthesis of Compound 1, Compound 1-P1 and Compound 1-P2

[0753] Step a:

[0754] N-(3-Bromo-2-fluorophenyl)-2-chloroacetamide

[0755] 2-Chloroacetyl chloride (5.84 g, 51.71 mmol) was added dropwise to a solution of 3-bromo-2-fluoroaniline (6.55 g, 34.47 mmol) and potassium carbonate (5.84 g, 42.25 mmol) in dichloromethane (150 mL) at 0 °C, and the mixture was stirred at 0 °C for 4 hours. After the reaction was completed, the reaction mixture was poured into an aqueous solution and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound Int 1-a (7.08 g, yield 77.1%).

[0756] 1 H NMR (400MHz, CDCl3): δ8.55(s,1H),8.28(m,1H),7.37-7.28(m,1H),7.07(m,1H),4.25(s,2H).

[0757] Step b:

[0758] N-(3-Bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide

[0759] A solution of compound Int 1-a (7.08 g, 26.57 mmol), hydroxylamine hydrochloride (5.55 g, 79.87 mmol), and N,N-diisopropylethylamine (10.31 g, 79.77 mmol) in isopropanol (90 mL) was stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to give crude Int 1-b (5.90 g, yield 85.1%), which was used directly in the next step without further processing.

[0760] MS m / z (ESI): 259.0 [MH] + .

[0761] Step c:

[0762] 6-Bromo-7-fluoroindole-2,3-dione

[0763] A sulfuric acid (15 mL) solution of compound Int1-b (0.75 g, 2.87 mmol) was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was then poured into an ice-water solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound Int1-c (0.27 g, yield 38.4%).

[0764] 1 H NMR (400MHz, DMSO-d6): δ11.73(s,1H),7.38(dd,1H),7.31(d,1H).

[0765] Step d:

[0766] 6-Bromo-3-cycloheptyl-7-fluoro-3-hydroxyindole-2-one

[0767] Under nitrogen protection, a solution of cycloheptayl magnesium bromide (1 M in tetrahydrofuran, 4.90 mL, 4.90 mmol) was added to a tetrahydrofuran (10 mL) solution of compound Int1-c (300 mg, 1.23 mmol) at -78 °C, and stirring was continued for 1 hour. After the reaction was completed, the temperature was brought to room temperature, and the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound Int1-d (110 mg, yield 26.1%).

[0768] 1 H NMR (400MHz, DMSO-d6): δ10.96(s,1H),7.24(dd,1H),7.03(d,1H),6.05(s,1H),2.07-2 .02(m,1H),1.94-1.88(m,1H),1.73-1.68(m,1H),1.55-1.17(m,9H),0.81-0.73(m,1H).

[0769] Step e:

[0770] 6-Bromo-3-cycloheptyl-7-fluoro-3-(4-hydroxyphenyl)indol-2-one

[0771] A solution of compound Int1-d (150 mg, 0.44 mmol), phenol (206 mg, 2.19 mmol), and p-toluenesulfonic acid (566 mg, 3.29 mmol) in 1,2-dichloroethane (15 mL) was stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound Int1-e (160 mg, yield 87.3%).

[0772] 1 HNMR(400MHz, CDCl3): δ7.84(s,1H),7.22-7.18(m,1H),7.11(d,2H),6.92(d,1H),6 .66(d,2H),5.42(s,1H),2.60-2.55(m,1H),1.64-1.19(m,11H),0.82-0.75(m,1H).

[0773] Step f:

[0774] (SR)-3-Cycloheptyl-7-fluoro-6-(hydroxymethyl)-3-(4-hydroxyphenyl)indol-2-one

[0775] Under nitrogen protection, a solution of compound Int1-e (380 mg, 0.91 mmol), tributyltin-methanol (583 mg, 1.82 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2, 71.5 mg, 0.091 mmol) in 1,2-dioxane (12 mL) was heated to 85 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The crude product was subjected to rapid silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain a white solid. This white solid was then purified by high performance liquid chromatography (Welchrom). C18, 20*150mm, 5μm; mobile phase A: 5mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%), to obtain compound 1 (151mg, yield 45.0%).

[0776] 1HNMR (400MHz, DMSO-d6): δ10.83(s,1H),9.36(s,1H),7.11-7.07(m,4H),6.68(d,2H) ,5.26(t,1H),5.56(d,2H),2.51-2.48(m,1H),1.61-1.24(m,11H),0.86-0.80(m,1H).

[0777] MS m / z (ESI): 370.2 [M+H] + .

[0778] Step g:

[0779] 170.0 mg of compound 1 was purified by preparative supercritical fluid chromatography under the following conditions: column: CHIRALPAK IBN-5, 3×25 cm, 5 μm; mobile phase A: Hex, mobile phase B: EtOH; flow rate: 55 mL / min; gradient: 30% B; detector: UV 214 nm; retention time 1: 4.31 min; retention time 2: 5.83 min.

[0780] The enantiomer with a relatively fast elution rate and a retention time of 4.31 min is compound 1-P1: (S)-3-cycloheptyl-7-fluoro-6-(hydroxymethyl)-3-(4-hydroxyphenyl)indol-2-one (69.0 mg, ee value: 99.8%).

[0781] 1-P1: 1 H NMR(400MHz,DMSO_d6)δ10.83(s,1H),9.36(s,1H),7.11-7.07(m,4H),6.68(d,2H), 5.26(t,1H),5.56(d,2H),2.51-2.48(m,1H),1.61-1.24(m,11H),0.86-0.80(m,1H);

[0782] MS m / z (ESI): 370.1 [M+H] + .

[0783] The enantiomer with a slower elution rate and a retention time of 5.83 min is compound 1-P2: (R)-3-cycloheptyl-7-fluoro-6-(hydroxymethyl)-3-(4-hydroxyphenyl)indol-2-one (74.3 mg, ee value: 100%).

[0784] 1-P2: 1H NMR(400MHz,DMSO_d6)δ10.83(s,1H),9.36(s,1H),7.11-7.07(m,4H),6.68(d,2H), 5.26(t,1H),5.56(d,2H),2.51-2.48(m,1H),1.61-1.24(m,11H),0.86-0.80(m,1H);

[0785] MS m / z (ESI): 370.1 [M+H] + .

[0786] Examples 1-2: Synthesis of Compound 2, Compound 2-P1 and Compound 2-P2

[0787] Step a:

[0788] N-(3-Bromo-2-methylphenyl)-2-chloroacetamide

[0789] 2-Chloroacetyl chloride (3.68 g, 32.58 mmol) was added dropwise to a solution of 3-bromo-2-methylaniline (4.03 g, 21.66 mmol) and potassium carbonate (9.00 g, 65.12 mmol) in dichloromethane (150 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was poured into an aqueous solution and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound Int 2-a (5.00 g, yield 87.9%).

[0790] 1 H NMR (400MHz, CDCl3): δ8.30(s,1H),7.80(d,1H),7.49(d,1H),7.14(dd,1H),4.28(s,2H),2.43(s,3H).

[0791] Step b:

[0792] N-(3-Bromo-2-methylphenyl)-2-(hydroxyimino)acetamide

[0793] A solution of compound Int 2-a (2.63 g, 10.02 mmol), hydroxylamine hydrochloride (2.08 g, 29.93 mmol), and N,N-diisopropylethylamine (3.88 g, 30.02 mmol) in isopropanol (100 mL) was stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane (300 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to give crude Int 2-b (2.10 g, yield 81.6%), which was used directly in the next step without further processing.

[0794] MS m / z (ESI): 255.0 [MH] + .

[0795] Step c:

[0796] 6-Bromo-7-methylindole-2,3-dione

[0797] A solution of compound Int 2-b (100 mg, 0.39 mmol) in methanesulfonic acid (4 mL) was stirred at 80 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was then poured into an ice-water solution and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane:tetrahydrofuran = 19:1) to give compound Int 2-c (30 mg, yield 31.9%).

[0798] 1 H NMR (400MHz, DMSO-d6): δ11.27(s,1H),7.34(d,1H),7.27(d,1H),2.25(s,3H).

[0799] Step d:

[0800] 6-Bromo-3-cycloheptyl-3-hydroxy-7-methylindol-2-one

[0801] Under nitrogen protection, a solution of cycloheptayl magnesium bromide (1 M in tetrahydrofuran, 2.92 mL, 2.92 mmol) was added to an 8 mL tetrahydrofuran solution of compound Int 2-c (280 mg, 1.17 mmol) at -78 °C, and stirring was continued for 40 minutes. After the reaction was completed, the mixture was brought to room temperature, and the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound Int 2-d (120 mg, yield 30.4%).

[0802] MS m / z (ESI): 320.1 [M-OH] + .

[0803] Step e:

[0804] 6-Bromo-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methylindol-2-one

[0805] A solution of compound Int 2-d (120 mg, 0.35 mmol), phenol (167 mg, 1.77 mmol), and p-toluenesulfonic acid (458 mg, 2.66 mmol) in 1,2-dichloroethane (15 mL) was stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound Int 2-e (100 mg, yield 68.0%).

[0806] 1 HNMR (400MHz, CDCl3): δ8.85(s,1H),7.29(d,1H),7.19(d,2H),7.00(d,1H),6.70(d,2H) ,5.65(brs,1H),2.63-2.61(m,1H),2.32(s,3H),1.73-1.24(m,11H),0.89-0.80(m,1H).

[0807] MS m / z (ESI): 412.0, 414.0 [MH] + .

[0808] Step f:

[0809] (SR)-3-Cycloheptyl-6-(hydroxymethyl)-3-(4-hydroxyphenyl)-7-methylindole-2-one

[0810] Under nitrogen protection, a solution of compound Int 2-e (100 mg, 0.24 mmol), tributyltin-methanol (232.5 mg, 0.72 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2, 19 mg, 0.024 mmol) in 1,2-dioxane (12 mL) was heated to 85 °C and stirred for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to give compound 2 (28.5 mg, yield 32.3%).

[0811] 1 HNMR (400MHz, DMSO-d6): δ10.34(s,1H),9.30(s,1H),7.11-7.03(m,4H),6.67(d,2H),5.03( t,1H),4.48(d,2H),2.51-2.44(m,1H),2.15(s,3H),1.63-1.24(m,11H),0.85-0.81(m,1H). MS m / z(ESI): 366.1[M+H] + .

[0812] Step g:

[0813] 536.0 mg of compound 2 was purified by preparative supercritical fluid chromatography under the following conditions: column: CHIRALPAK IBN-5, 3×25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 55 mL / min; gradient: 40% B; detector: UV 254 nm; retention time 1: 2.46 min; retention time 2: 4.28 min.

[0814] The enantiomer with a relatively fast elution rate and a retention time of 2.45 min is compound 2-P1: (S)-3-cycloheptyl-6-(hydroxymethyl)-3-(4-hydroxyphenyl)-7-methylindole-2-one (125.3 mg, ee value: 99.7%).

[0815] 2-P1: 1H NMR(400MHz,DMSO_d6)δ10.32(s,1H),9.29(brs,1H),7.11-7.02(m,4H),6.66(d,2H), 5.02(brs,1H),4.48(s,2H),2.51-2.45(m,1H),1.63-1.24(m,11H),0.85-0.81(m,1H);

[0816] MS m / z (ESI): 366.1 [M+H] + .

[0817] The enantiomer with a slower elution rate and a retention time of 4.28 min is compound 2-P2: (R)-3-cycloheptyl-6-(hydroxymethyl)-3-(4-hydroxyphenyl)-7-methylindole-2-one (125.6 mg, ee value: 100.0%).

[0818] 2-P2: 1 H NMR(400MHz,DMSO_d6)δ10.83(s,1H),9.36(s,1H),7.11-7.07(m,4H),6.68(d,2H), 5.26(t,1H),5.56(d,2H),2.51-2.48(m,1H),1.61-1.24(m,11H),0.86-0.80(m,1H);

[0819] MS m / z (ESI): 366.1 [M+H] + .

[0820] Synthesis of Compound 3 in Examples 1-3

[0821] Step a:

[0822] N-(3-methoxy-2-methylphenyl)-2-chloroacetamide

[0823] 2-Chloroacetyl chloride (23.70 g, 209.85 mmol) and triethylamine (57.90 g, 572.19 mmol) were added to a solution of 3-methoxy-2-methylaniline (25.00 g, 182.24 mmol) in dichloromethane (300 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude Int3-a (37.0 g, yield 95.0%). The crude product was used directly in the next step without further processing.

[0824] Step b:

[0825] N-(3-Methoxy-2-methylphenyl)-2-(hydroxyimino)acetamide

[0826] A solution of compound Int 3-a (37.00 g, 173.17 mmol), hydroxylamine hydrochloride (36.00 g, 518.06 mmol), and N,N-diisopropylethylamine (67.10 g, 519.19 mmol) in isopropanol (350 mL) was stirred at 80 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to give compound Int 2-b (15.2 g, yield 42.2%).

[0827] 1 H NMR (400MHz, DMSO-d6): δ12.15(s,1H),9.55(s,1H),7.66(s,1H),7.15(m,1H),7.05(m,1H),6.84(d,1H),3.77(s,3H),2.02(s,3H).

[0828] MS m / z (ESI): 209.3 [M+H] + .

[0829] Step c:

[0830] 6-Methoxy-7-methylindole-2,3-dione

[0831] At 0 °C, boron trifluoride diethyl ether (12.30 g, 86.67 mmol) was added to a tetrahydrofuran (300 mL) solution of compound Int 3-b (18.00 g, 86.45 mmol). The reaction mixture was stirred at 0 °C for 12 hours. After the reaction was completed, the mixture was brought to room temperature. The reaction mixture was then diluted with aqueous solution and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound Int 3-c (11.0 g, yield 66.6%).

[0832] 1H NMR (400MHz, CDCl3): δ8.35(s,1H),7.54(d,1H),6.55(d,1H),3.94(s,3H),2.08(s,3H). MS m / z(ESI): 192.3[M+H] + .

[0833] Step d:

[0834] 3-Cycloheptyl-3-hydroxy-6-methoxy-7-methylindole-2-one

[0835] Under nitrogen protection, a solution of cycloheptayl magnesium bromide (1 M in tetrahydrofuran, 7.85 mL, 7.85 mmol) was added to a tetrahydrofuran (25 mL) solution of compound Int 3-c (1.00 g, 5.23 mmol) at -78 °C, and stirring was continued for 45 minutes. After the reaction was completed, the mixture was brought to room temperature, and the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound Int 3-d (640 mg, yield 42.3%).

[0836] MS m / z (ESI): 272.4 [M+H-18] + .

[0837] Step e:

[0838] 3-Cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindole-2-one

[0839] A solution of compound Int 3-d (200 mg, 0.69 mmol), phenol (325 mg, 3.45 mmol), and p-toluenesulfonic acid (990 mg, 5.75 mmol) in 1,2-dichloroethane (10 mL) was stirred at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound Int 3-e (143 mg, yield 56.6%).

[0840] Step f:

[0841] 143.0 mg of compound Int 3-e was purified by preparative supercritical fluid chromatography under the following conditions: column: CHIRALPAK IC, 3×25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 55 mL / min; gradient: 35% B; detector: UV 254 nm; retention time 1: 2.28 min; retention time 2: 4.11 min.

[0842] The enantiomer with a relatively fast elution rate and a retention time of 2.28 min is compound Int 3-e-P1: (S)-3-cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindole-2-one (53.0 mg, ee value: 100.0%).

[0843] Int 3-e-P1: 1 H NMR (400MHz, CDCl3) δ7.52(s,1H),7.25(d,2H),7.08(d,1H),6.72(d,2H),6.56(d,1H),5.00(s,1H),3 .86(s,3H),2.62-2.55(m,1H),2.14(s,3H),1.75-1.65(m,2H),1.60-1.30(m,9H).1.00-0.80(m,1H).

[0844] MS m / z (ESI): 366.1 [M+H] + .

[0845] The enantiomer with a slower elution rate and a retention time of 4.11 min is compound Int 3-e-P2: (R)-3-cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindole-2-one (47.0 mg, ee value: 100.0%).

[0846] Int 3-e-P2: 1 H NMR(400MHz, CDCl3)δ7.76(s,1H),7.23(d,2H),7.07(d,1H),6.72(d,2H),6.56(d,1H),5.24(s,1H),3 .86(s,3H),2.62-2.55(m,1H),2.10(s,3H),1.75-1.65(m,2H),1.60-1.30(m,9H).1.00-0.80(m,1H).

[0847] MS m / z (ESI): 366.1 [M+H] + .

[0848] Step g:

[0849] 4-[(3S)-3-cycloheptyl-6-methoxy-7-methyl-2-oxo-1H-indol-3-yl]phenyl-2-(benzyloxy)acetic acid ester was added to a solution of compound Int 3-e-P1 (50 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol), and 4-dimethylaminopyridine (4.2 mg, 0.03 mmol) in dichloromethane (2 mL) with 2-(phenylmethoxy)acetic acid (27 mg, 0.16 mmol). The reaction mixture was stirred for 1 hour. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound Int 3-f (35 mg, yield 49.8%).

[0850] MS m / z (ESI): 512.1 [MH] + .

[0851] Step h:

[0852] 4-[(3S)-3-cycloheptayl-6-methoxy-7-methyl-2-oxo-1H-indol-3-yl]phenyl-2-hydroxyacetic acid ester was reacted under a hydrogen atmosphere by heating a 2 mL solution of compound Int 3-f (35 mg, 0.07 mmol) and palladium on carbon (7.25 mg) in tetrahydrofuran to 40 °C and stirring for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was diluted with 20 mL of water and extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to give compound 3 (6.7 mg, yield 23.2%).

[0853] 1 H NMR (400MHz, DMSO-d6): δ10.49(s,1H),7.35(d,2H),7.12-7.06(m,3H),6.63(d,1H),5.56(t,1H), 4.27(d,2H),3.79(s,3H),2.56-2.51(m,1H),2.06(s,3H),1.63-1.23(m,11H),0.91-0.83(m,1H).

[0854] MS m / z (ESI): 424.0 [M+H] + .

[0855] Synthesis of Compound 4 in Examples 1-4

[0856] Step a:

[0857] Under nitrogen protection, a mixture of compound Int 2-e (81 mg, 0.20 mmol), potassium N-aminomethyltrifluoroborate (139 mg, 0.59 mmol), cesium carbonate (255 mg, 0.78 mmol), and methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (Xphos Pd G3, 33 mg, 0.039 mmol) in 4.4 mL of 1,4-dioxane:water = 10:1 was heated to 90 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound Int 4-a (44 mg, yield 48.4%).

[0858] 1 H NMR (400MHz, DMSO-d6): δ10.35(s,1H),9.30(s,1H),7.25(t,1H),7.11-7.05(m,3H),6.88(d,1H),6.67( d,2H),4.12(d,2H),2.51-2.45(m,1H),2.14(s,3H),1.62-1.15(m,11H),1.41(s,9H),0.85-0.82(m,1H).

[0859] Step b:

[0860] (SR)-6-(aminomethyl)-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methylindole-2-one

[0861] A mixed solution (5 mL, dichloromethane:trifluoroacetic acid = 2:1) of compound Int 4-a (52 mg, 0.11 mmol) was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 8:1) to give compound 4 (30 mg, yield 73.5%).

[0862] 1 H NMR (400MHz, DMSO-d6): δ10.38(s,1H),9.32(s,1H),7.12-7.03(m,4H),6.67(d,2H),4.76(b rs,2H),3.81(s,2H),2.51-2.45(m,1H),2.19(s,3H),1.59-1.23(m,11H),0.89-0.79(m,1H). MS m / z(ESI): 365.1[M+H] + .

[0863] Synthesis of Compound 9 in Examples 1-5

[0864] Step a:

[0865] Non-1,8-dien-5-ol

[0866] Under a nitrogen atmosphere, a tetrahydrofuran solution (40 mL) of 4-bromobutene (6.65 g, 49.26 mmol) was added dropwise to a system containing magnesium powder (1.92 g, 78.98 mmol) and elemental iodine (150 mg, 0.59 mmol) at 0 °C. Then, ethyl formate (1.46 g, 19.71 mmol) was added dropwise to the system at the same temperature. The reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound Int 9-a (2.7 g, 97.7% yield).

[0867] 1H NMR (400MHz, CDCl3): δ5.82-5.72(m,2H),4.98(dd,2H),4.90(dd,2H),3.61-3.55(m,1H),2.19-2.01(m,4H),1.55-1.41(m,4H).

[0868] Step b:

[0869] 5-Ionon-1,8-diene

[0870] Under a nitrogen atmosphere, iodine (3.04 g, 11.98 mmol) was added to a tetrahydrofuran solution (40 mL) of compound Int 9-a (700 mg, 4.99 mmol), triphenylphosphine (3.14 g, 11.98 mmol), and 1H-imidazole (816 mg, 11.98 mmol) at 0 °C. The reaction mixture was then slowly brought to room temperature and stirred for 16 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium thiosulfate aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 99:1) to give compound Int 9-b (1.0 g, yield 80.1%).

[0871] 1 H NMR (400MHz, CDCl3): δ5.85-5.75(m,2H),5.10(dd,2H),5.03(dd,2H),4.13-4.08( m,1H),2.37-2.29(m,2H),2.25-2.15(m,2H),2.05-1.95(m,2H),1.85-1.75(m,2H).

[0872] Step c:

[0873] Non-1,8-dien-5-ylmagnesium iodide

[0874] In a nitrogen atmosphere, at 65°C, compound Int 9-b (300 mg, 1.20 mmol) was added to a tetrahydrofuran solution (1 mL) containing magnesium powder (274.6 mg, 11.30 mmol) and iodine (100 mg, 0.39 mmol). After the color of the reaction system disappeared, a tetrahydrofuran solution (4 mL) of compound Int 9-b (1.58 g, 6.32 mmol) was slowly added dropwise. The reaction system was stirred at 65°C for 2 hours and then cooled to room temperature to obtain a tetrahydrofuran solution of compound Int 9-c, which was then directly used for the next reaction.

[0875] Step d:

[0876] 6-Bromo-3-hydroxy-7-methyl-3-(non-1,8-dien-5-yl)indol-2-one

[0877] Under a nitrogen atmosphere, the above solution was added dropwise to a tetrahydrofuran solution (15 mL) of compound Int 2-c (180 mg, 0.75 mmol) at -78 °C. The reaction system was then slowly restored to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound Int 9-d (130 mg, yield 47.5%).

[0878] MS m / z (ESI): 364.1 [M+H] + .

[0879] Step e:

[0880] 6-Bromo-3-(cyclohept-4-en-1-yl)-3-hydroxy-7-methylindol-2-one

[0881] Under a nitrogen atmosphere, the above solution was added dropwise to a tetrahydrofuran solution (15 mL) of compound Int 2-c (180 mg, 0.75 mmol) at -78 °C. The reaction system was then slowly restored to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound Int 9-e.

[0882] MS m / z (ESI): 364.1 [M+H] + .

[0883] Step f:

[0884] 6-Bromo-3-(cyclohept-4-en-1-yl)-3-(4-hydroxyphenyl)-7-methylindol-2-one

[0885] Under a nitrogen atmosphere, a solution of compound Int 9-e (58 mg, 0.16 mmol) and phenylmethylene bis(tricyclohexylphosphine) ruthenium dichloride (Grubbs Catalyst, 6.6 mg, 0.008 mmol) in 1,2-dichloroethane (20 mL) was heated to 70 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound Int 9-f.

[0886] MS m / z (ESI): 336.1 [M+H] + .

[0887] Step g:

[0888] 3-(cyclohepta-4-en-1-yl)-6-(hydroxymethyl)-3-(4-hydroxyphenyl)-7-methylindole-2-one

[0889] Under a nitrogen atmosphere, diethylaminosulfur trifluoride (154 mg, 0.96 mmol) was added to a dichloromethane (5 mL) solution of compound Int 9-f (64 mg, 0.19 mmol) and phenol (180 mg, 1.91 mmol) at -78 °C, and stirring was continued for 1 hour. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1).

[0890] The crude product was then purified by preparative supercritical fluid chromatography under the following conditions: column: CHIRALPAK IC, 3×25cm, 5μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 55mL / min; gradient: 35% B; detector: UV 254nm; yielding compound 9: (S)-3-(cyclohept-4-en-1-yl)-6-(hydroxymethyl)-3-(4-hydroxyphenyl)-7-methylindole-2-one. The compounds of the typical drug D prepared in this example are shown in Table 5 below:

[0891] Table 5

[0892] Note: The compounds of drug D other than those in Examples 1-1 to 1-5 included in the table above were prepared in a manner similar to that in Examples 1-1 to 1-5. For example, referring to the preparation method of Example 1-1, compound 6 can be prepared by replacing 3-bromo-2-chloroaniline (CAS: 118804-39-0) with 3-bromo-2-fluoroaniline; referring to the preparation method of Example 1-1, compound 7 can be prepared by replacing 3-bromo-2-trifluoromethylaniline (CAS: 244246-71-7) with 3-bromo-2-fluoroaniline; referring to the preparation method of Example 1-1, compound 8 can be prepared by replacing 3-bromo-2-(difluoromethyl)aniline (1261849-45-9) with 3-bromo-2-fluoroaniline; referring to the preparation method of Example 1-2, compound 15 can be prepared by replacing phenol with 2-fluorophenol (CAS: 367-12-4) and p-toluenesulfonic acid with trifluoromethanesulfonic acid (CAS: 1493-13-6); referring to the preparation method of Example 1-4, compound 15 can be prepared by replacing Int 2-e with Int 1-e, and referring to...

[0893] Compound 39 can be prepared under the chiral preparation conditions of Examples 1-2.

[0894] Example 2 Preparation of LD compounds

[0895] Example 2-1 Synthesis of LD-Int1

[0896] Step a:

[0897] (9H-fluorene-9-yl)methyl-(S)-(2-((((3-cycloheptayl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindol-6-yl)methoxy)methyl)amino)-2-oxoethyl)carbamate

[0898] To a solution of compound 2-P1 (683 mg, 1.87 mmol) and methyl (2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)acetamido)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide)acetamide) 10 mL of tetrahydrofuran) was added, p-toluenesulfonic acid (162 mg, 0.94 mmol)). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether:tetrahydrofuran = 1:1) to give compound LD-Int 1-a (500 mg, yield 79.2%).

[0899] 1HNMR(400MHz,DMSO_d6): δ10.38(s,1H),9.31(s,1H),8.76(t,1H),7.89(d,2H) ,7.73(d,2H),7.61(t,1H),7.42(t,2H),7.33(t,2H),7.09(d,2H),7.06(d,1H) ,6.99(d,1H),7.67(d,2H),4.64(d,2H),4.44(s,2H),4.32-4.24(m,3H),3.67( d,2H),2.50-2.47(m,1H),2.15(s,3H),1.62-1.22(m,11H),0.87-0.80(m,1H).

[0900] MS m / z (ESI): 674.0 [M+H] + .

[0901] Step b:

[0902] (S)-2-amino-N-(((3-cycloheptayl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindol-6-yl)methoxy)methyl)acetamide

[0903] Hexahydropyridine (2.5 mL) was added to a solution of compound LD-Int 1-a (500 mg, 0.74 mmol) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by concentration under reduced pressure. The crude product was purified by reverse-phase silica gel column chromatography (water:acetonitrile = 95:5-65:35) to give compound LD-Int 1 (234 mg, yield 69.8%). MS m / z (ESI): 452.1 [M+H] + .

[0904] Example 2-2: Synthesis of LD-Int2

[0905] Step a:

[0906] tert-butyl((benzyloxy)carbonyl)glycylglycyl-L-phenylalanine ester

[0907] Under a nitrogen atmosphere and at 0 °C, N-benzyloxycarbonyl-glycine (3.10 g, 11.64 mmol) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.23 g, 11.64 mmol) and 2-hydroxypyridine-N-oxide (1.29 g, 11.64 mmol) in N,N-dimethylformamide (70 mL). The reaction system was stirred at 0 °C for 30 minutes. Then, N,N-diisopropylethylamine (3.13 g, 24.22 mmol) and L-phenylalanine tert-butyl hydrochloride (2.50 g, 9.70 mmol) were added. The reaction system was slowly restored to room temperature and stirred for 16.5 hours. After the reaction was complete, the reaction mixture was poured into an aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed successively with 1N hydrochloric acid aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound LD-Int 2-a (4.10 g, yield 90.0%).

[0908] 1 HNMR (400MHz, DMSO_d6): δ8.20(d,1H),8.09(t,1H),7.52(t,1H),7.37-7.20(m,10H),5. 04(s,2H),4.41-4.35(m,1H),3.74(d,2H),3.66(d,2H),2.98-2.90(m,2H),1.31(s,9H).

[0909] MS m / z (ESI): 470.0 [M+H] + .

[0910] Step b:

[0911] ((benzyloxy)carbonyl)glycylglycyl-L-phenylalanine

[0912] A mixture of trifluoroacetic acid and dichloromethane (5 mL, v / v = 1 / 1) of compound LD-Int 2-a (700 mg, 1.49 mmol) was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel column chromatography (dichloromethane:methanol = 9:1) to obtain compound LD-Int 2-b (492 mg, yield 79.8%).

[0913] 1HNMR(400MHz,DMSO_d6): δ12.75(br,1H),8.18(d,1H),8.06(t,1H),7.51(t,1H),7.37-7.1 8(m,10H),5.04(s,2H),4.41-4.41(m,1H),3.79-3.60(m,4H),3.05(dd,1H),2.86(dd,1H).

[0914] MS m / z (ESI): 414.0 [M+H] + .

[0915] Step c:

[0916] 4-O-4-phenylbut-2-en-2-yl(benzyloxycarbonyl)glycylglycyl-L-phenylalanine ester

[0917] A mixture of compound LD-Int 2-b (400 mg, 0.97 mmol) and 1-phenylbutane-2,3-dien-1-one (153.4 mg, 1.06 mmol) in dichloroethane (10 mL) and hexafluoroisopropanol (0.5 mL) was stirred at 25 °C for 20 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound LD-Int 2-c (395 mg, yield 73.2%).

[0918] MS m / z (ESI): 558.2 [M+H] + .

[0919] Step d:

[0920] Benzyl[(S)-9-benzyl-1-[(S)-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindol-6-yl]-5,8,11,14-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecan-15-yl]carbamate

[0921] A solution of compound LD-Int 2-c (280 mg, 0.50 mmol) and LD-Int 1 (226.8 mg, 0.50 mmol) in N,N-dimethylformamide (8 mL) was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reversed-phase silica gel column chromatography (water:acetonitrile = 95:5-55:45) to obtain compound LD-Int 2-d (370 mg, yield 87.0%).

[0922] 1HNMR (400MHz, DMSO_d6): δ10.38(s,1H),9.37(s,1H),8.72(t,1H),8.41(t,1H),8. 25(d,1H),8.09(t,1H),7.53(t,1H),7.35-6.99(m,14H),6.67(d,2H),5.02(s,2H) ,4.63(d,2H),4.54-4.49(m,1H),4.44(s,2H),3.82-3.57(m,6H),3.09(dd,1H),2. 84(dd,1H),2.50-2.47(m,1H),2.15(s,3H),1.62-1.23(m,11H),0.85-0.80(m,1H).

[0923] MS m / z (ESI): 846.9 [M+H] + .

[0924] Step e:

[0925] (S)-2-(2-(2-aminoacetamido)acetamido)-N-(2-((((S)-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindol-6-yl)methoxy)methyl)amino)-2-oxoethyl)-3-phenylpropionamide)

[0926] Under a hydrogen atmosphere, a mixed solution (15 mL, v / v = 10 / 1) of compound LD-Int 2-d (350 mg, 0.41 mmol), 1,1,2-trichloroethane (110.2 mg, 0.83 mmol), and palladium hydroxide / carbon catalyst (100.0 mg) in methanol and dichloromethane was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to obtain a crude product. The crude product was purified by reversed-phase silica gel column chromatography (water:acetonitrile = 95:5-60:40) to obtain compound LD-Int 2 (240 mg, yield 81.5%).

[0927] MS m / z (ESI): 713.0 [M+H] + .

[0928] Example 2-3 Synthesis of LD-Int3

[0929] Step a:

[0930] (2-Phenyl-4,5-dihydrooxazol-4,4-diyl)dimethylethanol

[0931] A methanol (150 mL) solution of benzonitrile (10.00 g, 96.97 mmol), 2-amino-2-(hydroxymethyl)propane-1,3-diol (58.75 g, 484.98 mmol), and sodium carbonate (10.28 g, 96.99 mmol) was heated to 50 °C and stirred for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound LD-Int 3-a (15.70 g, yield 78.1%).

[0932] 1 HNMR (400MHz, CDCl3): δ7.84-7.82(m,2H),7.47-7.42(m,1H),7.36-7.32(m,2H),4.38(s,2H),3.81(d,2H),3.66(d,2H),2.87(brs,2H).

[0933] Step b:

[0934] 4,4-Di(2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxanonatriacontyl)-2-phenyl-4,5-dihydrooxazole

[0935] Methylsulfonyl chloride (2.70 g, 23.57 mmol) was added to a toluene (100 mL) solution of methyl-PEG12-hydroxy (12.00 g, 21.40 mmol) and triethylamine (2.82 g, 27.87 mmol). The reaction system was heated to 40 °C and stirred for 2 hours. After the reaction was completed, the system was diluted with aqueous solution and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed successively with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude methyl-PEG12-methanesulfonate (13.60 g, yield 99.5%), which was directly used in the next reaction.

[0936] 1 HNMR (300MHz, CDCl3): δ4.39-4.35(m,2H), 3.77-3.74(m,2H), 3.67-3.62(m,42H), 3.55-3.37(m,2H), 3.37(s,3H), 3.07(s,3H).

[0937] Sodium hydride (60%, 0.56 g, 14.00 mmol) was added to a solution of compound LD-Int 3-a (1.20 g, 5.79 mmol) in N,N-dimethylformamide (20 mL), and the reaction mixture was stirred at room temperature for 20 minutes. Then, a solution of methyl-PEG12-methanesulfonate (10.00 g, 15.66 mmol) in N,N-dimethylformamide (30 mL) was added, and the reaction mixture was heated to 50 °C and stirred for 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed sequentially with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound LD-Int 3-b (6.18 g, yield 82.6%).

[0938] 1 HNMR (400MHz, CDCl3): δ8.01-7.96(m,2H),7.48-7.37(m,3H),4.40(s,2H),3.80-3.43(m,100H),3.36(s,6H).

[0939] MS m / z (ESI): 1292.4 [M+H] + .

[0940] Step c:

[0941] 40-Amino-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxa-tetra-nonadecanyl)-2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxa-tetra-41-ol

[0942] 40-amino-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxanonatriacontyl)-2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxahentetracontan-41-ol

[0943] The compound LD-Int 3-b (6.18 g, 4.78 mmol) was heated to 100 °C and stirred for 5 hours in a 6 M hydrochloric acid aqueous solution (70 mL). After the reaction was completed, the pH of the reaction system was adjusted to 10–12 with sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane (200 mL x 3). The combined organic layers were washed successively with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude LD-Int 3 (5.40 g, yield 93.6%), which was directly used in the next reaction.

[0944] 1 HNMR (400MHz, CDCl3): δ3.82-3.44 (m, 102H), 3.37 (s, 6H).

[0945] Examples 2-4: Synthesis of LD-Int4

[0946] Step a:

[0947] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxanonatetracontan-49-ylmethanesulfonate

[0948] Methylsulfonyl chloride (2.70 g, 23.57 mmol) was added to a toluene (20 mL) solution of methyl-PEG16-hydroxy (2.00 g, 2.71 mmol) and triethylamine (0.36 g, 3.56 mmol). The reaction system was heated to 40 °C and stirred for 2 hours. After the reaction was completed, the system was diluted with aqueous solution and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed successively with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude LD-Int 4-a (2.20 g, yield 99.5%), which was directly used in the next reaction.

[0949] 1 HNMR (300MHz, CDCl3): δ4.38-4.35(m,2H), 3.76-3.74(m,2H), 3.67-3.63(m,58H), 3.54-3.47(m,2H), 3.37(s,3H), 3.07(s,3H).

[0950] Step b:

[0951] 49-azido-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxanonatetracontane

[0952] A 20 mL ethanol solution of compound LD-Int 4-a (2.20 g, 2.70 mmol) and sodium azide (0.21 g, 3.23 mmol) was heated to 80 °C and slowly stirred for 16 hours. After the reaction was completed, the system was diluted with an aqueous solution and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed sequentially with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound LD-Int 4-b (1.84 g, yield 89.5%).

[0953] 1 HNMR (400MHz, CDCl3): δ3.68-3.61(m,60H), 3.55-3.62(m,2H), 3.40-3.37(m,5H).

[0954] Step c:

[0955] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxanonatetracontan-49-amine

[0956] At 0 °C, lithium aluminum hydride (91.66 mg, 2.42 mmol) was added to a tetrahydrofuran (20 mL) solution of compound LD-Int 4-b (1.84 g, 2.42 mmol). The reaction system was stirred at 0 °C for 2 hours. After the reaction was completed, the system was quenched with aqueous solution and the pH was adjusted to 12 with 30% sodium hydroxide aqueous solution. The system was then extracted with dichloromethane (100 mL x 3). The combined organic layers were washed successively with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude LD-Int 4-c (1.50 g, yield 84.4%).

[0957] 1HNMR (400MHz, CDCl3): δ3.64-3.63(m,58H), 3.54-3.47(m,4H), 3.37(s,3H), 2.85(t,2H). MS m / z(ESI):736.0[M+H] + .

[0958] Step d:

[0959] 5-(tert-butyl)-1-(4-oxo-4-phenylbut-2-en-2-yl)-(benzyloxy)carbonyl)-L-glutamic acid ester

[0960] A solution of N-benzyloxycarbonyl-L-glutamic acid-5-tert-butyl ester (900 mg, 2.67 mmol) and 1-phenylbutane-2,3-dien-1-one (384.6 mg, 2.67 mmol) in dichloroethane (20 mL) was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound LD-Int 4-d (798 mg, yield 62.1%).

[0961] MS m / z (ESI): 499.0 [M+18] + .

[0962] Step e:

[0963] tert-Butyl(S)-52-(((benzyloxy)carbonyl)amino)-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecoxa-50-azapentadecane-55-ester

[0964] tert-butyl(S)-52-(((benzyloxy)carbonyl)amino)-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-50-azapentapentacontan-55-oate

[0965] A solution of compounds LD-Int 4-d (580 mg, 1.20 mmol) and LD-Int 4-c (886.4 mg, 1.20 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 94:6) to obtain compound LD-Int 4-e (1100 mg, yield 86.5%).

[0966] 1 HNMR (400MHz, CDCl3): δ7.34-7.29(m,5H),6.80(s,1H),5.75(d,1H),5.09(s,2H),4.22-4.09(m,1H),3 .82-3.44(m,64H),3.38(s,3H),2.41-2.25(m,2H),2.11-2.06(m,1H),1.93-1.87(m,1H),1.43(s,9H).

[0967] MS m / z (ESI): 1072.1 [M+18] + .

[0968] Step f:

[0969] (S)-52-amino-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecoxa-50-azapentadecane-55-olate tert-butyl ester

[0970] tert-butyl(S)-52-amino-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-50-azapentapentacontan-55-oate

[0971] Under a hydrogen atmosphere, a methanol solution (15 mL) of compound LD-Int 4-e (1.10 g, 1.04 mmol), 1,1,2-trichloroethane (0.27 g, 2.02 mmol), and palladium hydroxide / carbon catalyst (0.20 g) was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated to obtain crude LD-Int4 (0.95 g, 99.0% yield), which was directly used in the next reaction step.

[0972] MS m / z (ESI): 922.0 [M+H] + .

[0973] Examples 2-5: Synthesis of LD-Int5

[0974] Step a:

[0975] 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-ylmethanesulfonate

[0976] 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl methanesulfonate

[0977] Methylsulfonyl chloride (1.12 g, 9.78 mmol) was added to a toluene (50 mL) solution of methyl-PEG12-hydroxy (5.00 g, 8.92 mmol) and triethylamine (1.17 g, 11.57 mmol). The reaction system was heated to 40 °C and stirred for 2 hours. After the reaction was completed, the system was diluted with aqueous solution and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed successively with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude LD-Int 5-a (5.60 g, yield 98.3%), which was directly used in the next reaction.

[0978] 1 HNMR (400MHz, CDCl3): δ4.32-4.30(m,2H), 3.71-3.68(m,2H), 3.61-3.56(m,42H), 3.49-3.46(m,2H), 3.31(s,3H), 3.02(s,3H).

[0979] Step b:

[0980] 37-Azide-2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane

[0981] 37-azido-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan

[0982] A solution of compound LD-Int 5-a (5.60 g, 8.77 mmol) and sodium azide (0.69 g, 10.61 mmol) in ethanol (60 mL) was heated to 80 °C and slowly stirred for 16 hours. After the reaction was completed, the system was diluted with aqueous solution and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed successively with aqueous solution and saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound LD-Int 5-b (5.00 g, yield 97.4%).

[0983] 1HNMR (400MHz, CDCl3): δ3.67-3.63(m,44H), 3.54-3.52(m,2H), 3.38-3.36(m,5H).

[0984] Step c:

[0985] 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-amine

[0986] 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-amine

[0987] At 0 °C, lithium aluminum hydride (0.33 g, 8.69 mmol) was added to a tetrahydrofuran (50 mL) solution of compound LD-Int 5-b (5.00 g, 8.54 mmol). The reaction system was brought back to room temperature and stirred for 2 hours. After the reaction was completed, the system was quenched with aqueous solution and the pH was adjusted to 12 with 30% sodium hydroxide aqueous solution. The system was then extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with aqueous solution and saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to obtain crude LD-Int 5-c (4.60 g, yield 96.3%).

[0988] 1 HNMR (400MHz, CDCl3): δ3.58-3.54(m,42H), 3.49-3.44(m,4H), 3.31(s,3H), 2.81(t,2H). MS m / z(ESI): 560.1[M+H] + .

[0989] Step d:

[0990] (S)-40-(((benzyloxy)carbonyl)amino)-39-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecoxa-38-azatetrazane-43-acid tert-butyl ester

[0991] tert-butyl(S)-40-(((benzyloxy)carbonyl)amino)-39-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azatritetracontan-43-oate

[0992] A solution of compounds LD-Int 4-d (600 mg, 1.25 mmol) and LD-Int 5-c (697.4 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 94:6) to obtain compound LD-Int 5-d (875 mg, yield 79.9%).

[0993] 1 HNMR (400MHz, CDCl3): δ7.38-7.27(m,5H),6.76(t,1H),5.73(d,1H),5.10(s,2H),4.23-4.18(m,1H),3 .81-3.44(m,48H),3.38(s,3H),2.43-2.25(m,2H),2.13-2.04(m,1H),1.95-1.87(m,1H),1.43(s,9H).

[0994] MS m / z (ESI): 879.6 [M+H] + .

[0995] Step e:

[0996] (S)-40-amino-39-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azatritetracontan-43-oate tert-butyl(S)-40-amino-39-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azatritetracontan-43-oate

[0997] Under a hydrogen atmosphere, a methanol solution (15 mL) of compound LD-Int 5-d (875 mg, 1.00 mmol), 1,1,2-trichloroethane (265.6 mg, 1.99 mmol), and palladium hydroxide / carbon catalyst (0.15 g) was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated to obtain crude LD-Int5 (719.2 mg, yield 97.0%), which was directly used in the next reaction step.

[0998] MS m / z (ESI): 745.2 [M+H] + .

[0999] Examples 2-6: Synthesis of compound LD-1

[1000] Solid-phase synthesis steps:

[1001] Step a:

[1002] N,N-diisopropylethylamine (4.33 g, 33.50 mmol) was added to a solution of 2-chlorotriphenylmethyl chloride resin (2-CTC Resin, 4.20 g, 1.0 mmol / g, 4.20 mmol) and Fmoc-L-phenylalanine (6.51 g, 16.80 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, dichloromethane was removed by vacuum filtration. Then, methanol (40 mL) was added to the resin, and nitrogen gas was bubbled into the mixture and stirred for 30 min. The methanol was then removed by vacuum filtration. The resin was then washed with dichloromethane and methanol alternately, and this process was repeated 5 times.

[1003] A solution of N,N-dimethylformamide (40 mL) containing 50% piperidine was added to the above system, and nitrogen gas was bubbled into the mixture and stirred for 2 hours. After the reaction was completed, the reaction system was filtered under reduced pressure, and the filter cake was washed with dichloromethane and methanol in turn, and this process was repeated 5 times alternately to finally obtain compound LD-1a.

[1004] Step b:

[1005] Under a nitrogen atmosphere, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP, 6.55 g, 12.59 mmol), Fmoc-glycyl-glycine (4.46 g, 12.59 mmol), and N,N-diisopropylethylamine (3.25 g, 25.15 mmol) were added to a 40 mL solution of N,N-dimethylformamide containing compound LD-1a. The mixture was then stirred for 3 hours at room temperature under nitrogen atmosphere. After the reaction was complete, the reaction system was filtered under reduced pressure, and the filter cake was washed sequentially with dichloromethane and methanol. This process was repeated five times alternately to obtain compound LD-1b.

[1006] Step c:

[1007] A solution of N,N-dimethylformamide (40 mL) containing 50% piperidine was added to the above system, and nitrogen gas was bubbled into the mixture and stirred for 2 hours. After the reaction was completed, the reaction system was filtered under reduced pressure, and the filter cake was washed with dichloromethane and methanol in turn, and this process was repeated 5 times alternately to finally obtain compound LD-1c.

[1008] Step d:

[1009] To a solution of compound LD-1c and succinimide 6-(maleimino)hexanoate in N,N-dimethylformamide (30 mL), N,N-diisopropylethylamine (1.63 g, 12.58 mmol) was added, and the mixture was stirred for 3 hours at room temperature under nitrogen atmosphere. After the reaction was complete, the reaction system was filtered under reduced pressure, and the filter cake was washed sequentially with dichloromethane and methanol, alternatingly, five times to obtain the crude product.

[1010] Add lysis buffer (30% hexafluoroisopropanol / 70% dichloromethane) (40 mL) to the crude product, and stir the mixture under nitrogen atmosphere for 10 minutes at room temperature. Then filter the reaction mixture under reduced pressure, dissolve the filter cake in lysis buffer (30% hexafluoroisopropanol / 70% dichloromethane) (40 mL), and continue stirring under nitrogen atmosphere for 10 minutes at room temperature. Filter the reaction mixture under reduced pressure again, combine the filtrates, and concentrate to obtain the crude product. The obtained crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol:acetic acid = 90:10:0.1) to obtain compound LD-1d (1.4 g, yield 22.1%).

[1011] 1 HNMR(400MHz,DMSO_d6): δ12.82(br,1H),8.09-7.99(m,3H),7.28-7.19(m,5H),7.00(s,2H),4.42-4.37(m,1H), 3.76-3.60(m,4H),3.37(t,2H),3.05(dd,1H),2.88(dd,1H),2.11(t,2H),1.52-1.43(m,4H),1.23-1.17(m,2H).

[1012] MS m / z (ESI): 473.3 [M+H] + .

[1013] Step e:

[1014] N-((S)-9-benzyl-1-((S)-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindol-6-yl)-5,8,11,14-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecan-15-yl)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexamethylene

[1015] Under a nitrogen atmosphere and at 0 °C, compound LD-1d (196.8 mg, 0.42 mmol) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79.8 mg, 0.42 mmol) and 2-hydroxypyridine-N-oxide (46.3 mg, 0.42 mmol) in N,N-dimethylformamide (6 mL). The reaction mixture was stirred at 0 °C for 30 min. Subsequently, N,N-diisopropylethylamine (80.7 mg, 0.62 mmol) and LD-Int 1 (94.0 mg, 0.21 mmol) were added, and the reaction mixture was stirred at 0 °C for another 2 h. After the reaction was completed, methanol (10 mL) was added to dilute the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel column chromatography (water:acetonitrile = 95:5-60:40) to give compound LD-1 (81.0 mg, yield 42.9%).

[1016] 1 HNMR(400MHz,DMSO_d6): δ10.37(s,1H),9.30(s,1H),8.61(t,1H),8.33(t,1H),8.13( d,1H),8.07(t,1H),8.02(t,1H),7.28-6.98(m,11H),6.66(d,2H),4.63(d,2H),4.54- 4.48(m,1H),4.44(s,2H),3.81-3.56(m,6H),3.36(t,2H),3.07(dd,1H),2.82(dd,1H) ,2.50-2.47(m,1H),2.15(s,3H),2.10(t,2H),1.62-1.14(m,17H),0.85-0.80(m,1H).

[1017] MS m / z (ESI): 906.4 [M+H] + .

[1018] Examples 2-7: Synthesis of compound LD-2

[1019] Step a:

[1020] 3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)propamido)tert-butyl propionate

[1021] A solution of tert-butyl 3-aminopropionate hydrochloride (2.50 g, 13.76 mmol), hydroxysuccinimide 3-maleimide propionate (3.85 g, 14.46 mmol), and N,N-diisopropylethylamine (3.56 g, 27.55 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed sequentially with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound LD-2a (3.85 g, 94.4% yield).

[1022] 1 HNMR (300MHz, CDCl3): δ6.68(s,2H),6.22(brs,1H),3.81(t,2H),3.46-3.40(m,2H),2.50-2.39(m,4H),1.44(s,9H).

[1023] Step b:

[1024] 3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)propamido)propionic acid

[1025] Trifluoroacetic acid (10 mL) was added to a dichloromethane (50 mL) solution of compound LD-2a (3.85 g, 12.99 mmol), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound LD-2b (2.60 g, yield 83.3%).

[1026] 1 HNMR (400MHz, DMSO_d6): δ12.17(brs,1H),8.02(t,1H),6.99(s,2H),3.60-3.56(m,2H),3.22-3.15(m,2H),2.34-2.28(m,4H).

[1027] MS m / z (ESI): 241.0 [M+H] + .

[1028] Step c:

[1029] 2,5-Dioxopyrrolidone-1-yl-3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)propionamido)propionate

[1030] Compound LD-2b (1.72 g, 7.16 mmol), N-hydroxysuccinimide (0.95 g, 8.25 mmol), 4-dimethylaminopyridine (0.04 g, 0.33 mmol), and N,N'-dicyclohexylcarbodiimide (1.70 g, 8.24 mmol) were reacted in dichloromethane (60 mL) and stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound LD-2c (1.01 g, yield 41.8%).

[1031] 1 HNMR (400MHz, CDCl3): δ6.68(s,2H),6.47(br,1H),3.85-3.81(m,2H),3.65-3.61(m,2H),2.91-2.85(m,4H),2.81(t,2H),2.52(t,2H).

[1032] MS m / z (ESI): 338.2 [M+H] + .

[1033] Step d:

[1034] 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-N-(40-(hydroxymethyl)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxanonadecane)-42-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxa-41-azatetratetradecane-44-yl)propionamide

[1035] 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(40-(hydroxymethyl)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tridecao xanonatriacontyl)-42-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxa-41-azatetratetracontan-44-yl)propanamide

[1036] LD-Int3 (4.00 g, 3.32 mmol) and compound LD-2c (1.45 g, 4.30 mmol) were reacted in a mixture of dichloromethane and tetrahydrofuran (30 mL, v / v = 1 / 2) and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was purified sequentially by reversed-phase silica gel column chromatography (water:acetonitrile = 95:5-65:35) and rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound LD-2d (3.10 g, yield 65.4%).

[1037] 1 HNMR (400MHz, CDCl3): δ6.91(br,1H),6.74(s,1H),6.70(s,2H),3.84-3.41(m,107H),3.36(s,6H),2.44(t,2H),2.34(t,2H).

[1038] MS m / z (ESI): 1428.7 [M+H] + .

[1039] Step e:

[1040] 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)propamido)propamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxanonadecane)-43-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,42-tetradecanooxa-44-azaheptadecane-47-tert-butyl ester

[1041] tert-butyl 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)propanamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-t ridecaoxanonatriacontyl)-43-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,42-tetradecaoxa-44-azaheptatetracontan-47-oate

[1042] Under a nitrogen atmosphere, a solution of compound LD-2d (3.00 g, 2.10 mmol), tert-butyl 3-isocyanate propionate (1.80 g, 10.51 mmol), and dibutyltin dilaurate (0.13 g, 0.21 mmol) in toluene (20 mL) was heated to 80 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase silica gel column chromatography (aqueous solution: acetonitrile = 95:5-65:35) to give compound LD-2e (3.10 g, yield 92.3%).

[1043] 1 HNMR (400MHz, CDCl3): δ6.94(br,1H),6.71(s,2H),6.58(s,1H),5.45(br,1H),4.37(s ,2H),3.85-3.38(m,106H),3.36(s,6H),2.47-2.42(m,4H),2.27(t,2H),1.45(s,9H).

[1044] MS m / z (ESI): 1600.8 [M+H] + .

[1045] Step f:

[1046] 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)propamido)propamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxanonadecane)-43-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,42-tetradecoxa-44-azaheptadecane-47-acid

[1047] 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)propanamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-t ridecaoxanonatriacontyl)-43-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,42-tetradecaoxa-44-azaheptatetracontan-47-oic acid

[1048] A mixture of trifluoroacetic acid and dichloromethane (6 mL, v / v = 2 / 1) of compound LD-2e (1.60 g, 1.00 mmol) was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase silica gel column chromatography (dichloromethane:methanol = 98:2-80:20) to give compound LD-2f (0.95 g, yield 61.5%).

[1049] 1 HNMR(400MHz,DMSO_d6): δ7.91(t,1H),7.35(s,1H),7.13(t,1H),7.00(s,2H),4.15(s,2H), 3.69-3.31(m,103H),3.24(s,6H),3.19-3.12(m,4H),2.37(t,2H),2.30(t,2H),2.21(t,2H).

[1050] MS m / z (ESI): 1543.7 [M+H] + .

[1051] Step g:

[1052] 2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propamido)propamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxanonadecane)-43-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,42-tetradecoxa-44-azaheptadecane-47-ester 2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propa-namido)propanamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-t ridecaoxanonatriacontyl)-43-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,42-tetradecaoxa-44-azaheptatetracontan-47-oate

[1053] Under a nitrogen atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.3 mg, 0.26 mmol) and 4-dimethylaminopyridine (4.3 mg, 0.04 mmol) were added to a dichloromethane (3 mL) solution of compound LD-2f (270.0 mg, 0.17 mmol) and N-hydroxysuccinimide (30.2 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 3.5 hours. After the reaction was complete, the reaction mixture was diluted with aqueous solution and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed sequentially with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane:methanol = 98:2-80:20) to give compound LD-2g (170 mg, yield 59.3%).

[1054] MS m / z (ESI): 821.4 [1 / 2M+H] + .

[1055] Step h:

[1056] 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)propamido)propamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxanonadecane)-2,5,8,11,14,17,20,23,26,29,32,35,38-tetraoxatetracosan-41-yl((S)-9- Benzyl-1-((S)-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindol-6-yl)-5,8,11,14,17-pentoxo-2-oxa-4,7,10,13,16-pentazanonadecan-19-yl)carbamate 40-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanami do)propanamido)-40-(2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxanonatriacontyl)-2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxahentetracontan-41-yl((S) -9-benzyl-1-((S)-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methyl-2-oxoindolin-6-yl)-5,8,11,14,17-pentaoxo-2-oxa-4,7,10,13,16-pentaazanonadecan-19-yl)carbamate

[1057] The compound LD-2 g (170.7 mg, 0.10 mmol), LD-Int 2 (65.0 mg, 0.09 mmol), and N,N-diisopropylethylamine (22.4 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) were stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase silica gel column chromatography (dichloromethane:methanol = 98:2-80:20) and high performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to give compound LD-2 (50.0 mg, yield 24.5%).

[1058] 1HNMR (400MHz, DMSO_d6): δ10.38(s,1H),9.97(brs,1H),8.66-8.60(m,1H),8.38-8.33(m,1H),8. 21-8.04(m,3H),7.91-7.87(m,1H),7.35-6.98(m,13H),6.69-6.65(m,2H),4.64(d,2H),4.55-4. 48(m,1H,)4.44(s,2H),4.15(s,2H),3.81-3.12((m,112H),3.24(s,6H),3.07(dd,1H),2.82(dd, 1H),2.50-2.44(m,1H),2.39-2.19((m,6H),2.16(s,3H),1.62-1.21(m,11H),0.87-0.81(m,1H).

[1059] MS m / z (ESI): 2238.1 [M+H] + .

[1060] Examples 2-8: Synthesis of compound LD-3

[1061] Step a:

[1062] (S)-52-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-50-azapentapentacontan-55-oate tert-butyl(S)-52-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-50-azapentapentacontan-55-oate

[1063] N,N-diisopropylethylamine (0.26 g, 2.01 mmol) was added to a solution of LD-Int 4 (1.00 g, 1.09 mmol) and succinimide 6-(maleimide)hexanoate (0.37 g, 1.20 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was subjected to reversed-phase silica gel column chromatography (aqueous solution: acetonitrile = 95:5-70:30) to give compound LD-3a (748 mg, yield 61.8%).

[1064] 1 HNMR (400MHz, CDCl3): δ7.16(t,1H),6.69(s,2H),6.53(d,1H),4.46-4.41(m,1H),3.82-3.44(m,66H),3.38(s,3 H),2.41-2.17(m,4H),2.10-2.01(m,1H),1.94-1.86(m,1H),1.69-1.55(m,4H),1.44(s,9H),1.34-1.25(m,2H).

[1065] MS m / z (ESI): 1131.1 [M+18] + .

[1066] Step b:

[1067] (S)-52-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-51-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-50-azapentapentacontan-55-oic acid

[1068] A mixed solution (10 mL, v / v = 1 / 1) of compound LD-3a (740 mg, 0.66 mmol) in dichloromethane and trifluoroacetic acid was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with aqueous solution and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed sequentially with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to give compound LD-3b (625 mg, yield 88.9%).

[1069] 1 HNMR (400MHz, CDCl3): δ7.12(t,1H),6.75(d,1H),6.70(s,2H),4.56-4.53(m,1H),3.66-3.43(m,66H), 3.38(s,3H),2.51-2.35(m,2H),2.21(t,2H),2.09-1.94(m,2H),1.67-1.56(m,4H),1.34-1.28(m,2H).

[1070] MS m / z (...

Claims

1. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, characterized in that, The ligand-drug conjugate has a structure shown in Formula (I): B#—(L—D)n Formula (I) B# is a ligand that binds to a target; n is an average drug ligand coupling ratio, n is an integer or a decimal number from 1 to 16; L is a linking unit; D is a drug having a structure represented by formula (IV): wherein, R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 2 and R 3 are the same or different and each is independently selected from a hydrogen atom and a halogen; R 4 selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 5 selected from a hydrogen atom and -C(O)CH2OH; X is selected from O, S and NH; and the wavy line represents a bond connecting L and D.

2. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; preferably, said R 11 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl; more preferably, said R 1 selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl; even more preferably, said R 1 is F or -CH3; still more preferably, said R 1 is F; or, still more preferably, said R 1 is -CH3.

3. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F, CI and Br; preferably, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F and CI; more preferably, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom and F; even more preferably, said R 2 and R 3 are both a hydrogen atom; or, even more preferably, said R 2 and R 3 one is a hydrogen atom and the other is F.

4. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, said R 4 is selected from the group consisting of a hydrogen atom, a halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; preferably, said R 4 is selected from the group consisting of a hydrogen atom, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl; more preferably, said R 4 is selected from the group consisting of a hydrogen atom, F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl; even more preferably, said R 4 is a hydrogen atom or F; even more preferably, said R 4 is a hydrogen atom.

5. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, said R 5 is a hydrogen atom; or, in some other embodiments of the compounds of Formula (I), said R 5 is -C(O)CH2OH.

6. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein, The X is -OH or -SH; or, preferably, the X is -NH2; or, preferably, the X is -OH; or, preferably, the X is -SH.

7. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F and Cl1, said R 5 is a hydrogen atom or -C(O)CH2OH; preferably, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom and F, said R 5 is a hydrogen atom; or, preferably, said R 2 is a hydrogen atom or F, said R 3 is a hydrogen atom, said R 5 is a hydrogen atom; or, preferably, said R 2 , R 3 and R 5 are all hydrogen atoms.

8. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, said R 1 selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl, said R 4 is selected from the group consisting of hydrogen atom, F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl, said X is selected from the group consisting of -OH, -SH and -NH2; preferably, said R 1 is selected from the group consisting of F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl, said R 4 is a hydrogen atom or F, said X is -OH or -SH; more preferably, said R 1 is selected from the group consisting of F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl, said R 4 is a hydrogen atom, said X is -OH; more preferably, said R 1 is F or -CH3, said R 4 is a hydrogen atom, said X is -OH.

9. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, characterized in that The ligand-drug conjugate has a structure shown in Formula (I): B#—(L—D)n Formula (I) B# is a ligand that binds to a target; n is an average drug ligand coupling ratio, n is an integer or a decimal number from 1 to 16; L is a linking unit; D is a drug having a structure according to Formula (II) or Formula (II-S): wherein, R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 2 selected from a hydrogen atom and a halogen; and the wavy line represents a bond connecting L and D.

10. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 9, wherein said R 2 is selected from the group consisting of a hydrogen atom, F, Cl and Br; Preferably, said R 2 is selected from a hydrogen atom, F and Cl; More preferably, said R 2 is selected from a hydrogen atom and F; Further preferably, said R 2 is a hydrogen atom.

11. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 9 or 10, characterized in that, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; Preferably, said R 1 selected from F, CI, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl; More preferably, said R 1 selected from F, CI, -CH3, -CH2F, -CHF2, -CF3, and vinyl; Further preferably, R 1 is F or -CH3; More preferably, said R 1 is F; More preferably, said R 1 is -CH3.

12. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 9-11, wherein, The D has a structure represented by Formula (III) or Formula (III-S): wherein, R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl.

13. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 12, wherein said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; Preferably, said R 1 selected from F, CI, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl; More preferably, said R 1 is selected from F, CI, -CH3, -CH2F, -CHF2, -CF3, and vinyl; Further preferably, R 1 is F or -CH3; More preferably, said R 1 is F; More preferably, said R 1 is -CH3.

14. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein, D is selected from the following structures:

15. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein, The L has the following structure: —L4—L3—L2—L1—; wherein L1 is absent or is a self-cleavage unit, L1 is connected to D; L2 is absent or is a conditionally cleavable unit; L3 is absent or is a hydrophilic unit; L4 is a ligand linking unit, L4 is connected to B#.

16. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 15, wherein said L4 is selected from: wherein X is -(C(R 4a )(R 4b )) m -, m is an integer > 1; Y is -C(=O)-; position 1 is attached to the ligand and position 2 is attached to L3; each of the 0 or more methylene units of X is independently optionally replaced with -N(R 4c )C(=O)-, -C(=O)N(R 4c )-, -NR 4c -, -(OCH2CH2) m1 -O-, -O-, -S-, -SO-, -SO2-, -N(R 4c )SO2-, -SO2N(R 4c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=S)-, -C(=NR 4c )-, -C=C-, -N=N-, -C=N-, or -N=C-; m1 is an integer > 1; each R 4a , R 4b , R 4c is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR 4 , -SR 4 , -(CH2CH2O) m2 -R 4 , -(CH2) m3 NH(CH2CH2O) m4 R 4 , -(CH2) m3 NH(CH2) m4 R 4 , -(CH2) m2 N(R 4d )(R 4e ), -(CH2) m2 C(O)R 4 , -(CH2) m2 CO2R 4 , -C(O)CH2C(O)R 4 , -S(O)R 4 , -S(O)2R 4 , -C(O)N(R 4d )(R 4e ), -SO2N(R 4d )(R 4e ), -OC(O)R 4 , -N(R)SO2R 4 , or C 1-6 alkyl; wherein each R 4 R 4d R 4e each independently is 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, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy; m2 is an integer ≥ 0, m3 is an integer ≥ 0, m4 is an integer ≥ 0; the L3 is absent or is s is an integer > 1, 1 position is attached to L4, 2 position is attached to L2; each of the 0 or more methylene units of L3 is independently optionally substituted with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, -O-, -S-, -SO-, -SO2-, -N(R 3c )SO2-, -SO2N(R 3c )-, -C(=S)-, -C(=NR 3c )-, -C=C-, -N=N-, -C=N-, or -N=C- instead; each R 3a , R 3b , R 3c is independently hydrogen, protium, deuterium, tritium, halogen, -OR 3 , -SR 3 , -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 R 3 ; wherein each R 3 is independently hydrogen, protium, deuterium, tritium, or C 1-6 1-6 alkyl; s1 is an integer ≥ 0, s2 is an integer ≥ 0; L2 is absent or selected from an amino acid, a peptide consisting of 2-10 amino acids, or an oligosaccharide; said amino acid is selected from a natural amino acid residue, a non-natural amino acid residue, or a stereoisomer thereof; when said amino acid residue is Lys, the side chain amino of said Lys is optionally substituted with 1 or 2 C 1-6 alkyl groups; preferably, when said amino acid residue is Lys, the side chain amino of said Lys is optionally substituted with 1 or 2 C 1-3 alkyl groups; more preferably, when said amino acid residue is Lys, the side chain amino of said Lys is optionally substituted with 2 ethyl groups or 2 n-propyl groups; said L1is absent or selected from the group consisting of: wherein 1 is connected to L2, and 2 is connected to D.

17. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 15 or 16, characterized in that, said L4 is selected from the group consisting of: Where X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 10; Y is -C(=O)-; position 1 is connected to the ligand, position 2 is connected to L3; 0 or more methylene units of X are independently and arbitrarily coupled to -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or substituted; m1 is an integer from 1 to 12; each R 4a , R 4b , R 4c each independently is hydrogen, protium, deuterium, tritium, -(CH2CH2O) m2 - R 4 , -(CH2) m3 NH(CH2CH2O) m4 R 4 , -(CH2) m3 NH(CH2) m4 R 4 or C 1-6 alkyl; wherein each R 4 independently is hydrogen, protium, deuterium, tritium, halogen, -CO2H, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, or haloC 1-6 alkoxy; m2 is an integer from 0 to 20, m3 is an integer from 0 to 20, and m4 is an integer from 0 to 20.

18. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 16 or 17, characterized in that, each R 4a and R 4b are each independently hydrogen, deuterium, -(CH2CH2O) m2 -R 4 , -(CH2) m3 NH(CH2CH2O) m4 R 4 or -(CH2) m3 NH(CH2) m4 R 4 ; Preferably, R 4a , R 4b are each hydrogen; or R 4a and R 4b where one is hydrogen and the other is -(CH2CH20) m2 R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 or -(CH2) m3 NH(CH2) m4 R 4 .

19. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-18, wherein, Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 alkyl; Preferably, each R 4c each independently is hydrogen, deuterium, -(CH2CH20)n- m2 -R 4 , -CH3or -C2H5; More preferably, R 4c is hydrogen; More preferably, R 4c is -(CH2CH2O) m2 -R 4 ; More preferably, R 4c is -CH3.

20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-19, wherein, m is an integer from 1 to 8; Preferably, m is an integer from 1 to 6; More preferably, m is an integer from 1 to 5.

21. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-20, wherein, m1 is an integer from 1 to 8; Preferably, m1 is an integer from 1 to 6; More preferably, m1 is an integer from 1 to 4; More preferably, m1 is 1.

22. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-21, wherein, m2 is an integer from 1 to 20; Preferably, m2 is an integer from 8 to 20; More preferably, m2 is an integer from 12 to 18; More preferably, m2 is 16.

23. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-22, wherein, m3 is an integer from 0 to 8; Preferably, m3 is an integer from 1 to 6; More preferably, m3 is an integer from 1 to 3; More preferably, m3 is 1.

24. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-23, wherein m4 is an integer from 0 to 8; Preferably, m4 is an integer from 1 to 6; More preferably, m4 is an integer from 1 to 3; More preferably, m4 is 1; More preferably, m4 is 2.

25. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-24, wherein Each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; Preferably, each R 4 is independently hydrogen, deuterium, halogen, -CO2H, -CH3, or -OCH3; More preferably, each R 4 independently -CO2H, -CH3, or -OCH3; More preferably, R 4 -CO2H; More preferably, R 4 is -CH3; More preferably, R 4 is -OCH3.

26. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-25, wherein, The L4 is selected from: wherein X is -(C(R 4a )(R 4b )) m -, m is an integer from 1 to 8; Y is -C(=O)-; the 1 position is attached to the ligand and the 2 position is attached to L3; each of the 0 or 1 methylene units of X is independently optionally replaced with -N(R 4c )C(=O)-, -C(=O)N(R 4c )-, -NR 4c -, -(OCH2CH2) m1 -O-, or ; m1 is an integer from 1 to 8; each of R 4a and R 4b is independently hydrogen, deuterium, -(CH2CH2O) m2 -R 4 , -(CH2) m3 NH(CH2CH2O) m4 R 4 , or -(CH2) m3 NH(CH2) m4 R 4 ; each R 4c is independently hydrogen, deuterium, -(CH2CH2O) m2 -R 4 , or C 1-6 alkyl; wherein each R 4 is independently hydrogen, -CO2H, or C 1-6 alkyl; m2 is an integer from 1 to 20, m3 is an integer from 0 to 8, and m4 is an integer from 0 to 8.

27. The ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 16-26, wherein, said L4 is selected from: wherein X is -(C(R 4a )(R 4b )) m -; m is an integer from 1 to 5; Y is -C(=O)-; position 1 is attached to the ligand and position 2 is attached to L3; each of the 0 or 1 methylene units of X is independently optionally replaced with -N(R 4c )C(=O)-, -C(=O)N(R 4c )-, -NR 4c -, -(OCH2CH2) m1 -O-, or ; m1 is an integer from 1 to 4; each R 4a and R 4b is independently hydrogen, deuterium, -(CH2CH2O) m2 -R 4 , -(CH2) m3 NH(CH2CH2O) m4 R 4 , or -(CH2) m3 NH(CH2) m4 R 4 ; each R 4c is independently hydrogen, deuterium, -(CH2CH2O) m2 -R 4 , or C 1-6 alkyl; wherein each R 4 is independently hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; m2 is an integer from 12 to 18, m3 is an integer from 1 to 3, and m4 is an integer from 1 to 3.

28. The ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 16-27, wherein, The L4 is selected from:

29. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-28, wherein, said L3 is s is an integer from 1 to 10; 1 position is attached to L4 and 2 position is attached to L2; each of the 0 or more methylene units of L3 is independently optionally replaced with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, or -O-; each R 3a , R 3b , R 3c is independently hydrogen, protium, deuterium, tritium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; wherein each R 3 is independently hydrogen, protium, deuterium, tritium, or C 1-6 alkyl; s1 is an integer from 1 to 24 and s2 is an integer from 0 to 8.

30. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-29, wherein, each R 3a and R 3b are each independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Preferably, R 3a and R 3b are both hydrogen; R 3a and R 3b one of which is hydrogen and the other is -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; more preferably, R 3a and R 3b one of which is hydrogen and the other is -C(=O)NH(CH2CH2O) s1 -R 3 ; R 3a and R 3b are each -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; more preferably, R 3a and R 3b are each -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 .

31. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-30, wherein each R is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) 3c each independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Preferably, R 3c is hydrogen.

32. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-31, wherein s is an integer from 1 to 8; Preferably, s is an integer from 1 to 6; More preferably, s is an integer from 3 to 6; More preferably, s is 3; or More preferably, s is 6.

33. The ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 16-32, wherein, s1 is an integer from 1 to 20; Preferably, s1 is an integer from 8 to 20; More preferably, s1 is an integer from 12 to 18; More preferably, s1 is 12; or More preferably, s1 is 16.

34. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-33, wherein, s2 is an integer from 0 to 6; Preferably, s2 is an integer from 0 to 4; More preferably, s2 is an integer from 1 to 3; More preferably, s2 is 1.

35. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-34, wherein, each R is independently hydrogen, deuterium, or C1-C4alkyl; 3 independently hydrogen, deuterium, or C1-C4alkyl; 1-6 alkyl; Preferably, each R 3 independently hydrogen, deuterium, -CH3, or -C2H5; More preferably, R 3 is -CH3.

36. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-35, wherein, the L3 is s is an integer from 1-8; each of the 0, 1, or 2 methylene units of L3 is independently optionally replaced with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -NR 3c -, or -O-; each R 3a and R 3b is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; each R 3c is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; wherein each R 3 is independently hydrogen, protium, deuterium, tritium, or C 1-6 alkyl; s1 is an integer from 1-20, and s2 is an integer from 0-6.

37. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-36, wherein, L3 is s is an integer from 1-6; each of the 0, 1, or 2 methylene units of L3 is independently optionally replaced with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -NR 3c -, or -O-; each R 3a and R 3b is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; each R 3c is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; wherein each R 3 is independently hydrogen, deuterium, -CH3, or -C2H5; s1 is an integer from 8-20 and s2 is an integer from 0-4.

38. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-37, wherein, said L3 is selected from the group consisting of:

39. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-38, wherein, L2is selected from the group consisting of an amino acid, a peptide of 2-10 amino acids, and an oligosaccharide; the amino acid residues are selected from the group consisting of natural amino acid residues, unnatural amino acid residues, or stereoisomers thereof; when the amino acid residue is Lys, the distal amino group of the Lys is optionally substituted with 1, 2, or 3 C 1-6 alkyl groups; Preferably, when the amino acid residue is Lys, the side chain amino group of the Lys is optionally substituted with 1 or 2 C 1-4 alkyl; More preferably, when the amino acid residue is Lys, the side chain amino group of the Lys is optionally substituted with 2 methyl groups, 2 ethyl groups, or 2 n-propyl groups.

40. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-39, wherein, said L2 is selected from the group consisting of -Lys-, -Ala-Lys-, -Gly-Lys-, -Lys-Gly-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Lys-Val-, -Ala-Ala-Asn-, -Ala-Ala-Asn-, -Ala-Ala-Asp-, -Ala-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Lys-Gly-, -Lys-Ala-Asn-, -Val-Lys-Gly-, -Gly-Gly-Phe-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Val-Lys-Gly-Gly-, and wherein the distal amino group of Lys is optionally substituted with 1, 2, or 3 C 1-6 alkyl groups.

41. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 16-40, wherein, said L2 is selected from:

42. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-41, wherein, said L1is selected from the group consisting of:

43. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 16-42, wherein, L is selected from the structures in Table 1.

44. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-43, wherein, The B# can be an antibody or an antigen-binding fragment thereof.

45. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-44, wherein, The B# is selected from the group consisting of a chimeric antibody, a humanized antibody, and a fully human antibody.

46. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-45, wherein, The B# is an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45 (PTPRC), CD46, CD47, CD49D (ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-a, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4b7, integrin a5b6, trophoblast glycoprotein, and tissue factor.

47. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-46, wherein, The B# is an antibody that targets the following targets: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, and EGFR.

48. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-47, wherein, said B# is an anti-Trop-2 antibody or an antigen-binding fragment thereof; Preferably, said B# is datopotamab, sacituzumab or an antigen-binding fragment thereof.

49. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-47, wherein, said B# is an anti-Her 2 antibody or an antigen-binding fragment thereof; Preferably, said B# is anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, timigutuzumab, zanidatamab, Trastuzumab, Pertuzumab or an antigen-binding fragment thereof. More preferably, said B# is an anti-Her 2 antibody or an antigen-binding fragment thereof; comprising two heavy chains and two light chains, said heavy chains comprising a heavy chain variable region comprising a heavy chain complementarity determining region 1 (HCDR1) as set forth in SEQ ID NO: 11, a heavy chain complementarity determining region 2 (HCDR2) as set forth in SEQ ID NO: 12, and a heavy chain complementarity determining region 3 (HCDR3) as set forth in SEQ ID NO: 13, said light chains comprising a light chain variable region comprising a light chain complementarity determining region 1 (LCDR1) as set forth in SEQ ID NO: 14, a light chain complementarity determining region 2 (LCDR2) as set forth in SEQ ID NO: 15, and a light chain complementarity determining region 3 (LCDR3) as set forth in SEQ ID NO: 16; Further preferably, said heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 17, and said light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 18; More preferably, said heavy chains comprise an amino acid sequence as set forth in SEQ ID NO: 6, and said light chains comprise an amino acid sequence as set forth in SEQ ID NO:

5.

50. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-47, wherein, said B# is an anti-Her 3 antibody or an antigen-binding fragment thereof; Preferably, said B# is barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody or an antigen-binding fragment thereof.

51. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-47, wherein, said B# is an anti-EGFR antibody or an antigen-binding fragment thereof; Preferably, said B# is demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomuzotuximab, zalutumumab, Cetuximab or an antigen-binding fragment thereof.

52. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-47, wherein, the B# is an anti-B7H3 antibody or an antigen-binding fragment thereof; Preferably, the B# is 1D1, 1D1-01, 2E3, 2E3-02 antibody, enoblituzumab, mirzotamab, omburtamab or an antigen-binding fragment thereof.

53. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-47, wherein, the B# is an anti-LIV1 antibody or an antigen-binding fragment thereof; Preferably, the B# is Ladiratuzumab or an antigen-binding fragment thereof; More preferably, the B# is an anti-LIV1 antibody or an antigen-binding fragment thereof; it comprises two heavy chains and two light chains, the heavy chain comprising a heavy chain variable region comprising a heavy chain complementarity determining region 1 (HCDR1) as set forth in SEQ ID NO: 19, a heavy chain complementarity determining region 2 (HCDR2) as set forth in SEQ ID NO: 20, and a heavy chain complementarity determining region 3 (HCDR3) as set forth in SEQ ID NO: 21, the light chain comprising a light chain variable region comprising a light chain complementarity determining region 1 (LCDR1) as set forth in SEQ ID NO: 22, a light chain complementarity determining region 2 (LCDR2) as set forth in SEQ ID NO: 23, and a light chain complementarity determining region 3 (LCDR3) as set forth in SEQ ID NO: 24; Further preferably, the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 25, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 26; More preferably, the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 7, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO:

8.

54. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-53, wherein, the average drug-to-ligand ratio n is an integer or a fraction from 1 to 10; Preferably, the average drug-to-ligand ratio n is an integer or a fraction from 3 to 8; or Preferably, the average drug-to-ligand ratio n is an integer or a fraction from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10; or Preferably, the average drug-to-ligand ratio n is 1, 2, 3, 4, 5, 6, 7, or 8.

55. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-54, wherein, the ligand-drug conjugate is selected from the structures in Table 2.

56. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-54, wherein, the ligand-drug conjugate is selected from the structures in Table 3.

57. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-56, wherein, the ligand-drug conjugate is isotopically substituted; Preferably, the isotopic substitution is deuterium atom substitution.

58. A compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, of the formula: ###0017### 58 the compound has a structure according to Formula (IA): L—D Formula (IA); wherein L is a linker unit having the following structure: L4'— L3— L2— L1— ; wherein L1 is absent or is a self-immolative unit, L1 is connected to D; L2 is absent or is a conditionally- cleavable unit; L3 is absent or is a hydrophilic unit; L4' is a ligand linker unit, which can be used to connect to a ligand, said L4' is selected from the group consisting of: wherein G is a leaving group for a nucleophilic substitution reaction; D is a drug having a structure represented by formula (IV): wherein R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 2 and R 3 are the same or different and each is independently selected from a hydrogen atom and a halogen; R 4 selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 5 selected from a hydrogen atom and -C(O)CH2OH; X is selected from O, S, and NH; and the wavy line represents the bond connecting L and D.

59. The compound of claim 58, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; preferably, said R 1 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl; more preferably, said R 1 selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl; even more preferably, said R 1 is F or -CH3; still more preferably, said R 1 is F; or, still more preferably, said R 1 is -CH3.

60. The compound of claim 58 or 59, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 3 are the same or different and each independently selected from the group consisting of a hydrogen atom, F, CI and Br; preferably, R 2 and R 3 are the same or different and each independently selected from the group consisting of a hydrogen atom, F and CI; more preferably, R 2 and R 3 are the same or different and each independently selected from the group consisting of a hydrogen atom and F; still more preferably, R 2 and R 3 are both hydrogen atoms; or, still more preferably, R 2 and R 3 one is a hydrogen atom and the other is F.

61. The compound of any one of claims 58-60, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 4 is selected from the group consisting of a hydrogen atom, a halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; preferably, said R 4 is selected from the group consisting of a hydrogen atom, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl; more preferably, said R 4 is selected from the group consisting of a hydrogen atom, F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl; even more preferably, said R 4 is a hydrogen atom or F; even more preferably, said R 4 is a hydrogen atom.

62. The compound of any one of claims 58-61, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 5 is a hydrogen atom; or, in some other embodiments of the compounds of Formula (I), said R 5 is -C(O)CH2OH.

63. The compound of any one of claims 58-62, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, the X is -OH or -SH; or, preferably, the X is -NH2; or, preferably, the X is -OH; or, preferably, the X is -SH.

64. The compound of any one of claims 58-63, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F and CI, R 5 is a hydrogen atom or -C(0)CH2OH; preferably, R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom and F, R 5 is a hydrogen atom; or, preferably, R 2 is a hydrogen atom or F, R 3 is a hydrogen atom, R 5 is a hydrogen atom; or, preferably, R 2 , R 3 and R 5 are each a hydrogen atom.

65. The compound of any one of claims 58-64, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl, said R 4 is selected from the group consisting of hydrogen atom, F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl, said X is selected from the group consisting of -OH, -SH and -NH2; preferably, said R 1 is selected from the group consisting of F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3 and vinyl, said R 4 is a hydrogen atom or F, said X is -OH or -SH; more preferably, said R 1 is selected from the group consisting of F, Cl, -CH3, -CH2F, -CHF2, -CF3 and vinyl, said R 4 is a hydrogen atom, said X is -OH; even more preferably, said R 1 is F or -CH3, said R 4 is a hydrogen atom, said X is -OH.

66. A compound of Formula (I), or a tautomer, meso, racemic, enantiomeric, diastereomeric form thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, the compound has a structure according to Formula (IA): L—D Formula (IA); wherein L is a linker unit having the following structure: L4'— L3— L2— L1— ; wherein L1 is absent or is a self-immolative unit, L1 is connected to D; L2 is absent or is a conditionally- cleavable unit; L3 is absent or is a hydrophilic unit; L4' is a ligand linker unit for connecting to a ligand, said L4' is selected from: wherein G is a leaving group for a nucleophilic substitution reaction; D is a drug having a structure according to Formula (II) or Formula (II-S): wherein R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 2 selected from a hydrogen atom and a halogen; the wavy line represents the bond connecting L and D.

67. The compound of claim 66, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is selected from the group consisting of halogen, sulfonyl, sulfonate, nitro, and optionally substituted with one or more substituents selected from the group consisting of alkylsulfide, arylsulfide, heteroarylsulfide, alkylsulfoxide, arylsulfoxide, heteroarylsulfoxide, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, wherein each substituent is independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, CN, nitro, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, 6-10 membered aryl, and 5-16 membered heteroaryl; Preferably, G is selected from the group consisting of F, Cl, Br, I, OMs, OTs, OTf, methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl, and naphthalenesulfonyl; More preferably, G is selected from the group consisting of F, Cl, Br, OMs, OTs, methylsulfonyl, and p-toluenesulfonyl. More preferably, G is selected from the group consisting of Cl and methylsulfonyl.

68. The compound of claim 66 or 67, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2 is selected from the group consisting of a hydrogen atom, F, Cl and Br; Preferably, said R 2 is selected from a hydrogen atom, F and Cl; More preferably, said R 2 is selected from a hydrogen atom and F; Further preferably, said R 2 is a hydrogen atom.

69. The compound of any one of claims 66-68, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; Preferably, said R 1 selected from F, CI, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl; More preferably, said R 1 is selected from F, CI, -CH3, -CH2F, -CHF2, -CF3, and vinyl; Further preferably, R 1 is F or -CH3; More preferably, said R 1 is F; or, more preferably, said R 1 is -CH3.

70. The compound of any one of claims 66-69, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, D has the structure of Formula (III) or Formula (III-S): wherein R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl.

71. The compound of claim 70, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; Preferably, said R 1 selected from F, CI, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl; More preferably, said R 1 selected from F, CI, -CH3, -CH2F, -CHF2, -CF3, and vinyl; Further preferably, R 1 is F or -CH3; More preferably, said R 1 is F; More preferably, said R 1 is -CH3.

72. The compound of any one of claims 58-71, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, D is selected from the following structures:

73. The compound of any one of claims 58-72, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, In L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer ≥ 1; Y is -C(=O)-; 0 or more methylene units of X are each independently and arbitrarily selected by -N(R 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-、 -O-, -S-, -SO-, -SO2-, -N(R 4c SO2-, -SO2N(R) 4c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=S)-, -C(=NR 4c -, -C = C-, -N = N-, -C = N-, or -N = C- are substitutes; m1 is an integer ≥ 1; each R 4a R 4b R 4c Each can be independently represented as hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, or -OR. 4 -SR 4 -(CH2CH2O) m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 -(CH2) m2 N(R 4d (R) 4e -(CH2) m2 C(O)R 4 -(CH2) m2 CO2R 4 -C(O)CH2C(O)R 4 -S(O)R 4 -S(O)2R 4 -C(O)N(R) 4d (R) 4e -SO2N(R) 4d (R) 4e -OC(O)R 4 -N(R)SO2R 4 or C 1-6 Alkyl; wherein each R 4 R 4d R 4e each independently 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, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy; m2 is an integer ≥ 0, m3 is an integer ≥ 0, m4 is an integer ≥ 0; said L3 is absent or is -NH-(C(R 3a )(R 3b )) s -C(=O)-, s is an integer ≥ 1 ; each of the 0 or more methylene units of L3 is independently optionally substituted with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, -O-, -S-, -SO-, -SO2-, -N(R 3c )SO2-, -SO2N(R 3c )-, -C(=S)-, -C(=NR 3c )-, -C=C-, -N=N-, -C=N-, or -N=C- instead; each R 3a , R 3b , R 3c is independently hydrogen, protium, deuterium, tritium, halogen, -OR 3 , -SR 3 , -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 R 3 ; wherein each R 3 is independently hydrogen, protium, deuterium, tritium, or C 1-6 1-6 alkyl; s1 is an integer ≥ 0, s2 is an integer ≥ 0; L2 is absent or selected from an amino acid, a peptide consisting of 2-10 amino acids, or an oligosaccharide; the amino acid residues are selected from natural amino acid residues, unnatural amino acid residues, or stereoisomers thereof; when the amino acid residue is Lys, the side chain amino of the Lys is optionally substituted with 1 or 2 C 1-6 alkyl groups; preferably, when the amino acid residue is Lys, the side chain amino of the Lys is optionally substituted with 1 or 2 C 1-3 alkyl groups; more preferably, when the amino acid residue is Lys, the side chain amino of the Lys is optionally substituted with 2 ethyl groups or 2 n-propyl groups; said L1is absent or selected from the group consisting of: wherein 1 is connected to L2, and 2 is connected to D.

74. The compound of any one of claims 58-73, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, In L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 10; Y is -C(=O)-; 0 or more methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 12; each R 4a R 4b R 4c Each can be independently classified as hydrogen, protium, deuterium, tritium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 -(CH2) m3 NH(CH2) m4 R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group; m2 is an integer from 0 to 20, m3 is an integer from 0 to 20, and m4 is an integer from 0 to 20.

75. The compound of any one of claims 58-74, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, each R 4a and R 4b are each independently hydrogen, deuterium, -(CH2CH2O) m2 -R 4 , -(CH2) m3 NH(CH2CH2O) m4 R 4 or -(CH2) m3 NH(CH2) m4 R 4 ; Preferably, R 4a , R 4b are each hydrogen; or Preferably, R 4a and R 4b One of them is hydrogen, and the other is -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 .

76. The compound of any one of claims 58-75, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 alkyl; Preferably, each R 4c each independently is hydrogen, deuterium, -(CH2CH20)n- m2 -R 4 , -CH3or -C2H5; More preferably, R 4c is hydrogen; More preferably, R 4c is -(CH2CH2O) m2 -R 4 ; More preferably, R 4c is -CH3.

77. The compound of any one of claims 58-76, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, m is an integer from 1 to 8; Preferably, m is an integer from 1 to 6; More preferably, m is an integer from 1 to 5.

78. The compound of any one of claims 58-77, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, m1 is an integer from 1 to 8; Preferably, m1 is an integer from 1 to 6; More preferably, m1 is an integer from 1 to 4. More preferably, m1 is 1.

79. The compound of any one of claims 58-78, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, m2 is an integer from 1 to 20; Preferably, m2 is an integer from 8 to 20; More preferably, m2 is an integer from 12 to 18. More preferably, m2 is 16.

80. The compound of any one of claims 58-79, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, m3 is an integer from 0 to 8; Preferably, m3 is an integer from 1 to 6; More preferably, m3 is an integer from 1 to 3. More preferably, m3 is 1.

81. The compound of any one of claims 58-80, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, m4 is an integer from 0 to 8; Preferably, m4 is an integer from 1 to 6; More preferably, m4 is an integer from 1 to 3. More preferably, m4 is 1; or, More preferably, m4 is 2.

82. The compound of any one of claims 58-81 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; Preferably, each R 4 is independently hydrogen, deuterium, halogen, -CO2H, -CH3, or -OCH3; More preferably, each R 4 independently -CO2H, -CH3, or -OCH3; More preferably, R 4 is -CO2H; or More preferably, R 4 is -CH3; or More preferably, R 4 is -OCH3.

83. The compound of any one of claims 58-82, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, In L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 8; Y is -C(=O)-; 0 or 1 methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 8; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently hydrogen, -CO2H, or C 1-6 Alkyl; m2 is an integer from 1 to 20, m3 is an integer from 0 to 8, and m4 is an integer from 0 to 8.

84. The compound of any one of claims 58-83, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, In L4', X is -(C(R) 4a (R) 4b )) m -, m is an integer from 1 to 5; Y is -C(=O)-; 0 or 1 methylene units of X are each independently and arbitrarily selected by -N(R) 4c )C(=O)-、-C(=O)N(R 4c )-、-NR 4c -、-(OCH2CH2) m1 -O-, or Replacement; m1 is an integer from 1 to 4; each R 4a and R 4b Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 -(CH2) m3 NH(CH2CH2O) m4 R 4 Or -(CH2) m3 NH(CH2) m4 R 4 ; Each R 4c Each can be independently classified as hydrogen, deuterium, or -(CH2CH2O). m2 -R 4 Or C 1-6 Alkyl; wherein each R 4 Independently, it can be hydrogen, protium, deuterium, tritium, halogen, -CO2H, -CH3, -C2H5, -CF2H, -CF3, -OCH3, -OC2H5, or -OCF3; m2 is an integer from 12 to 18, m3 is an integer from 1 to 3, and m4 is an integer from 1 to 3.

85. The compound of any one of claims 58-84, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said L3 is s is an integer from 1 to 10; 1 position is attached to L4 and 2 position is attached to L2; each of the 0 or more methylene units of L3 is independently optionally replaced with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -OC(=O)-, -C(=O)O-, -NR 3c -, or -O-; each R 3a , R 3b , R 3c is independently hydrogen, protium, deuterium, tritium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; wherein each R 3 is independently hydrogen, protium, deuterium, tritium, or C 1-6 alkyl; s1 is an integer from 1 to 24 and s2 is an integer from 0 to 8.

86. The compound of any one of claims 58-85, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, each R is independently hydrogen, deuterium, -C(=0)NH(CH2CH2O) 3a and R 3b are each independently hydrogen, deuterium, -C(=0)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=0)NH(CH2CH2O) s1 -R 3 ; Preferably, R 3a and R 3b are both hydrogen; R 3a and R 3b one of which is hydrogen and the other is -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; more preferably, R 3a and R 3b one of which is hydrogen and the other is -C(=O)NH(CH2CH2O) s1 -R 3 ; R 3a and R 3b are each -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; more preferably, R 3a and R 3b are each -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 .

87. The compound of any one of claims 58-86, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, each R is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) 3c each independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; Preferably, R 3c is hydrogen.

88. The compound of any one of claims 58-87, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, s is an integer from 1 to 8; Preferably, s is an integer from 1 to 6; More preferably, s is an integer from 3 to 6. More preferably, s is 3; or More preferably, s is 6.

89. The compound of any one of claims 58-88, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, s1 is an integer from 1 to 20; Preferably, s1 is an integer from 8 to 20; More preferably, s1 is an integer from 12 to 18. More preferably, s1 is 12; or More preferably, s1 is 16.

90. The compound of any one of claims 55-89, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, s2 is an integer from 0 to 6; Preferably, s2 is an integer from 0 to 4; More preferably, s2 is an integer from 1 to 3. More preferably, s2 is 1.

91. The compound of any one of claims 58-90, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, each R is independently hydrogen, deuterium, or C1-C4alkyl; 3 is independently hydrogen, deuterium, or C1-C4alkyl; 1-6 alkyl; Preferably, each R 3 independently hydrogen, deuterium, -CH3, or -C2H5; More preferably, R 3 is -CH3.

92. The compound of any one of claims 58-91, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said L3 is s is an integer from 1-8; each of the 0, 1, or 2 methylene units of L3 is independently optionally replaced with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -NR 3c -, or -O-; each R 3a and R 3b is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; each R 3c is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; wherein each R 3 is independently hydrogen, protium, deuterium, tritium, or C 1-6 alkyl; s1 is an integer from 1-20, and s2 is an integer from 0-6.

93. The compound of any one of claims 58-92, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, the L3 is s is an integer from 1-6; each of the 0, 1, or 2 methylene units of L3 is independently optionally replaced with -N(R 3c )C(=O)-, -C(=O)N(R 3c )-, -C(=O)-, -NR 3c -, or -O-; each R 3a and R 3b is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; each R 3c is independently hydrogen, deuterium, -C(=O)NH(CH2CH2O) s1 -R 3 , -(CH2) s2 O(CH2CH2O) s1 -R 3 , or -(CH2) s2 OC(=O)NH(CH2CH2O) s1 -R 3 ; wherein each R 3 is independently hydrogen, deuterium, -CH3, or -C2H5; s1 is an integer from 8-20 and s2 is an integer from 0-4.

94. The compound of any one of claims 58-93, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said L3 is selected from the group consisting of:

95. The compound of any one of claims 58-92, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, L2 is selected from the group consisting of an amino acid, a peptide of 2-10 amino acids, and an oligosaccharide; said amino acid is selected from the group consisting of a natural amino acid residue, a non-natural amino acid residue, or a stereoisomer thereof; when said amino acid residue is Lys, the distal amino group of said Lys is optionally substituted with 1, 2, or 3 C 1-6 alkyl groups; Preferably, when the amino acid residue is Lys, the side chain amino group of the Lys is optionally substituted with 1 or 2 C 1-4 alkyl; More preferably, when the amino acid residue is Lys, the side chain amino group of the Lys is optionally substituted with 2 methyl groups, 2 ethyl groups, or 2 n-propyl groups.

96. The compound of any one of claims 58-95, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said L2 is selected from the group consisting of -Lys-, -Ala-Lys-, -Gly-Lys-, -Lys-Gly-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Lys-Val-, -Ala-Ala-Asn-, -Ala-Ala-Asn-, -Ala-Ala-Asp-, -Ala-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Lys-Gly-, -Lys-Ala-Asn-, -Val-Lys-Gly-, -Gly-Gly-Phe-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Val-Lys-Gly-Gly-, and wherein the distal amino group of Lys is optionally substituted with 1, 2, or 3 C 1-6 alkyl groups.

97. The compound of any one of claims 58-96, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said L2 is selected from:

98. The compound of any one of claims 58-97, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said L1is selected from the group consisting of:

99. The compound of any one of claims 58-98, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (IA) is selected from the structures in Table 4.

100. The compound of any one of claims 58-99, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The ligand-drug conjugate is isotopically substituted; Preferably, the isotopic substitution is deuterium atom substitution.

101. A compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has a structure represented by Formula (IVA): wherein: R 1 selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 2 and R 3 are the same or different and each is independently selected from a hydrogen atom and a halogen; R 4 selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl and vinyl; R 5 selected from a hydrogen atom and -C(O)CH2OH; X is selected from the group consisting of -OH, -SH, and -NH2.

102. The compound of claim 101, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; preferably, said R 1 is selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl; more preferably, said R 1 is selected from F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl; even more preferably, said R 1 is F or -CH3; yet more preferably, said R 1 is F; or, yet more preferably, said R 1 is -CH3.

103. The compound of claim 101 or 102, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F, CI and Br; preferably, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F and CI; more preferably, said R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom and F; even more preferably, said R 2 and R 3 are both a hydrogen atom; or, even more preferably, said R 2 and R 3 wherein one is a hydrogen atom and the other is F.

104. The compound of any one of claims 101-103, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 4 is selected from the group consisting of a hydrogen atom, a halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl; preferably, said R 4 is selected from the group consisting of a hydrogen atom, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl; more preferably, said R 4 is selected from the group consisting of a hydrogen atom, F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl; even more preferably, said R 4 is a hydrogen atom or F; even more preferably, said R 4 is a hydrogen atom.

105. The compound of any one of claims 101-104, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, In some embodiments of the compounds of Formula (I), R 5 is a hydrogen atom; or, in some other embodiments of the compounds of Formula (I), R 5 is -C(O)CH2OH.

106. The compound of any one of claims 101-105, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Preferably, X is -OH or -SH; or, preferably, X is -NH2; or, preferably, X is -OH; or, preferably, X is -SH.

107. The compound of any one of claims 101-106, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom, F and CI, R 5 is a hydrogen atom or -C(O)CH2OH; preferably, R 2 and R 3 are identical or different and each independently selected from the group consisting of a hydrogen atom and F, R 5 is a hydrogen atom; or, preferably, R 2 is a hydrogen atom or F, R 3 is a hydrogen atom, R 5 is a hydrogen atom; or, preferably, R 2 , R 3 and R 5 are each a hydrogen atom.

108. The compound of any one of claims 102-107, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and vinyl, said R 4 is selected from the group consisting of hydrogen atom, F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl, said X is selected from the group consisting of -OH, -SH and -NH2; preferably, said R 1 is selected from the group consisting of F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3and vinyl, said R 4 is a hydrogen atom or F, said X is -OH or -SH; more preferably, said R 1 is selected from the group consisting of F, Cl, -CH3, -CH2F, -CHF2, -CF3and vinyl, said R 4 is a hydrogen atom, said X is -OH; more preferably, said R 1 is F or -CH3, said R 4 is a hydrogen atom, said X is -OH.

109. A compound or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has a structure represented by Formula (IIA): wherein R 1 selected from halogen, C 1-6 alkyl, C1-6haloalkyl and vinyl; R 2 is selected from hydrogen atom and halogen.

110. The compound of claim 109, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 2 is selected from the group consisting of a hydrogen atom, F, Cl and Br; Preferably, said R 2 is selected from a hydrogen atom, F and Cl; More preferably, said R 2 is selected from a hydrogen atom and F; Further preferably, said R 2 is a hydrogen atom.

111. The compound of claim 109 or 110, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, said R 1 selected from halogen, C1-3alkyl, C 1-3 haloalkyl and vinyl; Preferably, said R 1 selected from F, CI, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CHF2, -CH2CF3, -CF2CF3, and vinyl; More preferably, said R 1 is selected from F, CI, -CH3, -CH2F, -CHF2, -CF3, and vinyl; Further preferably, R 1 is F or -CH3; More preferably, said R 1 is F; or, more preferably, said R 1 is -CH3.

112. The compound of any one of claims 109-111 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The compounds have a structure according to Formula (IIA-S):

113. The compound of any one of claims 101-111 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound has a structure represented by formula (IIIA):

114. The compound according to any one of claims 101-113, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound has a structure represented by formula (IIIA-S):

115. The compound of any one of claims 101-114, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

116. The compound of any one of claims 101-115, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is isotopically substituted; Preferably, the isotopic substitution is deuterium atom substitution.

117. A method of preparing the ligand-drug conjugate of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-57, wherein, The method comprises contacting a ligand B# with a structure represented by formula (IA) as described in any one of claims 58-100. The method comprises contacting a ligand B# with a structure represented by formula (IA) as described in any one of claims 58-100.

118. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains the ligand-drug conjugate according to any one of claims 1-57, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

119. A pharmaceutical composition comprising, The pharmaceutical composition contains the compound according to any one of claims 58-100, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

120. A pharmaceutical composition comprising, The pharmaceutical composition contains the compound according to any one of claims 101-116, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

121. Use of the ligand-drug conjugate according to any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 118, in the manufacture of a medicament for treating and / or preventing a tumor.

122. Use of the compound according to any one of claims 58-100, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing a tumor. Preferably, the medicament is a ligand-drug conjugate.

123. Use of the compound according to any one of claims 101-116, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 120, in the manufacture of a medicament for treating and / or preventing a tumor.

124. A method of treating and / or preventing a tumor, comprising administering to a subject in need thereof the ligand-drug conjugate according to any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 118.

125. A method of treating and / or preventing a tumor, comprising administering to a subject in need thereof the compound according to any one of claims 101-116, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 120.

126. The ligand-drug conjugate according to any one of claims 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 118, for use in treating and / or preventing a tumor.

127. The compound according to any one of claims 101-116, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 120, for use in treating and / or preventing a tumor.

128. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is selected from the group consisting of tumors associated with expression of 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45 (PTPRC), CD46, CD47, CD49D (ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CD11b, CEA, CEACAM5, Claudin 18.2, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-a, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, short proteoglycans, mesothelin, sodium phosphate cotransporter 2B, endothelin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4b7, integrin a5b6, trophoblast glycoprotein, and tissue factor.

128. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt or pharmaceutical composition thereof according to claim 126, the compound or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof according to claim 127, wherein the tumor is selected from a tumor associated with expression of HER2, HER3, B7H3, TROP2, LIV-1, Claudin 18.2, CD30, CD33, CD70, or EGFR.

129. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of HER2.

130. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of HER3.

131. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of B7H3.

132. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of TROP2.

133. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of LIV-1.

134. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of Claudin 18.

2.

135. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of CD30.

136. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of CD33.

137. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of CD70.

138. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is a tumor associated with expression of EGFR.

139. The use according to any one of claims 121-123, the method according to claim 124 or 125, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 126, the compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to claim 127, characterized in that, The tumor is selected from the group consisting of lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, renal cancer, bladder cancer, urothelial cancer, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric mucinous tumor, lymphoma, leukemia, plasmacytoma, sinoatrial node cell tumor, tenosynovial giant cell tumor, brain cancer, squamous cell carcinoma, epidermal carcinoma, non-Hodgkin's lymphoma; more preferably, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, malignant lymphoma, liver cancer, and leukemia; Preferably, the cancer is ER positive and / or TRPM4 positive expressing; or Preferably, wherein the breast cancer is ER+ breast cancer or ER+ / HER2- breast cancer; or Preferably, wherein the lung cancer is non-small cell lung cancer; or Preferably, wherein the prostate cancer is castration-resistant prostate cancer.

140. A kit comprising the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-57, the compound or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 101-116, and / or the pharmaceutical composition according to claim 118 or 120.

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