Linker, ligand-drug conjugate and medical use thereof

Abstract

A new drug linker, and a linker-drug system further prepared on the basis of the linker, a ligand-drug conjugate, an antibody conjugate drug, a pharmaceutical composition comprising the conjugate, and the medical use of the conjugate and the pharmaceutical composition. The new drug-linker system has a relatively high drug-antibody ratio (DAR) value, and the drug-ligand conjugate prepared on this basis has a relatively good tumor-inhibitory effect and has a relatively good clinical application prospect.

Description

A linker, ligand-drug conjugate and its medical use

[0001] This application claims priority to:

[0002] Chinese patent CN202410116532.5 filed on January 29, 2024,

[0003] Chinese patent CN202410564053.X filed on May 8, 2024,

[0004] Chinese patent CN202411388187.7 filed on October 8, 2024,

[0005] Chinese patent CN202411429924.4 filed on October 14, 2024,

[0006] Chinese patent CN202411783791.X filed on December 6, 2024,

[0007] Chinese patent CN202411429096.3 filed on October 14, 2024,

[0008] Chinese patent CN202411795873.6 filed on December 9, 2024,

[0009] Chinese patent CN202411947010.6 filed on December 27, 2024. Technical Field

[0010] The present invention relates to the field of medical technology, and in particular to a novel linker, a ligand-drug conjugate, a pharmaceutical composition comprising the conjugate, and uses of the conjugate or the pharmaceutical composition. Background Art

[0011] Antibody-drug conjugates (ADCs) consist of three components: an antibody (mAb), a cytotoxic payload, and a linker (connecting unit or structure). The antibody is coupled to the cytotoxic drug via the linker, which together imparts cell targeting and cell-killing potency to the ADC, enabling precise and efficient elimination of cancer cells. These ADCs have become a hot topic in anti-cancer drug research and development. Ideally, an ADC drug should remain stable in the bloodstream, accurately reach its therapeutic target, and ultimately release its cytotoxic payload near the target (e.g., cancer cells).

[0012] Nectin-4, also known as poliovirus receptor-related protein 4 (PVRL4), is a type I transmembrane protein belonging to the Nextins family of immunoglobulin-like molecules. Studies have found that nectin-4 has limited expression in healthy adult tissues but is overexpressed in various malignancies, including bladder cancer, breast cancer, and lung cancer. As a tumor-associated inducer, it is associated with various aspects of tumor progression, including proliferation, metastasis, and epithelial-mesenchymal transition, making it an ideal anti-tumor drug target (Chatterjee, S., S. Sinha, and CN Kundu, Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. Eur J Pharmacol, 2021.911: p.174516).

[0013] Eribulin is a mitotic microtubule dynamics inhibitor that has demonstrated therapeutic activity against a variety of tumors (such as breast cancer, soft tissue sarcoma, and urothelial carcinoma) in clinical trials, with a favorable bystander effect. Eribulin has been extensively studied in the treatment of advanced breast cancer and is typically used in patients who have received at least two prior chemotherapy regimens. Eribulin primarily inhibits microtubule dynamics by binding to specific sites on tubulin, leading to irreversible mitotic arrest and subsequent cell apoptosis, potentially overcoming resistance to other anti-tumor drugs. In addition, Eribulin can reverse epithelial-mesenchymal transition (EMT), overcome immune escape and cause vascular remodeling, thereby inhibiting the migration and spread of tumor cells (Menis, J. and C. Twelves, Eribulin (Halaven): a new, effective treatment for women with heavily pretreated metastatic breast cancer. Breast Cancer (Dove Med Press), 2011. 3: p. 101-11; Seshadri, P., B. Deb, and P. Kumar, Multifarious targets beyond microtubules-role of eribulin in cancer therapy. Front Biosci (Schol Ed), 2021. 13 (2): p. 157-172).

[0014] Currently, a variety of ADC drugs have been used in clinical practice or clinical research, but further development of ADC drugs with better efficacy is still needed. Summary of the Invention

[0015] The first aspect of the present invention provides a compound as shown in Formula 1-1 or a pharmaceutically acceptable salt thereof, TM-L1——L 23 -L4-L5-G formula 1-1

[0016] wherein T is a linker unit; preferably T is selected from R at each occurrence is independently selected from halogen and -S-Ar; preferably, R at each occurrence is independently selected from F, Cl, Br, I and -S-Ar;

[0017] Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl,

[0018] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, and a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, and heterocycloalkylene group are unsubstituted or optionally substituted by one or more R a replace;

[0019] L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a replace;

[0020] When L 23 When L5 is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, L5 is a spacer unit having a side chain comprising a hydrophilic unit; wherein the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof, preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; provided that when L 23 When it is a single bond, L5 does not contain a triazole ring; or

[0021] When L5 is any spacer unit, L 23 Selected from -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-, and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group, or the heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a Replacement; provided that, when T is When L1 contains an alkynylene group, L5 is a spacer unit having a side chain containing a hydrophilic unit;

[0022] n7, and n10 are each independently selected from 0, 1, 2, 3, 4, 5 and 6;

[0023] n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0024] M, L1, and L 23 Not all are single bonds;

[0025] L4 is a peptide residue consisting of amino acids or -NR a -alkylene-NR a -, wherein the alkylene, and amino acid are unsubstituted or optionally substituted with one or more R a replace;

[0026] G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and

[0027] R a Each occurrence is independently selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, carboxyl, -NH-C 1-6 Alkyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-NHC(O)-C 1-6 Alkyl, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, 6-10 membered aryl and 5-13 membered heteroaryl, wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkylamino, aryl and heteroaryl.

[0028] In one embodiment, wherein

[0029] When L5 is selected from a single bond, -N(R b )-(CH2) g -O-(CH2) g -OC(O)-、-N(R b )-(CH2) g -O-(CH2-CH2-O) g -C(O)-, When L 23 Selected from -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10-C(O)-, and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group or a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group or the heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R b The hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, L 23 Selected from -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -C(O)-, -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -C(O)-, 1, 2, 3 or more of; or

[0030] When L 23 Selected from single bond, -(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -(OCH2CH2) n1 -、-C(O)-、-Cy1-C 1-10 Alkylene-C(O)-, -Cy1-C(O)-, and -Cy1-(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2-C(O)-, when there is one, two, three or more of them, L5 is a spacer unit having a side chain comprising a hydrophilic unit; the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof;

[0031] in,

[0032] Each occurrence of Cy1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted by one or more R a substituted; preferably, Cy1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Substitution; preferably, Cy1 is selected from Preferably, Cy1 is selected from

[0033] n1, n2 and n3 are each independently selected from an integer from 0 to 30; preferably, n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28;

[0034] n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;

[0035] n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0036] n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 at each occurrence; and n12 and n15 are not both 0;

[0037] Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0038] j is independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;

[0039] Each occurrence of Cy3 is independently selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substitution; preferably, Cy3 is selected from Preferably, Cy3 is

[0040] X1 is

[0041] g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6; and

[0042] R a and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 The aryl group and the 5-13 membered heteroaryl group are substituted by 1, 2, 3 or more substituents.

[0043] The second aspect of the present invention provides a compound as shown in Formula 1 or a pharmaceutically acceptable salt thereof, TM-L1-L2-L3-L4-L5-G Formula 1

[0044] wherein T is a linker unit; preferably T is selected from R is selected from halogen and -S-Ar; preferably, R is selected from F, Cl, Br, I and -S-Ar;

[0045] Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl,

[0046] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, and a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, and heterocycloalkylene group are unsubstituted or optionally substituted by one or more R a replace;

[0047] L1 is selected from a single bond, C2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 2-10 Alkylene, and C 1-10 wherein said alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a replace;

[0048] L2 is a single bond, -(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -, or -(CH2) n3 -(OCH2CH2) n1 -;

[0049] L3 is selected from a single bond, -C(O)-, -Cy1-C 1-10 Alkylene-C(O)-, -Cy1-C(O)-, and -Cy1-(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -C(O)-; Cy1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, or heterocycloalkylene being unsubstituted or optionally substituted with one or more R a Preferably, the arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a Preferably, each occurrence of Cy1 is independently selected from Preferably, Cy1 is

[0050] M, L1, L2 and L3 are not single bonds at the same time;

[0051] L4 is a peptide residue composed of amino acids or -NR a -C 1-6 Alkylene-NR a -; wherein the amino acid and alkylene are unsubstituted or optionally substituted with one or more R a replace;

[0052] L5 is a spacer unit having a side chain comprising a hydrophilic unit; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamate glucosamine, glycosyl, phosphate, sulfonate and combinations thereof;

[0053] G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2;

[0054] n1, n2, and n3 are each independently selected from an integer from 0 to 30; preferably, n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28; and

[0055] R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 The aryl group and the 5-13 membered heteroaryl group are substituted by 1, 2, 3 or more substituents.

[0056] In one embodiment, wherein

[0057] Among them, L5 is

[0058] L a Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-10 Alkylene and C 2-10 wherein the alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a Substituted; preferably, L a Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a replace;

[0059] Cy2 is selected from 6-13 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally further substituted by one or more R a Preferably, Cy2 is selected from 6-10 membered arylene, 5-10 membered heteroarylene, 3-12 membered cycloalkylene and 3-12 membered heterocycloalkylene, wherein the arylene, heteroarylene, cycloalkylene and heterocycloalkylene are unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace;

[0060] L b Selected from single bond, alkynylene, alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with one or more R a Substituted; preferably, L b Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NRa -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a replace;

[0061] L c Selected from CR a R s , R s is a side chain comprising 1-30 hydrophilic units, wherein the hydrophilic units are selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic units are selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate, one or a combination of two or more; preferably, R s Selected from More preferably, Rs is selected from

[0062] j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6;

[0063] Each occurrence of n is independently selected from any integer between 1 and 30; preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0064] L d Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-、C 1-10 Alkylene and C 1-10 wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a Substituted; preferably, L d Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、O、-C(O)-、-NRa -C(O)-、C 1-6 Alkylene and C 1-6 wherein said alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a replace;

[0065] R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 aryl and 5-13 membered heteroaryl 1, 2, 3 or more substituents; preferably, R a Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl, and C1-C3 alkoxy;

[0066] Preferably, L5 is selected from Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; Rb Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 aryl and 5-13 membered heteroaryl 1, 2, 3 or more substituents; preferably, R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

[0067] In one embodiment, the compound is as shown in Formula 4: TM-L1——M a -L6-L7-G formula 4

[0068] wherein T is a linker unit; preferably T is selected from R is selected from halogen and -S-Ar; preferably, R is selected from F, Cl, Br, I and -S-Ar;

[0069] Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl,

[0070] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group and a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group and heterocycloalkylene group are unsubstituted or optionally substituted by one or more R b replace;

[0071] L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR b -、-O-、-C(O)-、-NR b -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with one or more R b replace;

[0072] M a Selected from and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group or a 3-15 membered heterocycloalkylene group; the arylene group, heteroarylene group, cycloalkylene group or heterocycloalkylene group being unsubstituted or optionally further substituted with one or more R b Substitution; the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof;

[0073] L6 is a peptide residue composed of amino acids or -NRb -alkylene-NR b -; wherein the alkylene and amino acid are unsubstituted or optionally further substituted with one or more R b replace;

[0074] L7 is a spacer unit; provided that, when T is When L1 contains an alkynylene group, L7 is a spacer unit having a side chain containing a hydrophilic unit;

[0075] G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2;

[0076] R a and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 substituted by one, two, three or more substituents selected from aryl and 5-13 membered heteroaryl; and

[0077] n17 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28.

[0078] In one embodiment, wherein

[0079] M a Selected from -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -C(O)-,

[0080] -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -C(O)-,

[0081] -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -C(O)-,

[0082] -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -C(O)-, -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-, 1, 2, 3 or more combinations of;

[0083] n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;

[0084] n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0085] n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, and n12 and n15 are not 0 at the same time;

[0086] j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6;

[0087] Each occurrence of Cy3 is independently selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Preferably, each occurrence of Cy3 is independently selected from Preferably, Cy3 is and / or

[0088] L7 is selected from a single bond, -N(R b )-(CH2) g -O-(CH2) g -OC(O)-、-N(R b )-(CH2) g -O-(CH2-CH2-O) g -C(O)-,

[0089] X1 is selected from

[0090] g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6;

[0091] Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0092] R a and R b selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkyl-C(O)NH-, C1-C6 alkyl-OC(O)-NH-, C1-C6 alkyl-NHC(O)-NH-, C6-C 15 Aryl and 5-15 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15Aryl and 5-15 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 15 aryl and 5-15 membered heteroaryl are substituted with one or more substituents; preferably, R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

[0093] In one embodiment, wherein

[0094] T is selected from R is independently selected from halogen and -S-Ar at each occurrence; preferably, R is independently selected from F, Cl, Br, I and -S-Ar at each occurrence; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl,

[0095] Preferably, T is selected from

[0096] and / or,

[0097] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group and a 3-15 membered heterocycloalkylene group, said arylene group, heteroarylene group, cycloalkylene group and heterocycloalkylene group being unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a substituted; preferably, M is selected from a single bond, a phenylene group, a 5-7 membered heteroaryl group, a 3-7 membered cycloalkylene group and a 3-7 membered heterocycloalkylene group, wherein the arylene group, the heteroaryl group, the cycloalkylene group and the heterocycloalkylene group are unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, M is selected from a single bond,

[0098] and / or,

[0099] L1 is selected from a single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L1 is selected from a single bond, C 2-3 Alkynylidene, C 2-3 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-3 Alkylene and C 1-3 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L1 is selected from a single bond, O,

[0100] and / or,

[0101] L 23 and M a Each independently selected from wherein each occurrence of n17 is independently selected from 6, 8, 12 and 24;

[0102] L4 and L6 are each independently a peptide residue consisting of 2, 3, 4, 5, 6 or 7 amino acids or -NR b -C 1-6Alkylene-NR b -, wherein the amino acid is selected from D-alanine, L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine and asparagine, and the alkylene group and the amino acid are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Preferably, L4 and L6 are each independently selected from -NH-CH2CH2-NH-,

[0103] and / or

[0104] L5 and L7 are each independently selected from: a single bond,

[0105] and / or,

[0106] G is selected from hydrogen, halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; preferably, G is selected from hydrogen, F, Cl, Br, I, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2;

[0107] and / or,

[0108] R a and R b is selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 aryl and 5-13 membered heteroaryl 1, 2, 3 or more substituents; preferably, R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

[0109] 8. A compound as shown in Formula 1-5 or a pharmaceutically acceptable salt thereof, TM-L1——L 23 -L4-L5-G formula 1-5

[0110] Wherein, T is the linker unit;

[0111] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace;

[0112] L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a replace;

[0113] L 23 It is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof;

[0114] L4 is a peptide residue composed of amino acids or -NRa-alkylene-NRa-; wherein the alkylene group and the amino acid are unsubstituted or optionally further substituted with one or more Ra;

[0115] L5 is any spacer unit, or L5 is a spacer unit having a side chain comprising a hydrophilic unit; the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof;

[0116] G is a leaving group;

[0117] Each occurrence of n1, n2, and n3 is independently selected from a natural number between 0 and 30;

[0118] R a Selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocyclic group, -NH-C 1-6 Alkyl, C 1-6 Alkyl NH2, -C 1-6 Alkyl NHCOC 1-6 Alkyl, -C 1-6 AlkylCONH2, C 1-6 Alkyl O-CONH, -C 1-6 AlkylNHCONH2, 6-10 membered aryl and 5-13 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl;

[0119] The conditions are:

[0120] When L5 is any spacer unit, L 23 for or L 23 It is a chemically linked structure comprising 1 to 30 hydrophilic units and simultaneously comprises a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace;

[0121] Each occurrence of n17 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28;

[0122] Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0123] 9. A compound as shown in formula 1-5-2 or a pharmaceutically acceptable salt thereof, TM-L1-L2-L3-L4-L5-G Formula 1-5-2

[0124] Wherein, T is the linker unit;

[0125] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace;

[0126] L1 is selected from a single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 2-10 Alkylene, and C 1-10 1, 2, 3 or more combinations of heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a replace;

[0127] L2 is a single bond or -(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -(OCH2CH2) n1 -;

[0128] L3 is selected from a single bond, -C(O)-, -Cy1-C 1-10 Alkylene-C(O)-, -Cy1-C(O)-, and -Cy1-(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -C(O)-; Cy1 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more Ra Preferably, the arylene, heteroarylene, cycloalkylene, heterocycloalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Substitution; preferably, Cy1 is selected from Preferably, Cy1 is selected from

[0129] L4 is a peptide residue consisting of amino acids; wherein the amino acids are not substituted or are optionally further substituted with one or more R a replace;

[0130] L5 is a spacer unit having a side chain comprising a hydrophilic unit;

[0131] G is a leaving group;

[0132] Each occurrence of n1, n2, and n3 is independently selected from a natural number between 0 and 30;

[0133] R a Selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocyclic group, -NH-C 1-6 Alkyl, C 1-6 Alkyl NH2, -C 1-6 Alkyl NHCOC 1-6 Alkyl, -C 1-6 AlkylCONH2, C 1-6 Alkyl O-CONH, -C 1-6 AlkylNHCONH2, 6-10 membered aryl and 5-13 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl.

[0134] 10. The compound according to claim 7 or 8 or a pharmaceutically acceptable salt thereof, wherein:

[0135] L5 is

[0136] L a Selected from single bond, C 2-10Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-10 Alkylene, and C 2-10 1, 2, 3 or more combinations of heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by one or more R a Substituted; preferably, L a Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace;

[0137] Cy2 is selected from 6-13 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, wherein the arylene, heteroarylene, cycloalkylene, heterocycloalkylene is unsubstituted or optionally further substituted with one or more R a Preferably, Cy2 is selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene, unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace;

[0138] L b Selected from single bond, alkynylene, alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by one or more R a Substituted; preferably L b Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-61, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace;

[0139] L c Selected from CR a R s , R s is a side chain comprising 1-30 hydrophilic units, wherein the hydrophilic units are selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic units are selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, R s Selected from

[0140] Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0141] Each occurrence of n is independently selected from any integer between 1 and 30. Preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0142] L d Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-、C1 -10 Alkylene, and C 1-10 1, 2, 3 or more combinations of heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by one or more R a Substituted; preferably L d Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 Ra replace.

[0143] 11. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, TM-L1-M a -L6-L7-G formula 1-5-4

[0144] Wherein, T is the linker unit;

[0145] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R b replace;

[0146] L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR b -、-O-、-C(O)-、-NR b -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R b replace;

[0147] M a for or M a It is a chemically linked structure comprising 1 to 30 hydrophilic units and simultaneously comprises a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace;;

[0148] L6 is a peptide residue composed of amino acids or -NR b -alkylene-NR b -; wherein the alkylene group, amino acid is unsubstituted or optionally further substituted with one or more R b replace;

[0149] L7 is a spacer unit;

[0150] G is a leaving group;

[0151] R bselected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an aryl group and a heteroaryl group.

[0152] 12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein

[0153] M a Selected from -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -CO-,

[0154] -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -CO-,

[0155] -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -CO-,

[0156] -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -CO-,

[0157] Each occurrence of n7, n9, n10, n10, n11, n13, and n14 is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0158] Each occurrence of n8 and n17 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28;

[0159] Each occurrence of n12 and n15 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15;

[0160] n12 and n15 are not 0 at the same time;

[0161] Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0162] Cy3 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5, or 6 R a Substitution; preferably, Cy3 is selected from Preferably, Cy3 is selected from and / or

[0163] L7 is selected from

[0164] X1 is selected from

[0165] Each occurrence of g is independently selected from 1, 2, 3, 4, 5, and 6;

[0166] R b selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkylCONH2, C1-C6 alkylOCONH2, C1-C6 alkylNHCONH2, C6-C 15 Aryl and 5-15 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-15 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 aryl and 5-15 membered heteroaryl are substituted with one or more substituents; preferably, R bEach occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

[0167] 13. The compound according to any one of claims 8 to 11 or a pharmaceutically acceptable salt thereof, wherein:

[0168] T is selected from R is selected from halogen, -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, wherein W is selected from amino, -NR a -C 1-6 alkyl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl may be optionally substituted with 0, 1, 2, 3, or 4 R a Replace; and / or

[0169] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or

[0170] L1 is selected from a single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or

[0171] L4 is -NR b -C 1-6 Alkylene-NR b-, or 2-7 amino acid residues, wherein the amino acids are selected from D / L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine, asparagine, which are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L4 is selected from -NH-C2H4-NH-,

[0172] and / or

[0173] G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and / or

[0174] n1, n2, n3 each occurrence are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; and / or

[0175] R a selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C6 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C6 15 aryl and 5-13 membered heteroaryl are substituted with one or more substituents; preferably, R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy;

[0176] Preferably, T is selected from R is selected from halogen, -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, wherein W is selected from amino, -NR a -C 1-6 alkyl, and / or

[0177] M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or

[0178] L1 is selected from a single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or

[0179] Cy1 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5, or 6 R a Substitution; preferably, Cy1 is selected from Preferably, Cy1 is selected from and / or

[0180] L4 is a peptide residue consisting of 2-7 amino acids, wherein the amino acids are selected from D / L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine, and asparagine, which are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L4 is selected from and / or

[0181] G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and / or

[0182] n1, n2, n3 each occurrence are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; and / or R a selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C6 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C6 15 substituted by one or more substituents in aryl and 5-13 membered heteroaryl; preferably, R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy.

[0183] 14. The compound according to any one of claims 9, 10 or 13, or a pharmaceutically acceptable salt thereof, wherein R s Selected from

[0184] Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0185] Each occurrence of n is independently selected from any integer between 1 and 30. Preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.

[0186] In one embodiment, the compound is selected from:

[0187] The third aspect of the present invention provides a compound as shown in Formula 2-1, 2-2 or 2-3 or a pharmaceutically acceptable salt thereof,

[0188] in,

[0189] T, M, L1, L2, L3, L4, L5, M a , L6, L7 and L 23 As defined above;

[0190] D is selected from the group consisting of cytotoxic drug moieties, drug moieties for treating autoimmune diseases, and anti-inflammatory drug moieties; preferably, D is selected from the group consisting of cytotoxic drug moieties; preferably, D is selected from the group consisting of topoisomerase I (TOP1) inhibitor moieties, tubulin polymerization inhibitor moieties, topoisomerase II (TOP2) inhibitor moieties, dihydrofolate reductase inhibitor moieties, DNA alkylating agent moieties, thymidine synthetase inhibitor moieties, purine nucleoside synthetase inhibitor moieties, ribonucleotide reductase inhibitor moieties, DNA polymerase inhibitor moieties, RNA polymerase II inhibitor moieties, and other compound moieties capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of (Eribulin portion) and The wavy line indicates the connection point between D and L.

[0191] In one embodiment, the compound is selected from:

[0192] n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 at each occurrence.

[0193] The fourth aspect of the present invention provides a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate is as shown in Formula 3-1,

[0194] Wherein, Ab is a ligand, and the ligand is an antibody or an antigen-binding fragment thereof;

[0195] m is any integer or decimal from 1 to 12;

[0196] D is selected from the group consisting of a cytotoxic drug moiety, a drug moiety for treating autoimmune diseases, and an anti-inflammatory drug moiety; preferably, D is a cytotoxic drug moiety; preferably, D is selected from the group consisting of a topoisomerase I (TOP1) inhibitor moiety, a tubulin polymerization inhibitor moiety, a topoisomerase II (TOP2) inhibitor moiety, a dihydrofolate reductase inhibitor moiety, a DNA alkylating agent moiety, a thymidine synthetase inhibitor moiety, a purine nucleoside synthetase inhibitor moiety, a ribonucleotide reductase inhibitor moiety, a DNA polymerase inhibitor moiety, an RNA polymerase II inhibitor moiety, and other moieties capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of (Eribulin portion) and The wavy line indicates the connection point between D and L;

[0197] L is Where T a at represents the connection point with the antibody or antigen-binding fragment thereof, L 5c at Indicates the connection point with D;

[0198] T a Selected from wherein T a On the left side of the structure Indicates the connection point with the antibody or antigen-binding fragment thereof, the T a On the right side of the structure Indicates that c connection points;

[0199] M c is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group and a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group and the heterocycloalkylene group are unsubstituted or optionally substituted by one or more R a replace;

[0200] L 1c Selected from single bond, alkynylene, alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a replace;

[0201] L 2c Selected from single bond, -(CH2) n7 -(OCH2CH2) n8 -O-(CH2)n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -C(O)-, -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -C(O)-, -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-, 1, 2, 3 or more combinations of;

[0202] n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;

[0203] n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0204] n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, and n12 and n15 are not 0 at the same time;

[0205] j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6;

[0206] Cy3 is selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a replace;

[0207] M c 、L 1c , and L 2c Not all are single bonds;

[0208] L 4c is a peptide residue consisting of amino acids or -NRa-alkylene-NRa-, wherein the alkylene, and amino acid are unsubstituted or optionally further substituted with one or more Ra;

[0209] L 5c Selected from single bond, -N(R b )-(CH2) g -O-(CH2) g -OC(O)-、-N(R b )-(CH2) g -O-(CH2-CH2-O) g -C(O)-, And when L 2c When selected from single bonds, L 5c Not for When T a for and L 1c When containing an alkynylene group, L 5c for

[0210] Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0211] X1 is selected from

[0212] g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6;

[0213] R a and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 The aryl group and the 5-13 membered heteroaryl group are substituted by 1, 2, 3 or more substituents.

[0214] In one embodiment, wherein

[0215] m is any integer or decimal from 1 to 10; preferably, m is any integer or decimal from 2 to 8; preferably, m is any integer or decimal from 2 to 6; and / or

[0216] D is selected from the group consisting of a topoisomerase I (TOP1) inhibitor portion, a tubulin polymerization inhibitor portion, a topoisomerase II (TOP2) inhibitor portion, a dihydrofolate reductase inhibitor portion, a DNA alkylating agent portion, a thymidine synthetase inhibitor portion, a purine nucleoside synthetase inhibitor portion, a ribonucleotide reductase inhibitor portion, a DNA polymerase inhibitor portion, an RNA polymerase II inhibitor portion, and other compound portions capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of (Eribulin portion) and The wavy line indicates the point where D and L connect; and / or

[0217] M c is selected from a single bond, a phenylene group, a 5-7 membered heteroarylene group, a 3-7 membered cycloalkylene group and a 3-7 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group and the heterocycloalkylene group are unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, M c Selected from single bonds, and / or

[0218] L 1c Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L 1c Selected from single bond, C 2-3 Alkynylidene, C 2-3 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-3 Alkylene and C 1-3 wherein said alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Replace; and / or

[0219] Cy3 is selected from Preferably, Cy3 is selected from and / or

[0220] L 4c is a peptide residue consisting of 2, 3, 4, 5, 6 or 7 amino acids or -NRa-C 1-6 Alkylene-NRa-, wherein the amino acid is selected from D-alanine, L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine and asparagine, and the alkylene and amino acid are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L 4c Selected from -NH-CH2CH2-NH-, and / or

[0221] L 5c Selected from: single bond, and / or

[0222] R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

[0223] In one embodiment, wherein

[0224] D is selected from (Eribulin portion) and The wavy line indicates the point where D and L connect; and / or

[0225] M c Selected from single bonds, and / or

[0226] L 1c Selected from single bond, C 2-3 Alkynylidene, C 2-3 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-3 Alkylene and C 1-3 wherein said alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Replace; and / or

[0227] L 2c Selected from single bonds, wherein n17 is independently selected from 6, 8, 12 and 24 at each occurrence; and / or

[0228] L 4c Selected from -NH-CH2CH2-NH-, and / or

[0229] L 5c Selected from: single bond, and or

[0230] R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

[0231] In one embodiment, wherein

[0232] L is Among them, T a As defined above, M, L1, L2, L3, L4, L5, M a , L6, L7 and L 23 As defined above.

[0233] In one embodiment, wherein L is selected from the following structures:

[0234] wherein n and n1 are each independently selected from any integer between 1 and 30; preferably, n and n1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;

[0235] n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 at each occurrence.

[0236] 22. A ligand-drug conjugate as shown in Formula 3-1 or 3-2, or a pharmaceutically acceptable salt thereof,

[0237] Wherein, Ab is a ligand; preferably, the ligand is an antibody or antigen-binding fragment capable of binding to nectin-4; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 1; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 2; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 4; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 3; m is any integer or decimal from 1 to 10;

[0238] D as defined in claim 8;

[0239] L is a chemical linking structure;

[0240] Preferably, L is

[0241] T a Selected from

[0242] M c is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace;

[0243] L 1c Selected from single bond, alkynylene, alkenylene, -NR a -、-O-、-C(O)-、-NR a-C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a replace;

[0244] L 2c It is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof;

[0245] L 4c is a peptide residue composed of amino acids or -NRa-alkylene-NRa-; wherein the alkylene group and the amino acid are unsubstituted or optionally further substituted with one or more Ra;

[0246] L 5c is any spacer unit;

[0247] R a Selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocyclic group, -NH-C 1-6 Alkyl, C 1-6 Alkyl NH2, -C 1-6 Alkyl NHCOC 1-6 Alkyl, -C 1-6 AlkylCONH2, C 1-6 Alkyl O-CONH, -C 1-6 AlkylNHCONH2, 6-10 membered aryl and 5-13 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl;

[0248] More preferably, L is Among them, -M-, -L1-, -L2-, -L3-, -L4-, -L5-, -M a-, L6, L7 as defined in claim 8.

[0249] 23. A ligand-drug conjugate of Formula 3 or a pharmaceutically acceptable salt thereof,

[0250] Wherein, Ab is a ligand; preferably, the ligand is an antibody or antigen-binding fragment against nectin-4; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 1; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 2; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 4; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 3;

[0251] m is any integer or decimal from 1 to 10;

[0252] D as defined in claim 6; It is a chemically connected structure;

[0253] Preferably, As defined above; preferably, T a is a linker portion for connecting ligands, preferably, T a Selected from

[0254] In one embodiment, the ligand-drug conjugate is selected from the following structures:

[0255] Wherein, Ab is a ligand, and the ligand is an antibody or an antigen-binding fragment thereof;

[0256] m and m1 are each independently selected from integers or decimals from 1 to 12 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 1 to 10 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 2 to 8 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 2 to 6 at each occurrence; preferably, m and m1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 at each occurrence; and

[0257] n1, n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8 at each occurrence.

[0258] In one embodiment, wherein

[0259] The antibody is selected from the group consisting of a chimeric antibody, a humanized antibody, and a fully human antibody;

[0260] Preferably, the antibody or antigen-binding fragment thereof is selected from anti-nectin-4 antibody, anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 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-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody and antigen-binding fragments thereof;

[0261] Preferably, the ligand is an anti-nectin-4 antibody or an antigen-binding fragment thereof;

[0262] Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and / or a light chain, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDRs), wherein the amino acid sequence of heavy chain complementarity determining region 1 (HCDR1) is shown in SEQ ID NO: 7, the amino acid sequence of heavy chain complementarity determining region 2 (HCDR2) is shown in SEQ ID NO: 8, and the amino acid sequence of heavy chain complementarity determining region 3 (HCDR3) is shown in SEQ ID NO: 9; and / or the light chain comprises a light chain variable region, wherein the light chain variable region comprises three light chain complementarity determining regions (LCDRs), wherein the amino acid sequence of light chain complementarity determining region 1 (LCDR1) is shown in SEQ ID NO: 10, the amino acid sequence of light chain complementarity determining region 2 (LCDR2) is shown in SEQ ID NO: 11, and the amino acid sequence of light chain complementarity determining region 3 (LCDR3) is shown in SEQ ID NO: 12;

[0263] Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and / or a light chain variable region, wherein the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 14; and / or the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 13;

[0264] Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and / or a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 1, and / or the amino acid sequence of the light chain is shown in SEQ ID NO: 2; or, the amino acid sequence of the light chain is shown in SEQ ID NO: 4, and / or the amino acid sequence of the heavy chain is shown in SEQ ID NO: 3; or, the antibody light chain sequence is shown in SEQ ID NO: 6, and / or the antibody heavy chain sequence is shown in SEQ ID NO: 5;

[0265] Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and / or a light chain, wherein the amino acid sequence of the light chain is shown in SEQ ID NO: 4, and / or the amino acid sequence of the heavy chain is shown in SEQ ID NO: 3.

[0266] In one aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0267] The present invention also provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or any of the aforementioned ligand-drug conjugates or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing tumors;

[0268] Preferably, the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer.

[0269] The present invention also provides a method for preventing or treating tumors, comprising administering to a subject in need thereof an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above;

[0270] Preferably, the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer.

[0271] The present invention also provides a compound or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above, for use in preventing or treating tumors;

[0272] Preferably, the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer.

[0273] Beneficial effects of the present invention:

[0274] ① The antibody-drug conjugate of the present invention achieves an average DAR value of 3.5-4.5 by adopting a novel bridged maleimide linker and a cleavable linker, significantly improving the homogeneity of the antibody-drug conjugate and specifically releasing the cytotoxic payload under the action of tumor cell lysosomes, thereby improving the safety of the drug while ensuring efficacy;

[0275] ② The nectin4-targeting antibody-drug conjugate of the present invention, using eribulin as a payload, exhibited significant inhibitory effects on triple-negative breast cancer, breast cancer, and bladder cancer tumors. In the triple-negative breast cancer MDA-MB-468 CDX model, the antibody-drug conjugate of the present invention exhibited superior efficacy compared to the positive control drugs, enfortumab vedotin and 9MW2821. Specifically, at a dose of 2 mg / kg, the antibody-drug conjugate of the present invention achieved a TGI of 100% and 99.73%, respectively, in the triple-negative breast cancer MDA-MB-468 CDX model and the breast cancer MDA-MB-453 CDX model, demonstrating significant efficacy. In the bladder cancer HT1376 CDX model, the antibody-drug conjugate of the present invention exhibited superior efficacy compared to enfortumab vedotin, with a tumor inhibition rate of 2.5 mg / kg for the antibody-drug conjugate of the present invention comparable to that of 5 mg / kg for enfortumab vedotin.

[0276] ③ Compared with Enfortumab vedotin, the antibody-drug conjugate of the present invention has better safety. In toxicology experiments on BALB / C mice and humanized mice, obvious adverse reactions and mouse deaths were observed in the Enfortumab vedotin control group, while no mouse deaths were observed in the antibody-drug conjugate group obtained by the present invention, and the survival rate was high, that is, it has better safety and can reduce the serious side effects of Nectin4 target skin toxicity to a certain extent. BRIEF DESCRIPTION OF THE DRAWINGS

[0277] Figure 1 shows the changes in tumor volume in the MDA-MB-468 model.

[0278] Figure 2 shows the changes in tumor volume in the MDA-MB-453 model.

[0279] Figure 3 shows the changes in tumor volume in the HT1376 model at a dose of 4 mg / kg.

[0280] Figure 4 shows the changes in tumor volume in the HT1376 model at a dose of 8 mg / kg.

[0281] Figure 5 shows the changes in tumor volume in the HT1376 model.

[0282] FIG6 is a graph showing the changes in tumor volume in the RT4 / Nectin 4 model.

[0283] Figure 7 shows the acute toxicity survival curve of BALB / C mice.

[0284] Figure 8 is the body weight change curve of BALB / C mice in acute toxicity.

[0285] Figure 9 shows the long-term toxicity survival curve of BALB / C mice.

[0286] Figure 10 is the body weight change curve of BALB / C mice after long-term toxicity.

[0287] Figure 11 shows the HIC analysis results of the ADC drug Enfortumab vedotin.

[0288] FIG12 is a graph showing the results of NECTIN 4-ADC-11 HIC analysis.

[0289] FIG13 is a graph showing the results of HIC analysis of NECTIN 4-ADC-18.

[0290] FIG14 is a graph showing the results of HIC analysis of NECTIN 4-ADC-26.

[0291] FIG15 shows the tumor volume inhibition rate of the MDA-MB-453 model.

[0292] FIG16 shows the MDA-MB-468 tumor volume inhibition rate.

[0293] Figure 17 shows the survival curve of the humanized mouse toxicology MTD experiment.

[0294] Figure 18 shows the body weight change rate in the toxicology MTD experiment of humanized mice.

[0295] Figure 19 shows the survival curve of repeated-dose toxicology experiments in humanized mice.

[0296] Figure 20 shows the body weight change rate in repeated-dose toxicology experiments in humanized mice.

[0297] FIG21 shows the pharmacokinetic results of MMAE and Eribulin free payload in BALB / c mice.

[0298] Figure 22 Pharmacokinetic results of plasma ADC and total antibody in BALB / c mice

[0299] Figure 23 Pharmacokinetic test results of HT1376 tumor-bearing mice DETAILED DESCRIPTION

[0300] Terms and Definitions

[0301] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meanings as commonly understood by one of ordinary skill in the art.

[0302] Certain compounds of the present invention may exist in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereomers and enantiomers), tautomers, solvates, polymorphs and isotopic compounds, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite thereof. Therefore, when referring to a "compound of the present invention" herein, it is also intended to encompass the various derivative forms of the compound described above.

[0303] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without any adverse biological effects. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, including salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as malic acid, fumaric acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, acrylic acid, mandelic acid, etc.; or (2) base addition salts, including salts formed with alkali metals such as lithium, sodium, potassium, etc.; and salts formed with alkaline earth metals such as calcium, magnesium, etc.; and salts formed with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, triethanolamine, dehydroabietylamine, etc. Other pharmaceutically acceptable salts are known to those skilled in the art.

[0304] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, prodrugs are functional derivatives that are easily converted into the desired compound in vivo. Therefore, the term "administering" in the treatment methods provided herein includes administering the compounds disclosed herein, or methods that, although not explicitly disclosed, can be converted into the compounds disclosed herein in vivo after administration to a subject to treat the various diseases described. Conventional methods for selecting and preparing suitable prodrug derivatives are described in books such as "Design of Prodrugs" (H. Bundgaard, Elsevier, 1985).

[0305] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0306] The compounds of the present invention do not have a precise stereostructure at any particular position within the compounds. The present invention encompasses all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also encompassed by the present invention. During the synthetic process for preparing such compounds, or using racemization or epimerization methods known to those skilled in the art, the resulting products may be mixtures of stereoisomers.

[0307] When the compounds of the present invention exist in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0308] When the compounds of the present invention and their pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent used to form the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and the like can be used.

[0309] The present invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of iodine (e.g. 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 34 S).

[0310] The term "ligand" refers to a macromolecular compound that recognizes and binds to an antigen or receptor associated with a target cell. The function of a ligand is to present a drug to the target cell population bound to the ligand. In some embodiments of the present invention, the ligand is represented by an Ab. The ligand can form a bond with a linker through a heteroatom on the ligand. The ligand is preferably an antibody, an antigen-binding fragment thereof, or a polypeptide. The antibody is selected from a chimeric antibody, a humanized antibody, a fully human antibody, or a murine antibody; preferably, a monoclonal antibody.

[0311] The term "drug" refers to a chemical substance that can alter or identify physiological functions and pathological states of the body and can be used to prevent, diagnose, and treat disease. Drugs include cytotoxic drugs. There is no strict distinction between drugs and poisons. Poisons are chemical substances that can have toxic effects on the body at relatively low doses, potentially damaging human health. Excessive doses of any drug can produce toxic reactions.

[0312] Cytotoxic drugs are substances that inhibit or prevent cellular function and / or cause cell death or destruction. Cytotoxic drugs can, in principle, kill tumor cells at sufficiently high concentrations. However, due to their lack of specificity, they can also induce apoptosis of normal cells while killing tumor cells, leading to serious side effects. Cytotoxic drugs include toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, radioactive isotopes, chemotherapeutic agents, antibiotics, and nucleolytic enzymes.

[0313] The term "linker unit" or "linking fragment" or "linking unit" refers to a fragment or bond in a chemical structure that is connected to a ligand at one end and to a drug at the other end, and can also be connected to other linkers before being connected to the drug.

[0314] The term "ligand-drug conjugate" refers to a ligand linked to a biologically active drug via a stable linker. In the present disclosure, a "ligand-drug conjugate" is preferably an antibody-drug conjugate (ADC), which refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a stable linker.

[0315] Drug loading, also known as drug-to-antibody ratio (DAR), is the average number of drugs coupled to each antibody in the ADC. It can be, for example, in the range of about 1 to about 12 drugs coupled to each antibody, and in certain embodiments, in the range of about 1 to about 8 drugs coupled to each antibody, preferably in the range of 2-8, 2-7, 2-6, 2-5, 2-4, 3-4, 3-5, 5-6, 5-7, 5-8 and 6-8. Exemplarily, the drug loading can be an average of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of the invention, the drug loading can be expressed as m or m1, which is a decimal or integer. Conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assay and HPLC can be used to determine the drug loading.

[0316] The term "hydrophilic unit" refers to -CH2-CH2-O-, hydrophilic amino acids, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamate glucosamine, glycosyl, phosphate, sulfonate or a combination thereof.

[0317] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0318] The term "antibody" refers to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and order of the constant region of immunoglobulins' heavy chains vary, resulting in different antigenicity. Consequently, immunoglobulins can be divided into five classes, or isotypes, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε, respectively. Within the same class, Igs are further divided into subclasses based on the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five Ig classes can have either kappa or lambda chains. The antibodies disclosed herein are preferably specific antibodies against cell surface antigens on target cells, and non-limiting examples thereof include the following antibodies: anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 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 antibody. Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody or an antigen-binding fragment thereof; more preferably, the antibody or antigen-binding fragment thereof is an anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-HER3 (ErbB3) antibody, anti-LIV-1 antibody, anti-ROR1 antibody or an antigen-binding fragment thereof; most preferably, the antibody or antigen-binding fragment thereof is Sacituzumab, Trastuzumab or Pertuzumab.

[0319] The antibodies of the present invention include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, with humanized antibodies and fully human antibodies being preferred.

[0320] The term "murine antibody" as used herein refers to antibodies produced in mice according to the knowledge and skills in the art. During production, a test subject is injected with a specific antigen and then a hybridoma expressing an antibody with the desired sequence or functional properties is isolated.

[0321] The term "chimeric antibody" refers to an antibody created by fusing the variable region of a mouse antibody with the constant region of a human antibody, which can mitigate the immune response induced by the mouse antibody. To create a chimeric antibody, one must first establish a hybridoma that secretes mouse-specific monoclonal antibodies. The variable region genes are then cloned from the mouse hybridoma cells. Furthermore, the constant region genes of the human antibody are cloned as needed. The mouse variable region genes and the human constant region genes are then linked to form a chimeric gene, which is then inserted into an expression vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic system.

[0322] The term "humanized antibody," also known as a CDR-grafted antibody, refers to an antibody produced by grafting murine CDR sequences onto a human variable region framework, i.e., different types of human germline antibody framework sequences. This overcomes the xenobiotic response induced by chimeric antibodies due to the presence of a large amount of murine protein.

[0323] 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 are both human, eliminating immunogenicity and toxic side effects.

[0324] The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Examples of binding fragments included in "antigen-binding fragments" include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge on the hinge region, (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a single domain or dAb fragment (Ward et al., (1989) Nature 341: 544-546), which consists of a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii) a combination of two or more isolated CDRs, optionally connected by a synthetic linker. In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be connected by synthetic linkers using recombinant methods, so that they can be produced as a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85: 5879-5883). Such single-chain antibodies are also intended to be included in the term "antigen-binding fragment" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for functionality in the same manner as for intact antibodies. Antigen-binding portions can be produced by recombinant DNA technology or by enzymatic or chemical fragmentation of intact immunoglobulins.

[0325] Fab is an antibody fragment having a molecular weight of approximately 50,000 and antigen-binding activity, among fragments obtained by treating IgG antibody molecules with the protease papain (cleaving the amino acid residue at position 224 of the H chain), in which approximately half of the N-terminal side of the H chain and the entire L chain are bound together by a disulfide bond.

[0326] F(ab')2 is an antibody fragment having a molecular weight of about 100,000 and antigen-binding activity, obtained by digesting the portion below the two disulfide bonds in the hinge region of IgG with the enzyme pepsin, and comprises two Fab regions linked at the hinge position.

[0327] Fab' is an antibody fragment having a molecular weight of about 50,000 and antigen-binding activity, obtained by cleaving the disulfide bond of the hinge region of the above-mentioned F(ab')2.

[0328] Furthermore, the Fab' fragment of the antibody can be produced by inserting a DNA encoding the Fab' fragment into a prokaryotic expression vector or a eukaryotic expression vector and introducing the vector into a prokaryotic or eukaryotic organism to express the Fab'.

[0329] The term "single-chain antibody", "single-chain Fv" or "scFv" refers to a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker. Such scFv molecules can have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof, for example, variants using 1-4 repeats (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448). Other linkers useful in the present disclosure are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol.

[0330] The term "CDR" refers to one of the six hypervariable regions in the variable domain of an antibody that primarily contribute to antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat EA et al. (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242). As used herein, the Kabat definition of CDR is only applied to CDR1, CDR2, and CDR3 (LCDR1, LCDR2, LCDR3, or L1, L2, L3) of the light chain variable domain, and CDR1, CDR2, and CDR3 (HCDR1, HCDR2, HCDR3, or H1, H2, H3) of the heavy chain variable domain.

[0331] The term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid connected thereto. In one embodiment, a vector is a "plasmid", which refers to a circular double-stranded DNA loop into which another DNA segment can be connected. In another embodiment, a vector is a viral vector, in which another DNA segment can be connected to a viral genome. Vectors disclosed herein can autonomously replicate in the host cell into which they have been introduced (e.g., bacterial vectors and additional mammalian vectors with a bacterial origin of replication) or can be integrated into the genome of the host cell after introducing the host cell, thereby replicating (e.g., non-additional mammalian vectors) with the host genome.

[0332] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms. 1-6 "Alkyl" refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). For example, "C 1-6 The "alkyl" group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl, etc.

[0333] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0334] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyls include spirocyclic, fused, and bridged heterocyclyls.

[0335] The term "aryl" refers to a 6- to 15-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, with phenyl being preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

[0336] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 15 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0337] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens.

[0338] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms.

[0339] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0340] The terms "substituted" and "substituted" mean that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valency in the present context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0341] If a substituent is described as "optionally substituted with...", the substituent may be (1) unsubstituted, or (2) substituted. If an atom or group is described as optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced with independently selected, optional substituents. If a substituent is described as "independently selected from" or "each independently is," each substituent is selected independently of the others. Thus, each substituent may be the same as or different from another substituent. For example, when a substituent or substitution position or different substituents or substitution positions have R groups (such as, but not limited to, R2, R3, Rh, Ri, Rx, and / or Ry) that may be designated by the same or different symbols, each R is selected independently of the others, i.e., may be the same or different. The same is true for the selection of numerical values ​​such as d, g, m, and n.

[0342] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0343] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0344] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0345] As used herein, a "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the active ingredient is administered and which is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

[0346] As used herein, the term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") refers to an amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the appearance of the condition or its symptoms.

[0347] As used herein, unless otherwise indicated, the term "treat," ...

[0348] Example

[0349] The experimental methods in the following examples are conventional methods unless otherwise specified. The chemical raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified. The abbreviations and their meanings appearing in this article are as follows

[0350] Cell name and origin

[0351] Unless otherwise stated, the cell strains or cell lines used in the examples of the present invention can be obtained through commercial channels.

[0352] Example 1:

[0353] Synthesis route:

[0354] Synthesis of intermediate 1-3:

[0355] 1-1 (200 mg, 0.46 mmol) was dissolved in DMF (2 mL), and 1-2 (eribulin mesylate, 351 mg, 0.46 mmol), HATU (209 mg, 0.55 mmol), and DIEA (227 μL, 1.38 mmol) were added sequentially. The mixture was allowed to react overnight at room temperature. Purification was performed by reverse-phase column chromatography, and the solvent was removed by distillation under reduced pressure to obtain 1-3 (190 mg, 36%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1148.9.

[0356] Synthesis of intermediate 1-4:

[0357] 1-3 (79 mg, 0.058 mmol) was dissolved in DCM (5 mL) and HCl / EA (4 M, 72.5 μL) was added. The mixture was reacted at room temperature for 4 h. The solvent was removed by distillation under reduced pressure and the product was used directly in the next step without further purification. LC-MS (ESI): m / z found [M+H] + =1048.75.

[0358] Synthesis of compound 1:

[0359] Intermediate 1-4 (25 mg, 0.024 mmol) was dissolved in DMF (2 mL), and maleimide-diethylene glycol-carboxylic acid (6.13 mg, 0.024 mmol), HATU (10.88 mg, 0.029 mmol), and DIEA (19.7 μL, 0.119 mmol) were added sequentially. The mixture was reacted at room temperature for 3 h. Pre-HPLC preparation and lyophilization afforded Compound 1 (6.7 mg, 21.8%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1288.00.

[0360] Example 2:

[0361] Synthesis route:

[0362] Synthesis of intermediate 2-3:

[0363] Compound 2-1 (500 mg, 1.22 mmol) was dissolved in DMF (10 mL), and compound 2-2 (150 mg, 1.22 mmol), HATU (464 mg, 1.22 mmol), and DIEA (604 μL, 3.66 mmol) were added sequentially. The mixture was reacted at room temperature for 5 h. Purification by reverse-phase column chromatography (H2O:MeCN=1:2) and lyophilization afforded 2-3 (580 mg, 92.3%) as a pale yellow solid. LC-MS (ESI): m / z found [M+2H]+ =517.2.

[0364] Synthesis of intermediate 2-4:

[0365] Compound 2-3 (580 mg, 1.12 mmol) was dissolved in DMF (8 mL), and di(p-nitrobenzene) carbonate (410 mg, 1.35 mmol) and DIEA (743 μL, 4.50 mmol) were added sequentially. The mixture was reacted at room temperature for 4 h. Purification by reverse-phase column chromatography (H2O:MeCN=30:70) and lyophilization afforded 2-4 (502 mg, 66.0%) as a yellow solid. LC-MS (ESI): m / z found [M+H] + =681.2.

[0366] Synthesis of intermediate 2-5:

[0367] Compound 2-4 (50 mg, 0.074 mmol) was dissolved in DMF (3 mL), and eribulin mesylate (54 mg, 0.074 mmol), HOBt (10 mg, 0.074 mmol), and DIEA (24 μL, 0.147 mmol) were added sequentially. The mixture was reacted at room temperature for 2 h. The mixture was purified by reverse-phase column chromatography (H2O:MeCN=1:2) and lyophilized to afford 2-5 (60 mg, 64.5%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1272.85.

[0368] Synthesis of intermediate 2-6:

[0369] Compound 2-5 (60 mg, 0.047 mmol) was dissolved in DMF (2 mL) and diethylamine (50 μL) was added under nitrogen in an ice bath. The reaction was allowed to proceed at room temperature for 2 h. Diethylamine was removed by distillation under reduced pressure, and the product was purified by reverse phase column chromatography (H2O:MeCN=2:1) ​​and lyophilized to obtain a colorless oil 2-6 (25 mg, 51%). LC-MS (ESI): m / z found [M+H] + =1049.85.

[0370] Synthesis of compound 2:

[0371] Intermediate 2-6 (25 mg, 0.024 mmol) was dissolved in DMF (2 mL), and maleimide-diethylene glycol-carboxylic acid (6 mg, 0.024 mmol), HATU (9 mg, 0.024 mmol), and DIEA (12 μL, 0.072 mmol) were added sequentially. The mixture was reacted at room temperature for 3 h. Pre-HPLC preparation and lyophilization afforded compound 2 (3.5 mg, 11.3%) as a white solid. LC-MS (ESI): m / z found [M+H]+ =1289.90.

[0372] Example 3:

[0373] Synthesis route:

[0374] Synthesis of intermediate 3-2:

[0375] Compound 3-1 (500 mg, 1.47 mmol) was dissolved in MeCN (7.5 mL). HOSU (178 mg, 1.55 mmol) and DCC (319 mg, 1.55 mmol) were added sequentially under ice-cooling, and the mixture was allowed to react at room temperature for 4 h. The white insoluble solid was removed by filtration, and the filtrate was concentrated by vacuum distillation to obtain a white solid 3-2, which was used directly in the next step without further purification. LC-MS (ESI): m / z found [M+H2O] + =454.2.

[0376] Synthesis of intermediate 3-3:

[0377] Intermediate 3-2 (700 mg, 1.148 mmol) was dissolved in DMF (5 mL), and Nε-(tert-butyloxycarbonyl)-L-lysine (283 mg, 1.148 mmol) and DIEA (190 μL) were added sequentially. The mixture was reacted at room temperature for 5 h. The mixture was purified by reverse phase column chromatography (H2O:MeCN=2:3) and lyophilized to obtain 3-3 as a white solid (570 mg, 82.4%). LC-MS (ESI): m / z found [M+H] + =567.2.

[0378] Synthesis of intermediate 3-4:

[0379] Intermediate 3-3 (200 mg, 0.35 mmol) was dissolved in DMF, and 4-aminobenzyl alcohol (43.1 mg, 0.35 mmol), HATU (51.7 mg, 0.399 mmol), and DIEA (65.9 μL, 0.399 mmol) were added sequentially. The mixture was reacted at room temperature until the starting material disappeared. Purification by reverse-phase column chromatography (63% MeCN:H2O) and lyophilization afforded 3-4 as a white solid (210.6 mg, 89.4%). LC-MS (ESI): m / z found [M+H] + =673.55.

[0380] Synthesis of intermediate 3-5:

[0381] Intermediate 3-4 (210 mg, 0.312 mmol) was dissolved in DMF (3 mL). Di(p-nitrobenzene) carbonate (105 mg, 0.344 mmol) and DIEA (81 mg, 0.625 mmol) were added sequentially under nitrogen in an ice bath. The reaction was allowed to react at room temperature overnight. Reverse-phase column chromatography (H2O:MeCN = 1:3) was performed and the product was lyophilized to afford 3-5 as a white solid (117 mg, 44.1%). LC-MS (ESI): m / z found [M+H] + =837.6.

[0382] Synthesis of intermediate 3-6:

[0383] Intermediate 3-5 (110 mg, 0.131 mmol) was dissolved in DMF (3 mL), and eribulin mesylate (96 mg, 0.131 mmol), HOBt (18 mg, 0.131 mmol), and DIEA (34 mg, 0.262 mmol) were added sequentially. The mixture was reacted at room temperature for 3 h. The product was purified by reverse-phase column chromatography (H2O:MeCN=2:3) and lyophilized to afford 3-6 as a white solid (70 mg, 37.4%). LC-MS (ESI): m / z found [M-56+H] + =1385.95.

[0384] Synthesis of intermediate 3-7:

[0385] 3-6 (60 mg, 0.042 mmol) was dissolved in DMF (3 mL) and diethylamine (75 μL) was added under nitrogen protection in an ice bath. The reaction was allowed to proceed at room temperature for 2 h. Reverse-phase column chromatography (H2O:MeCN = 1:1) was used for purification and lyophilization to obtain a colorless solid 3-7 (25 mg, 45.5%). LC-MS (ESI): m / z found [M+H] + =1207.00.

[0386] Synthesis of intermediate 3-8:

[0387] Intermediate 3-7 (25 mg, 0.022 mmol) was dissolved in DMF, and maleimide-PEG2-succinimide ester (8 mg, 0.022 mmol) and DIEA (7 mg, 0.044 mmol) were added sequentially. The mixture was reacted at room temperature for 3 h. Purification by reverse phase column chromatography (H2O:MeCN=2:3) and lyophilization afforded 3-8 as a colorless oil (20 mg, 62.5%). LC-MS (ESI): m / z found [M-100+H] + =1347.15.

[0388] Synthesis of compound 3:

[0389] Intermediate 3-8 (10 mg, 0.007 mmol) was dissolved in DCM (1 mL) and TFA (0.4 mL) was added. The mixture was reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, and the mixture was dissolved in a small amount of DMF. The mixture was prepared by Pre-HPLC and lyophilized to obtain compound 3 as a white solid. LC-MS (ESI): m / z found [M+H] + =1346.00.

[0390] Example 4:

[0391] Synthesis route:

[0392] Synthesis of intermediate 4-2:

[0393] Under ice-cooling, 4-1 (3 g, 7.93 mmol) was slowly added to HBr-AcOH (33%, 20 mL) and allowed to react overnight at room temperature. The mixture was diluted with DCM and extracted with water. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and concentrated by distillation under reduced pressure to obtain a brown oil 4-2 (3.1 g, 98.7%). LC-MS (ESI): m / z found [M+H] + =397.0.

[0394] Synthesis of intermediate 4-4:

[0395] Dissolve 5-formylsalicylic acid (4-3, 400 mg, 2.4 mmol) in DMF (5 mL) and add mono-Boc-ethylenediamine (460 mg, 2.9 mmol), EDCI (560 mg, 2.9 mmol), and HOBt (400 mg, 2.9 mmol) in an ice bath under nitrogen. React at room temperature for 5 h. Purify by reverse-phase column chromatography (H2O:MeCN=3:2) and lyophilize to obtain a light yellow solid 4-4 (530 mg, 71.7%). LC-MS (ESI): m / z found [M+H-56] + =253.0.

[0396] Synthesis of intermediate 4-5:

[0397] 4-4 (300 mg, 0.974 mmol) was dissolved in MeCN (10 mL). Intermediate 4-2 (425 mg, 1.071 mmol) and Ag2O (451 mg, 1.948 mmol) were added sequentially in an ice bath under nitrogen protection. The mixture was allowed to react overnight at room temperature. The mixture was filtered through Celite and the filtrate was concentrated by distillation under reduced pressure. The filtrate was purified by normal phase column chromatography (DCM:EA=1:1) to obtain 4-5 (498 mg, 82.0%) as a white oil. LC-MS (ESI): m / z found [M+H-100] +=525.2.

[0398] Synthesis of intermediate 4-6:

[0399] Intermediate 4-5 (250 mg, 0.477 mmol) was dissolved in EA, and Pd / C was added. The mixture was allowed to react at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through Celite and purified by a normal phase column (DCM:MeOH = 19:1). The mixture was then evaporated under reduced pressure to afford a colorless solid 4-6 (150 mg, 50.3%). LC-MS (ESI): m / z found [M+H-100] + =527.0.

[0400] Synthesis of intermediate 4-7:

[0401] Intermediate 4-6 (150 mg, 0.285 mmol) was dissolved in DMF (3 mL). Di(p-nitrobenzene) carbonate (96 mg, 0.313 mmol) and DIEA (94 μL) were added under nitrogen in an ice bath. The mixture was then allowed to react overnight at room temperature. Purification by reverse-phase column chromatography and lyophilization afforded 4-7 (210 mg, 93.0%) as a white solid. LC-MS (ESI): m / z found [M+H-100] + =692.2.

[0402] Synthesis of intermediate 4-8:

[0403] 4-7 (210 mg, 0.265 mmol) was dissolved in DMF, and Eribulin (194 mg, 0.265 mmol), HOBt (36 mg, 0.265 mmol), and DIEA (88 μL) were added sequentially. The mixture was allowed to react at room temperature for 2 h. Purification by reverse-phase column chromatography (H2O:MeCN=1:3) and lyophilization afforded 4-8 (228 mg, 62.3%) as a colorless solid. LC-MS (ESI): m / z found [M-100 / 2+H] + =641.8.

[0404] Synthesis of intermediate 4-9:

[0405] 4-8 (180 mg, 0.13 mmol) was dissolved in MeOH (2 mL), and LiOH·H2O (54 mg, 1.3 mmol) and H2O (2 mL) were added. The reaction was allowed to react at room temperature for 1.5 h. 0.5 M hydrochloric acid was added to adjust the pH to 5, and the methanol was removed by vortexing. The residue was extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by reverse column chromatography (H2O:MeCN=2:3) and lyophilized to afford 4-9 (157 mg, 97.5%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1242.85.

[0406] Synthesis of intermediate 4-10:

[0407] 4-9 (157 mg, 0.126 mmol) was dissolved in DCM (10 mL), TFA (1 mL) was added, and the mixture was allowed to react at room temperature for 1.5 h. Purification by reverse-phase column chromatography (H2O:MeCN=2:3) and freeze-dried to give 4-10 (60 mg, 41.7%) as a yellow solid. LC-MS (ESI): m / z found [M+H] + =1142.80.

[0408] Synthesis of compound 4:

[0409] 4-10 (30 mg, 0.026 mmol) was dissolved in DMF (2 mL), and maleimide-PEG2-succinimide ester (9 mg, 0.026 mmol) and DIEA (6.79 mg, 0.053 mmol) were added sequentially. The mixture was reacted at room temperature for 3 h. Pre-HPLC purification and lyophilization afforded compound 4 (2.7 mg, 7.5%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1381.95.

[0410] Example 5:

[0411] Synthesis route:

[0412] Synthesis of intermediate 5-3:

[0413] Compound 5-1 (200 mg, 1.3 mmol) was dissolved in MeOH (20 mL), and compound 5-2 (384 mg, 1.58 mmol) was added. The mixture was reacted at room temperature for 1.5 h. The solvent was removed by distillation under reduced pressure, and the mixture was slurried in DCM and filtered to obtain a brown solid 5-3 (436 mg, 93.7%). LC-MS (ESI): m / z found [M+H] + =359.2.

[0414] Synthesis of intermediate 5-4:

[0415] Intermediate 5-3 (100 mg, 0.278 mmol) was dissolved in DCM, and DCC (28.9 mg, 0.138 mmol) was added. After reacting at room temperature for 30 min, 2-[2-(propargyloxy)ethoxy]ethanamine (22.1 μL, 0.153 mmol) was added and the reaction continued at room temperature for 2 h. The mixture was concentrated under reduced pressure, dissolved in a small amount of MeOH, and purified by reverse phase column chromatography (37% MeCN:H2O). The mixture was lyophilized to obtain a brownish-red solid 5-4 (75 mg, 46.1%). LC-MS (ESI): m / z found [M+H]+ =486.15.

[0416] Synthesis of intermediate 5-5:

[0417] Azide-ethylene glycol-acetic acid (9.7 mg, 0.048 mmol) was dissolved in DMF, HATU (21.7 mg, 0.057 mmol) was added, and the mixture was stirred at room temperature for 5 min. DIEA (18.5 mg, 0.143 mmol) and intermediate 2-6 (50 mg, 0.048 mmol) were then added sequentially. The reaction was continued at room temperature for 2 h. Pre-HPLC preparation and lyophilization gave 5-5 as a colorless oil (40 mg, 68%). LC-MS (ESI): m / z found [M+H] + =1234.85.

[0418] Synthesis of compound 5:

[0419] Intermediates 5-5 (40 mg, 0.324 mmol) and 5-4 (31 mg, 0.648 mmol) were dissolved in THF (0.5 mL) and EtOH (1.5 mL). CuSO4·5H2O (8 mg, 0.324 mmol) and ascorbic acid (6 mg, 0.324 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen for 2 h. Pre-HPLC preparation and lyophilization afforded compound 5 (8 mg, 14.4%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1719.95.

[0420] Example 6:

[0421] Synthesis route:

[0422] Synthesis of intermediate 6-1:

[0423] Except that the starting material was replaced with 2-azidoacetic acid, the rest of the experimental steps were the same as those for the synthesis of intermediate 5-5 in Example 5 to obtain a light purple solid 6-1 (16 mg, 49%). LC-MS (ESI): m / z found [M+H] + =1132.80.

[0424] Synthesis of compound 6:

[0425] Except that intermediate 5-5 was replaced by intermediate 6-1, the remaining steps were the same as those for the synthesis of compound 5 to obtain white solid compound 6 (1.94 mg, 27.3%).

[0426] Example 7:

[0427] Synthesis route:

[0428] Synthesis of intermediate 7-2:

[0429] At room temperature, 2-amino-1-(4-nitrophenyl)-ethanone hydrochloride (7-1, 2 g, 9.23 mmol) was dissolved in DCM (20 mL), and KCO (3.8 g, 27.7 mmol) was dissolved in HO (8 mL). After cooling, KCO solution and (Boc)O (2.012 g, 9.23 mmol) were added. The reaction was allowed to react at room temperature for 2 h. TLC monitored the complete reaction. The reaction solution was extracted with DCM, washed with saturated NaCl, dried over anhydrous NaSO, and filtered. The organic phase was concentrated and purified by medium-pressure liquid chromatography (petroleum ether:ethyl acetate = 83:17) to afford product 7-2 (980 mg, 37.9% yield). LC-MS (ESI): m / z found [(M-100)+H] + =181.2.

[0430] Synthesis of intermediate 7-3:

[0431] Compound 7-2 (980 mg, 3.5 mmol) was dissolved in EtOH (20 mL) at room temperature, and NaBH₄ (200 mg, 5.28 mmol) was added. The mixture was allowed to react at room temperature for 2 h under N₂ protection. LC-MS confirmed the complete reaction of the starting material. The reaction solution was extracted with EA / H₂O, and the organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated. Purification by medium-pressure liquid chromatography (petroleum ether:ethyl acetate = 3:1) afforded product 7-3 (590 mg, 60% yield). LC-MS (ESI): m / z found [(M-56)+H] + =227.20.

[0432] Synthesis of intermediate 7-4:

[0433] Compound 7-3 (590 mg, 2.09 mmol) was dissolved in MeOH (10 mL) at room temperature, and Pd / C (22.2 mg, 0.209 mmol) was added. The mixture was reacted under H2 for 4 h at room temperature. LC-MS monitored the complete reaction of the starting material. The reaction solution was filtered, the filtrate was concentrated, and purified by medium pressure liquid chromatography (petroleum ether:ethyl acetate = 3:7) to obtain product 7-4 (450 mg, yield 85%). LC-MS (ESI): m / z found [(M-56)+H] + =179.20.

[0434] Synthesis of intermediate 7-5:

[0435] Compound 7-4 (450 mg, 1.78 mmol) was dissolved in DMF (4 mL) at room temperature and stirred for 5 min. DIEA (692 mg, 5.34 mmol) and N-[Fluorenylmethoxycarbonyl]-L-valyl-L-alanine (732 mg, 1.78 mmol) were added sequentially and reacted at room temperature for 2 h. The product was purified by reverse-phase column chromatography (48% MeCN in H2O) and concentrated to afford product 7-5 (1.05 g, 91% yield). LC-MS (ESI): m / z found [(M-100)+H] + =546.5.

[0436] Synthesis of intermediate 7-6:

[0437] Compound 7-5 (800 mg, 1.24 mmol) was dissolved in MeOH (5 mL) at room temperature, and 4 M HCl / EA (3 mL, 12.4 mmol) was added. The mixture was reacted at room temperature for 4 h, and then purified by reverse-phase column chromatography (50% MeCN in H2O) and lyophilized to obtain product 7-6 (380 mg, 56% yield). LC-MS (ESI): m / z found [M+H] + =545.2.

[0438] Synthesis of intermediate 7-7:

[0439] Compound 7-6 (380 mg, 0.698 mmol) was dissolved in DMF (5 mL) at room temperature, and DIEA (270.5 mg, 2.09 mmol) and methyl-PEG8-NHS (355.5 mg, 0.698 mmol) were added. The mixture was reacted at room temperature for 2 h. LC-MS confirmed the substantial reaction of the starting materials. The reaction solution was purified by reverse-phase column chromatography (42% MeCN in H2O) and lyophilized to obtain product 7-7 (350 mg, 53.4% ​​yield). LC-MS (ESI): m / z found [M+H] + =939.7.

[0440] Synthesis of intermediate 7-8:

[0441] Compound 7-7 (350 mg, 0.373 mmol) was dissolved in DMF (4 mL) at room temperature, and DIEA (48 mg, 0.373 mmol) and di(p-nitrobenzene) carbonate (226.7 mg, 0.746 mmol) were added. The mixture was reacted at room temperature for 2 h. The mixture was purified by reverse-phase column chromatography (50% MeCN in H2O) and lyophilized to obtain product 7-8 (120 mg, 29% yield). LC-MS (ESI): m / z found [M+H] + =1104.70.

[0442] Synthesis of intermediate 7-9:

[0443] Compound 7-8 (60 mg, 0.054 mmol) was dissolved in DMF (2 mL) at room temperature, and HOBT (8.1 mg, 0.059 mmol), DIEA (21 mg, 0.163 mmol), and eribulin mesylate (40 mg, 0.054 mmol) were added. The mixture was allowed to react at room temperature for 2 h. LC-MS confirmed the complete reaction of the starting material. The reaction solution was purified by reverse-phase C-18 column (45% MeCN in H2O) and lyophilized to obtain product 7-9 (47 mg, 51% yield). LC-MS (ESI): m / z found [M / 2+H] + =848.45.

[0444] Synthesis of intermediate 7-10:

[0445] Compound 7-9 (47 mg, 0.0277 mmol) was dissolved in DMF (1 mL) at room temperature, and diethylamine (125 μl) was added and reacted at room temperature for 4 h. The reaction solution was filtered, purified by Pre-HPLC, and lyophilized to obtain product 7-10 (25 mg, 62% yield). LC-MS (ESI): m / z found [M / 2+H] + =737.15.

[0446] Synthesis of compound 7:

[0447] Compound 7-10 (10 mg, 6.79 μmol) was dissolved in DMF (1 mL) at room temperature, and DIEA (1.75 mg, 13.58 μmol) and maleimide-PEG2-succinimide ester (7.2 mg, 20.37 μmol) were added. The mixture was reacted at room temperature for 4 h. After LC-MS monitoring showed that the starting material was no longer reduced, the reaction solution was filtered, purified by Pre-HPLC, and lyophilized to obtain product 7 (3.3 mg, 28.4% yield). LC-MS (ESI): m / z found [M / 2+H] + =857.10. 1H NMR(400MHz, DMSO-d6)δ9.93(s,1H),8.38(d,J=8.0Hz,1H),8.19(d,J=8.0Hz,1H),8.01–7 .90(m,1H),7.87(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.23(d,J= 8.0Hz,1H),7.02(d,J=4.0Hz,4H),6.55(s,1H),5.52(s,2H),5.32(t,J=4.0Hz,3H),5.02(d ,J=20.0Hz,2H),4.83(s,2H),4.75(s,2H),4.63(s,2H),4.58–4.50(m,4H),4.25(d,J=12.0 Hz,2H),4.13–4.07(m,4H),3.84–3.62(m,6H),3.57–3.52(m,8H),3.49(d,J=4.0Hz,32H),3 .47–3.38(m,4H),3.24(s,4H),3.23(s,6H),2.93(s,4H),2.83(d,J=8.0Hz,2H),2.67(t,J= 4.0Hz,2H),2.35–2.30(m,2H),2.00(dd,J=12.0,4.0Hz,4H),1.91(d,J=4.0Hz,2H),1.67(d ,J=12.0Hz,2H),1.32–1.28(m,2H),1.23(s,4H),1.03(d,J=8.0Hz,6H),0.88–0.83(m,3H).

[0448] Example 8:

[0449] Synthesis route:

[0450] Synthesis of compound 8:

[0451] The experimental steps were the same as those in Example 7, except that maleimide-PEG2-succinimide ester was replaced with 6-(maleimido)hexanoic acid succinimide ester, to obtain compound 8 (2.2 mg, 19.5%) as a white solid. LC-MS (ESI): m / z found [M / 2+H] + =834.20.

[0452] Example 9:

[0453] Synthesis route:

[0454] Synthesis of intermediate 9-3:

[0455] Compound 9-1 (250 mg, 0.736 mmol) was dissolved in DMF and added with compound 9-2 (300 mg, 0.590 mmol) and DIEA (124 mg, 0.874 mmol) under nitrogen in an ice bath. The mixture was allowed to react for 1 hour on ice and then at room temperature for 4 hours. Purification by reverse-phase column chromatography (H2O:MeCN=3:2) and lyophilization afforded 9-3 as a pale yellow oil (401 mg, 74.2%). LC-MS (ESI): m / z found [M+H] + =735.3.

[0456] Synthesis of intermediate 9-5:

[0457] Compound 9-4 (300 mg, 0.499 mmol) was dissolved in DMF, and di(p-nitrobenzene) carbonate (604 mg, 0.998 mmol) and DIEA (130 μL, 0.749 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. The mixture was extracted with EA / H₂O, washed with saturated aqueous NaCl, dried over anhydrous Na₂SO₄, filtered, concentrated by vacuum distillation, and purified by normal phase column chromatography (DCM:MeOH = 93:7). The solvent was removed by vacuum distillation to obtain 9-5 (249 mg, 65%) as a white solid. LC-MS (ESI): m / z found [M+H] + =767.2.

[0458] Synthesis of intermediate 9-6:

[0459] Compound 9-5 (27.9 mg, 0.007 mmol) and eribulin mesylate (30 mg, 0.007 mmol) were dissolved in DMF (3 mL). HOBt (5.4 mg, 0.008 mmol) and DIEA (18.9 μL, 0.022 mmol) were added sequentially and reacted at room temperature for 2 h. The mixture was extracted with DCM / H₂O (30 mL × 3), washed with saturated aqueous NaCl (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by normal phase column chromatography (DCM:MeOH = 91:9). The solvent was then evaporated under reduced pressure to yield 9-6 (40 mg, 81%) as a white solid. LC-MS (ESI): m / z found [M+H] + =1357.80.

[0460] Synthesis of intermediate 9-7:

[0461] Compound 9-6 (10 mg, 0.007 mmol) was dissolved in DMF (2 mL) and DBU (1.5 μL, 0.110 mmol) was added. The mixture was reacted at room temperature for 1.5 h. After the reaction was complete, the product was used directly in the next step without purification. LC-MS (ESI): m / z found [M+H] + =1135.86.

[0462] Synthesis of intermediate 9-8:

[0463] 9-7 (8.35 mg, 0.007 mmol) was dissolved in DMF, and intermediate 9-3 (5.4 mg, 0.007 mmol), HATU (3.9 mg, 0.010 mmol), and DIEA (1.2 μL, 0.007 mmol) were added sequentially. The mixture was reacted at room temperature for 2.5 h. Pre-HPLC preparation and lyophilization gave 9-8 (4 mg, 30.9%) as a white solid. LC-MS (ESI): m / z found [M / 2+H] + =927.2.

[0464] Synthesis of intermediate 9-9:

[0465] Intermediate 9-8 (24 mg, 0.013 mmol) was dissolved in DMF, DBU (2.8 μL) was added, and the mixture was allowed to react at room temperature for 2.5 h. Pre-HPLC preparation and lyophilization gave 9-9 as a white solid (10 mg, 48%). LC-MS (ESI): m / z found [M / 2+H] + =816.05.

[0466] Synthesis of compound 9:

[0467] Intermediate 9-9 (5 mg, 0.003 mmol) and N-succinimidyl maleimidoacetate (0.93 mg, 0.004 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 2.5 h. Pre-HPLC preparation and lyophilization gave compound 9 (3 mg, 56%) as a white solid. LC-MS (ESI): m / z found [M / 2+H] + =884.6. 1H NMR (400MHz, DMSO-d6) δ10.01(s,1H),8.46–8.40(m,1H),8.20(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.85( t,J=12.0Hz,1H),7.57(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),7.11(s,1H),5.99(dd,J=8.0,4.0Hz,1H),5.05 (s,2H),5.00(s,2H),4.93(s,2H),4.83(s,2H),4.75(s,2H),4.64(s,2H),4.55(d,J=4.0Hz,2H),4.35(d,J=8 .0Hz,4H),4.26(d,J=12.0Hz,2H),4.18(d,J=4.0Hz,2H),4.10(s,3H),4.07(s,2H),4.02(d,J=4.0Hz,1H),3.8 4–3.66(m,4H),3.58(t,J=16.0Hz,3H),3.49(s,30H),3.47(s,2H),3.44–3.41(m,2H),3.24(s,2H),3.08–2.8 7(m,6H),2.84(d,J=8.0Hz,1H),2.76–2.67(m,2H),2.33(d,J=8.0Hz,2H),2.30(s,2H),2.23(s,2H),2.20–2.1 0(m,2H),1.98(dd,J=20.0,8.0Hz,4H),1.92(s,4H),1.75(dd,J=12.0,4.0Hz,2H),1.71–1.65(m,4H),1.65–1. 55(m,4H),1.48(d,J=8.0Hz,2H),1.25(d,J=12.0Hz,3H),1.03(d,J=4.0Hz,3H),0.84(dd,J=12.0,8.0Hz,6H).

[0468] Example 10:

[0469] Synthesis route:

[0470] Synthesis of compound 10:

[0471] Compound 10-1 (3.3 mg, 0.012 mmol) was dissolved in DMF, and HOSU (1.99 mg, 0.017 mmol) and EDCI (3.2 mg, 0.017 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. Intermediate 9-9 (10 mg, 0.006 mmol) and DIEA (1.01 μL, 0.017 mmol) were then added, and the mixture was allowed to react at room temperature overnight. Pre-HPLC preparation and lyophilization gave compound 10 (2 mg, 17.7%) as a white solid. LC-MS (ESI): m / z found [M / 2+H] + =941.35.

[0472] Example 11:

[0473] Synthesis route:

[0474] Synthesis of intermediate 11-3:

[0475] 11-1 (100 mg, 0.326 mmol) was dissolved in THF (3 mL), and a catalytic amount of DMF was added. Oxalyl chloride (138 μL, 0.038 mmol) was added dropwise at 0°C under nitrogen. The reaction was then allowed to proceed at room temperature for 1 h, after which the solution turned clear from turbid. The reaction was then concentrated under reduced pressure. The acyl chloride intermediate was dissolved in DCM (2 mL), and TEA (453 μL, 3.26 mmol) and morpholine (11-2, 143 μL, 1.632 mmol) were added at 0°C. The reaction was then allowed to proceed at room temperature for 2 h. The product was extracted with DCM / H₂O, washed with saturated NaCl, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified on a normal phase column (MeOH:DCM). The product was concentrated under reduced pressure to afford 11-3 (141 mg, 97.3%) as a light brown oil. LC-MS (ESI): m / z found [M+H] + =445.0.

[0476] Synthesis of intermediate 11-4:

[0477] Dissolve 11-3 (2.89 g, 6.5 mmol) in EtOH (25 mL) and add NaBH4 (1.967 g, 52 mmol) twice, each time with a 0.5 h interval. Allow to react overnight at room temperature under nitrogen. Quench with saturated aqueous NH4Cl solution, extract with EA, dry over anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify with a normal phase column (10% MeOH:90% DCM). Concentrate under reduced pressure to obtain 11-4 (1.25 g, 41.1%) as a light yellow oil. LC-MS (ESI): m / z found [M+H] + =224.2.

[0478] Synthesis of intermediate 11-7:

[0479] 11-5 (200 mg, 1.142 mmol) and 11-6 (340.8 mg, 1.142 mmol) were dissolved in DMF (5 mL), and K2CO3 (316 mg, 2.284 mmol) was added. The mixture was refluxed at 100°C overnight. Extraction was performed with 1N dilute hydrochloric acid / DCM, and the mixture was dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. Purification was performed on a normal phase column (15% EA:85% PE) and concentrated under reduced pressure to obtain 11-7 (234.7 mg, 68.2%) as a light yellow oil. LC-MS (ESI): m / z found [M+H] + =302.2.

[0480] Synthesis of intermediate 11-8:

[0481] 11-7 (235 mg, 0.780 mmol) was dissolved in EtOH (8 mL), and H2O (2 mL), Fe (174.3 mg, 3.12 mmol), and NH4Cl (66.8 mg, 1.248 mmol) were added sequentially. The mixture was heated to 80°C and refluxed for 5 h. Filtered through Celite, the filtrate was concentrated under reduced pressure, and purified on a normal phase column (EA:PE). The product 11-8 (127.2 mg, 60.1%) was obtained as a light yellow oil. LC-MS (ESI): m / z found [M+H] + =272.2.

[0482] Synthesis of intermediate 11-9:

[0483] Dissolve 11-8 (23 mg, 0.085 mmol) in 1 mL of AcOH, add 2,3-dibromomaleic anhydride (21.7 mg, 0.085 mmol), and heat to 110°C and reflux for 3 h. Evaporate under reduced pressure, purify with a normal phase column (EA:PE), and concentrate under reduced pressure to obtain 11-9 (32.9 mg, 76.0%) as a white solid. LC-MS (ESI): m / z found [M+Na] + =526.8.

[0484] Synthesis of intermediate 11-10:

[0485] Dissolve 11-9 (32.9 mg, 0.065 mmol) in 2 mL of DCM, slowly add 11-4 (28.9 mg, 0.129 mmol) and DIEA (21.3 μL, 0.129 mmol) at 0°C, stir at 0°C for 5 minutes, then transfer to room temperature for 2 hours. Evaporate under reduced pressure, purify with a normal phase column, and concentrate under reduced pressure to obtain 11-10 (16.3 mg, 31.6%) as an orange solid. LC-MS (ESI): m / z found [M+H] + =794.0.

[0486] Synthesis of intermediates 11-13:

[0487] Dissolve 11-11 (1.87 g, 4.93 mmol) in DMF (10 mL), add 11-12 (0.5 g, 4.93 mmol) and EEDQ (1.46 g, 5.9 mmol) sequentially, and react at room temperature under nitrogen overnight. Purify with a reverse phase column (20% ACN:H2O) and concentrate under reduced pressure to obtain the product 11-13 (1.8 g, 78.9%) as a white solid. LC-MS (ESI): m / z found [M+H] + =463.5.

[0488] Synthesis of intermediates 11-14:

[0489] Compound 11-13 (525 mg, 1.14 mmol) was dissolved in DMF (4 mL), and (PNP)2CO (380 mg, 1.25 mmol) and DIEA (376 μL, 2.27 mmol) were added. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction as monitored by LC-MS, the product was purified by reverse phase column chromatography (H2O:ACN=1:1) to obtain a white solid product (590 mg, 82.6%). LC-MS (ESI): m / z found [M+H] + =628.45. Synthesis of Intermediate 11-15:

[0490] Compound 11-14 (300 mg, 0.48 mmol) was dissolved in DMF (3 mL), and HOBt (64 mg, 0.48 mmol), DIEA (80 μL, 0.96 mmol), and eribulin mesylate (400 mg, 0.48 mmol) were added. The mixture was reacted in an ice bath for 3 h. After completion of the reaction as monitored by LC-MS, the mixture was purified by reverse-phase column chromatography and lyophilized to obtain a white solid product (220 mg, 37.7%). LC-MS (ESI): m / z found [M+H] + =1219.60.

[0491] Synthesis of compound 11:

[0492] Compound 11-15 (200 mg, 0.16 mmol) was dissolved in DMSO (3 mL), and 11-10 (120 mg, 0.16 mmol), CuSO4·5H2O (48 mg, 0.20 mmol), and ascorbic acid (72 mg, 0.40 mmol) were added. The mixture was reacted at room temperature for 2 hours under nitrogen protection. After LC-MS monitoring, the reaction was completed, and the product was purified by HPLC and lyophilized to obtain a yellow solid product (54.1 mg, 16.8%). LC-MS (ESI): m / z found [M / 2+H] + =1007.30. 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),8.44(d,J=8.7Hz,1H),8.32(d,J=7.4Hz,1H),8.02(s,1H),7.57(d,J= 8.6Hz,2H),7.31(s,8H),7.28(s,1H),7.25(d,J=6.1Hz,2H),7.22(d,J=2.5Hz,1H),7.09(s,1H),6.00(s,1H) ,5.20(d,J=1.7Hz,2H),5.05(d,J=2.4Hz,1H),5.00(s,1H),4.94(d,J=2.4Hz,2H),4.84(s,1H),4.75(d,J=1 .8Hz,1H),4.64(td,J=4.2,3.7,1.8Hz,1H),4.56(t,J=4.2Hz,1H),4.52(s,2H),4.39(q,J=7.8Hz,1H),4.29( tt,J=10.8,6.2Hz,4H),4.17(td,J=10.2,4.2Hz,1H),4.13–4.07(m,3H),4.05–3.97(m,1H),3.84–3.75(m,3 H),3.74–3.69(m,4H),3.63–3.55(m,21H),3.25(d,J=4.0Hz,6H),2.98(h,J=10.4,8.1Hz,4H),2.84(dd,J=9. 7,2.0Hz,1H),2.74(td,J=18.0,16.9,8.0Hz,2H),2.62–2.54(m,1H),2.36–2.12(m,6H),2.03–1.88(m,7H),1 .79–1.59(m,7H),1.59–1.40(m,5H),1.39–1.26(m,5H),1.04(d,J=6.4Hz,3H),0.87(dd,J=12.4,6.7Hz,6H).

[0493] The compounds of Examples 12-19 were synthesized according to the synthetic route of Example 11. Their structures and LC-MS results are shown in the table below.

[0494] Table 1 Structural formula and LC-MS of Examples 12-19

[0495] Example 20:

[0496] Synthesis route:

[0497] Synthesis of intermediate 20-3:

[0498] At room temperature, 20-2 (500 mg) was dissolved in THF / DMF (5 mL / 5 mL), and DIEA (750 mg, 2 eq) and HATU (1.32 g, 1.2 eq) were added. After stirring at room temperature for 20 minutes, 20-1 (482 mg, 1.2 eq) was added and the mixture was allowed to react overnight at room temperature. The reaction solution was poured into water (40 V) and extracted twice with EA (40 V). The organic phases were combined and dried over anhydrous sodium sulfate. Purification by normal phase column chromatography gave a crude product, which was then purified by reverse phase column chromatography to give a yellow solid (400 mg, 47.2%). LC-MS (ESI): m / z found [M+H] + =293.

[0499] Synthesis of intermediate 20-4:

[0500] At room temperature, 20-3 (350 mg, 1 eq) was dissolved in EtOH / H2O (14 mL / 3.5 mL), and NH4Cl (128.2 mg, 2 eq) and Fe (268.5 mg, 4 eq) were added. The mixture was stirred at 78°C for 6 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered, extracted with water (60 V) and EA (40 V), and the organic phase was dried and concentrated to give a red oil (280 mg, 88.8%). LC-MS (ESI): m / z found [M+H] + =263.

[0501] Synthesis of intermediate 20-5:

[0502] At room temperature, 20-4 (250 mg, 1 eq) was dissolved in AcOH (10 V), and dibromomaleic anhydride (243 mg, 1 eq) was added. The mixture was allowed to react at 120°C for 1 hour. Upon completion of the reaction, the reaction solution was poured into water (30 V) and extracted twice with EA (20 V). The organic phases were combined, dried, and washed with silica gel. The sample was purified by normal phase column chromatography and concentrated to yield a yellow solid (320 mg, 67.3%). LC-MS (ESI): m / z found [M+H] + =501.

[0503] Synthesis of intermediate 20-6:

[0504] At room temperature, 20-5 (20 mg, 1 eq) was dissolved in DCM (1.5 ml), the atmosphere was replaced with nitrogen, and 11-4 (17.84 mg, 2 eq) and DIEA (10.32 mg, 2 eq) were added under ice-cooling. The mixture was kept under ice-cooling for 20 min, then stirred at room temperature for 2 hours. LCMS monitoring indicated that the reaction was complete and the signal was correct. The reaction solution was purified by reverse phase column chromatography and lyophilized to obtain a yellow solid (20 mg, 63.77%). LC-MS (ESI): m / z found [M+H] + =785.

[0505] Synthesis of compound 20:

[0506] At room temperature, 20-6 (5.5 mg, 1 eq) was dissolved in DMSO (0.5 ml), and 11-15 (10 mg, 1.2 eq), CuSO4·5H2O (1.76 mg, 1 eq), and ascorbic acid (1.24 mg, 1 eq) were added. The mixture was stirred at room temperature for 1.5 hours. LCMS and TLC monitoring indicated the reaction was complete. HPLC preparative purification afforded a yellow solid (6 mg, 42.8%). LC-MS (ESI): m / z found [1 / 2M+H] + =1002.

[0507] Example 21 was synthesized by referring to the synthetic route of Example 20. The structural formula and LC-MS results are shown in the table below.

[0508] Table 2 Structural formula and LC-MS of the compound of Example 21

[0509] Example 22:

[0510] Synthesis route:

[0511] Synthesis of intermediate 22-3:

[0512] At room temperature, 22-1 (3 g, 1 eq) was placed in a single-necked flask, and AcOH (10 V) was added. After sonication until the solid was completely dissolved, 22-2 (2.2 g, 1 eq) was added. The atmosphere was replaced with nitrogen three times, and the mixture was heated in an oil bath at 120°C with stirring for 1.5 h. TLC indicated the reaction was complete. After the reaction solution was cooled to room temperature, water (20 V), EA (20 V), and saturated brine (10 V) were added, and the mixture was extracted and separated. The organic phase was temporarily stored, and the aqueous phase was extracted again with EA (20 V). The organic phases were combined, dried over anhydrous sodium sulfate, and then washed with 3x silica gel. Purification by column chromatography (EA / PE = 21%) yielded a yellow oil (3.5 g, 62.6%). LC-MS (ESI): m / z found [M+H] + =426.

[0513] Synthesis of intermediate 22-4:

[0514] At room temperature, 22-3 (3 g, 1 eq) was dissolved in THF, and tert-butyl azidoacetate (1.3 g, 1.2 eq), CuSO₄·5H₂O (1.76 g, 1 eq), and ascorbic acid (1.24 g, 1 eq) were added. The atmosphere was replaced with nitrogen, and the reaction was stirred at room temperature for 1.5 hours. LCMS and TLC monitoring indicated completion of the reaction, with a positive MS signal. The reaction solution was poured into water (80 V), and EA (80 V) and saturated brine (40 V) were added. The mixture was extracted twice, and the combined organic phases were concentrated, filtered through silica gel (200-300 mesh), and purified by normal phase column chromatography to yield a yellow oil (2.58 g, 62.6%). LC-MS (ESI): m / z found [M+H] + =583.

[0515] Synthesis of intermediate 22-5:

[0516] At room temperature, 22-4 (2.5 g, 1 eq) was dissolved in Acetone (40 V), and NaN3 (1.11 g, 6 eq) was added. The mixture was protected by nitrogen and allowed to react at room temperature for 16 hours. Samples were taken for LCMS monitoring and the reaction was complete. The reaction solution was poured into water (80 V) and extracted with EA (60 V) three times. The organic phases were combined and dried over anhydrous sodium sulfate. The product was purified by normal column chromatography and concentrated under reduced pressure to obtain a yellow-green oil (1.85 g, 84.8%). LC-MS (ESI): m / z found [M+H] + =507.

[0517] Synthesis of intermediate 22-6:

[0518] At room temperature, 22-7 (1.85 g) was dissolved in EtOH (30 V), and Pd-C (1.85 g) was added. The atmosphere was replaced with hydrogen three times and stirred at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete and the signal was correct. The reaction solution was filtered and concentrated to give a red oil (1.6 g, 82.9%). LC-MS (ESI): m / z found [M+H] + =455.

[0519] Synthesis of intermediate 22-7:

[0520] At room temperature, 22-6 (400 mg, 1 eq) was dissolved in ACN (35 V), and 1,4-dibromo-2,3-butanedione (215 mg, 1.2 eq) was added and allowed to react at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete and a correct signal was obtained. The reaction solution was poured into water (70 V) and extracted with EA (50 V). The organic phases were combined, dried, and mixed with 2 g of silica gel. The sample was purified by normal column chromatography (75% EA retention). After concentration, a yellow-green oil (200 mg, 34.3%) was obtained. LC-MS (ESI): m / z found [M+H] + =663.

[0521] Synthesis of intermediate 22-8:

[0522] At room temperature, 22-7 (125 mg) was dissolved in DCM (8 mL), TFA (5 mL) was added, and the reaction was stirred at room temperature for 16 hours. LCMS monitoring showed that the reaction was complete. The product was replaced with acetonitrile and dried by spin drying at room temperature. The product was purified by HPLC and lyophilized to obtain a white solid (25 mg, 21.9%). LC-MS (ESI): m / z found [M+H] + =607.

[0523] Synthesis of compound 22:

[0524] Compound 22-8 (14 mg, 1 eq) was dissolved in DCM, and EEDQ (3 mg, 1.5 eq) and VC-PABL-Eribulin (10 mg, 0.8 eq) were added sequentially. The mixture was reacted at room temperature for 2 h. The reaction was monitored for completion by LC-MS. The product was prepared by pre-HPLC and lyophilized to obtain a white solid (1.1 mg, 4.9%). LC-MS (ESI): m / z found [M / 2+H] + =862.60.

[0525] Example 23:

[0526] Synthesis route:

[0527] Synthesis of intermediate 23-2:

[0528] At room temperature, 23-1 (500 mg, 2.448 mmol) was dissolved in acetic acid (5 mL), and 2,3-dibromomaleic anhydride (22-2, 626.4 mg, 2.448 mmol) was added. The temperature was raised to 40°C and the reaction was allowed to proceed overnight. After the reaction was complete, the product was concentrated under reduced pressure, dissolved in a small amount of DMF, and purified by dry phase column chromatography (PE:EA = 67:33) to obtain a white solid product (744.1 mg, 68.75%). LC-MS (ESI): m / z found [M-56] + =387.0.

[0529] Synthesis of intermediate 23-3:

[0530] Under ice-cooling, 23-2 (20 mg, 0.0452 mmol) was dissolved in DCM (3 mL). DIEA (15.76 μL, 0.0905 mmol) and 11-4 (20.21 mg, 0.0905 mmol) were slowly added while maintaining the ice-cooling reaction. The mixture was ventilated three times, stirred for 5 minutes, and then reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and dissolved in DMF. Pre-HPLC purification (ACN:H2O=54:46) gave a light yellow solid (13.2 mg, 80.29%). LC-MS (ESI): m / z found [M+H] + =727.4.

[0531] Synthesis of intermediate 23-4:

[0532] Under ice, 23-3 (13.2 mg, 0.018 mmol) was dissolved in DMF (2.5 mL), and HATU (8.21 mg, 0.0216 mmol) was added. After stirring for 30 min, 2-[2-(propargyloxy)ethoxy]ethanamine (2.6 mg, 0.018 mmol) and DIEA (3.135 μL, 0.018 mmol) were added sequentially. The reaction was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction solution was dried under reduced pressure, dissolved in DMF, and purified by pre-HPLC (ACN:H2O=46:54) to give a yellow solid (10.1 mg, 65.27%). LC-MS (ESI): m / z found [M+H] + =852.2

[0533] Synthesis of intermediate 23-5:

[0534] At room temperature, 23-4 (10.8 mg, 0.0126 mmol) was dissolved in DCM (2.5 mL), and HCl / EA solution (0.1 mL) was added. The mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by pre-HPLC (ACN:H2O = 23:77) to give a yellow solid (6.9 mg, 72.4%). LC-MS (ESI): m / z found [M+H] + =752.45.

[0535] Synthesis of compound 23:

[0536] At room temperature, 23-5 (6.5 mg, 0.0086 mmol) was dissolved in a mixture of EtOH (6 mL) and THF (2 mL). 11-15 (12.6 mg, 0.0104 mmol), copper sulfate pentahydrate (2.157 mg, 0.0086 mmol), and ascorbic acid (1.5 mg, 0.0086 mmol) were added. The atmosphere was purged with nitrogen three times and the mixture was allowed to react at room temperature for 3 h. After the reaction was complete, the reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, purified by pre-HPLC (ACN:H2O=26:74), and lyophilized to obtain a yellow solid (4.18 mg, 24.54%). LC-MS (ESI): m / z found [M+H / 2] + =986.3.

[0537] Except for replacing the corresponding reaction raw materials, Example 24 was synthesized by referring to Example 23 and the synthetic route. The structural formula and LC-MS are shown in the table below.

[0538] Table 3 Structural formula and LC-MS of Example 24

[0539] Example 25:

[0540] Synthesis route:

[0541] Synthesis of intermediate 25-2:

[0542] 25-1 (1 g, 0.824 mmol) was dissolved in DMF (4 mL), and 9-1 (280 mg, 0.824 mmol) and DIEA (150 μL, 0.906 mmol) were added. The mixture was allowed to react at room temperature for 4 hours. After the reaction was complete, the mixture was purified by reverse phase column chromatography and concentrated under reduced pressure to give a colorless oily product (1.15 g, 97.0%). LC-MS (ESI): m / z found [M+1] + =1440.2.

[0543] Synthesis of intermediate 25-3:

[0544] Compound 25-2 (150 mg, 0.104 mmol) was dissolved in DMF (1.5 mL), and HOSU (16 mg, 0.141 mmol) and EDCI (27 mg, 0.141 mmol) were added. After reacting at room temperature for 2 hours, DIEA (18 μL, 0.104 mmol) and 11-11 (53 mg, 0.141 mmol) were added and reacted at room temperature for 2 hours. After the reaction was complete, the product was purified by reverse phase column chromatography (H2O:ACN=1:1) to obtain a white solid product (143 mg, 76.5%). LC-MS (ESI): m / z found [M / 2+1] + =901.65.

[0545] Synthesis of intermediate 25-4:

[0546] Compound 25-3 (143 mg, 0.079 mmol) was dissolved in DMF (2 mL), and diethylamine (50 μL) was added. The mixture was allowed to react at room temperature for 3 hours. After the reaction was complete as monitored by LCMS, the product was purified by reverse phase column chromatography (H 2 O:ACN=2:1) ​​to obtain a colorless oily product (111 mg, 89.0%). LC-MS (ESI): m / z found [M / 2+1] + =790.60.

[0547] Synthesis of intermediate 25-5:

[0548] Azidoacetic acid (2.5 mg, 0.025 mmol) was dissolved in acetonitrile (2 mL), and HATU (11.4 mg, 0.030 mmol) and DIEA (8.4 μL, 0.051 mmol) were added. After reacting at room temperature for 0.5 hours, compound 25-4 (40 mg, 0.025 mmol) was added and reacted at room temperature for 3.5 hours. After LCMS monitoring indicated that the reaction was complete, the product was purified by reverse phase column chromatography (H2O:ACN=3:2) to obtain a colorless oily product (28.7 mg, 69.1%). LC-MS (ESI): m / z found [M+18 / 2+1] + =840.55.

[0549] Synthesis of intermediate 25-6:

[0550] 25-5 (45 mg, 0.024 mmol) was dissolved in DMF (1.5 mL), and (PNP)2CO (36 mg, 0.096 mmol) and DIEA (10 μL, 0.048 mmol) were added. The mixture was allowed to react at 50°C overnight. After the reaction was complete as monitored by LCMS, the product was purified by reverse phase column chromatography (H2O:ACN=1:1) to obtain the product as a colorless oil (26 mg, 59.4%). LC-MS (ESI): m / z found [M / 2+1] + =923.10.

[0551] Synthesis of intermediate 25-7:

[0552] 25-6 (26 mg, 0.014 mmol) was dissolved in DMF (1 mL), and eribulin mesylate (12 mg, 0.014 mmol), HOBT (3 mg, 0.021 mmol), and DIEA (3.5 μL, 0.021 mmol) were added. The mixture was allowed to react overnight at room temperature. After the reaction was complete as monitored by LCMS, the product was purified by reverse phase column chromatography (H2O:ACN=1:1) to give a white solid product (30.6 mg, 90.5%). LC-MS (ESI): m / z found [M / 2+1] + =1218.45.

[0553] Synthesis of compound 25:

[0554] Compound 25-7 (15 mg, 0.006 mmol) was dissolved in DMSO (1.5 mL), and 11-10 (5 mg, 0.006 mmol), copper sulfate pentahydrate (2 mg, 0.0072 mmol), and ascorbic acid (2.5 mg, 0.0144 mmol) were added. The mixture was reacted at room temperature for 2 hours under nitrogen protection. After LCMS monitoring, the reaction was completed, and the product was purified by HPLC and freeze-dried to obtain a yellow solid product (2.05 mg, 10.6%). LC-MS (ESI): m / z found [M / 3+1] + =1071.75.

[0555] Example 26:

[0556] Synthesis route:

[0557] Synthesis of intermediate 26-2:

[0558] Compound 26-1 (2 g, 3.571 mmol) was dissolved in THF (20 mL), and NaH (171 mg, 7.125 mmol) was added. The mixture was stirred on ice for 1 h, followed by the addition of bromoacetonitrile (843 mg, 7.14 mmol) and the temperature was raised to room temperature for 3 h. After completion of the reaction as monitored by LC-MS, water was added dropwise on ice to quench the reaction. The mixture was extracted with EA, dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow oil (2.1 g, 99%). LC-MS (ESI): m / z found [M+1] + =599.60.

[0559] Synthesis of intermediate 26-3:

[0560] 26-2 (1.2 g, 2.006 mmol) and (2S)-N-FMoc-6-azidohexanoic acid (800 mg) were dissolved in THF (5 mL) and EtOH (15 mL). Copper sulfate pentahydrate (505 mg, 2.028 mmol) and ascorbic acid (357 mg, 2.027 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen for 1.5 h. After completion of the reaction as monitored by LC-MS, the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure and dissolved in DMF. The product was purified by reverse phase column chromatography and concentrated to obtain a green oily liquid (1.86 g, 92.3%). LC-MS (ESI): m / z found [M+1] + =993.43.

[0561] Synthesis of intermediate 26-4:

[0562] 26-3 (1.8 g, 1.814 mmol) was dissolved in DMF (12 mL), and HATU (1.0 g, 2.631 mmol), 11-11 (711 mg, 1.873 mmol), and DIEA (604 mg, 4.682 mmol) were added sequentially. The mixture was allowed to react at room temperature for 5 h. LC-MS monitored the reaction completion, and the product was purified by reverse phase column chromatography and concentrated under reduced pressure to afford a white solid (2.3 g, 93.6%). LC-MS (ESI): m / z found [M / 2+1] + =678.45.

[0563] Synthesis of intermediate 26-5:

[0564] Compound 26-4 (2.3 g, 1.698 mmol) was dissolved in DMF (15 mL), and diethylamine (0.4 mL) was added. The mixture was allowed to react at room temperature for 1.5 h. The reaction was complete after LC-MS monitoring. The mixture was purified by reverse phase column chromatography and concentrated under reduced pressure to obtain a yellow solid (1.4 g, 73%). LC-MS (ESI): m / z found [M / 2+1] + =567.10.

[0565] Synthesis of intermediate 26-6:

[0566] Compound 26-5 (2.0 g, 1.768 mmol) was dissolved in DMF (12 mL), and maleimide-PEG2-succinimide ester (843 mg, 3.345 mmol) and DIEA (171 mg, 2.495 mmol) were added sequentially. The mixture was allowed to react at room temperature for 3 h. LC-MS monitored the reaction completion, and the mixture was purified by reverse phase column chromatography and concentrated under reduced pressure to obtain a white solid (1.1 g, 65%). LC-MS (ESI): m / z found [M / 2+1] + =635.85.

[0567] Synthesis of intermediate 26-7:

[0568] 26-6 (555 mg, 2.006 mmol) was dissolved in DMF (5 mL), and (PNP)2CO (492 mg, 2.028 mmol) and DIEA (505 mg, 2.028 mmol) were added sequentially. The reaction temperature was raised to 50°C for 2 h, then the reaction temperature was lowered to room temperature overnight. The reaction was complete as monitored by LC-MS. The product was purified by reverse phase column chromatography and concentrated under reduced pressure to afford a white solid (430 mg, 92.3%). LC-MS (ESI): m / z found [M / 2+1] + =769.43.

[0569] Synthesis of compound 26:

[0570] Compound 26-7 (50 mg, 0.032 mmol) was dissolved in DMF, and eribulin mesylate (26 mg, 0.032 mmol), HOBt (4 mg, 0.032 mmol), and DIEA (8 mg, 0.064 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. LC-MS monitored the reaction for completion, and the product was pre-HPLC prepared and lyophilized to obtain a yellow solid. LC-MS (ESI): m / z found [M / 2+1] + =1064.85. 1H NMR(400MHz, DMSO-d6)δ10.03(s,1H),8.05(q,J=20.0,8.0Hz,3H),7.78(d,J=8.0Hz,1H),7.59–7.53(m,2H),7 .30–7.20(m,2H),7.10(t,J=8.0Hz,1H),7.02(s,1H),6.55(s,1H),5.97(t,J=8.0Hz,1H),5.42(s,2H),5.08–4. 98(m,2H),4.92(s,2H),4.83(s,1H),4.75(s,1H),4.63(td,J=4.0,4.0Hz,1H),4.55(t,J=4.0Hz,1H),4.50(s,2 H),4.38(d,J=8.0Hz,2H),4.30(t,J=8.0Hz,3H),4.21–4.15(m,2H),4.10(dd,J=8.0,4.0Hz,2H),4.02(s,1H),3 .86–3.73(m,3H),3.71–3.62(m,2H),3.56–3.47(m,56H),3.44–3.39(m,4H),3.24(d,J=4.0Hz,6H),3.02(s,1H) ,2.95(d,J=4.0Hz,4H),2.84(d,J=8.0Hz,1H),2.74(s,2H),2.67(m,1H),2.37–2.29(m,4H),2.25(d,J=16.0Hz, 2H),2.20–2.12(m,2H),2.02–1.89(m,6H),1.79(t,J=8.0Hz,2H),1.68(dd,J=24.0,12.0Hz,6H),1.48(dd,J=24 .0,8.0Hz,3H),1.32(d,J=12.0Hz,4H),1.28–1.11(m,9H),1.03(d,J=4.0Hz,3H),0.83(dd,J=12.0,8.0Hz,6H).

[0571] Except for replacing the corresponding reaction raw materials, Example 27 was synthesized by referring to the synthetic route of Example 26. Its structure and LC-MS information are shown in the table below.

[0572] Table 4 Structural formula and LC-MS of Example 27

[0573] Example 28 was synthesized by referring to the synthetic route of Example 7. Its structure and LC-MS results are shown in the table below.

[0574] Table 5 Structural formula and LC-MS of Example 28

[0575] Example 29:

[0576] Synthesis route:

[0577] Synthesis of intermediate 29-3:

[0578] Compound 29-1 (300 mg, 1.292 mmol), compound 29-2 (334 μL, 3.876 mmol), and tetrabutylammonium bromide (10 mg, 0.031 mmol) were dissolved in toluene (3 mL) and 5% sodium hydroxide solution (3 mL) at room temperature and allowed to react overnight. TLC monitored the reaction for completion. 20 mL of water was added to the reaction solution, and the extract was washed with an appropriate amount of ethyl acetate. The organic phase was collected, concentrated under reduced pressure, and purified by normal phase column chromatography to yield the product as a white solid (164 mg, 47%).

[0579] Synthesis of intermediate 29-4:

[0580] 29-3 (50 mg, 0.185 mmol), iodomethane (12 μL, 0.185 mmol), and cesium carbonate (121 mg, 0.370 mmol) were dissolved in DMF (5 mL) at room temperature and allowed to react overnight. TLC monitored the reaction for completion. A small amount of ethyl acetate was added to the reaction mixture, and the extract was washed with an appropriate amount of water. The organic phase was collected and concentrated under reduced pressure to yield the crude product (62 mg, 100%).

[0581] Synthesis of intermediate 29-5:

[0582] At room temperature, 29-4 (62 mg, 0.218 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and allowed to react at room temperature for one hour. The solvent was removed by concentration under reduced pressure (toluene was added to remove most of the TFA). AcOH (5 mL) was then added to dissolve the mixture, and dibromomaleic anhydride (53 mg, 0.207 mmol) was added, followed by heating to 110°C and reacting for 2 hours. TLC monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to remove a large amount of acetic acid, and a small amount of DCM was added to dissolve the mixture. The product was purified by normal phase column chromatography (PE:EA=60:40) to obtain the product (24 mg, 46%). LC-MS (ESI): m / z found [M+H] + =322.8.

[0583] Synthesis of intermediate 29-6:

[0584] Azide-ethylene glycol-acetic acid (214 mg, 1.054 mmol) was dissolved in DMF (4 mL), and EEDQ (226 mg, 1.264 mmol) and 11-11 (400 mg, 1.054 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen for 16 h. LC-MS confirmed the reaction was complete, and the product was purified by reverse-phase column chromatography and concentrated under reduced pressure to obtain a white solid product (160 mg, 26.8%). LC-MS (ESI): m / z found [M+H] + =563.45.

[0585] Synthesis of intermediate 29-7:

[0586] 29-6 (25 mg, 0.044 mmol) was dissolved in DMF, and (PNP)2CO (40 mg, 0.133 mmol) and DIEA (12 mg, 0.089 mmol) were added. The mixture was allowed to react at room temperature for 4 h. After completion of the reaction as determined by LC-MS, the product was purified by reverse-phase column chromatography and concentrated under reduced pressure to afford the product as a white solid (17 mg, 52%).

[0587] Synthesis of intermediate 29-8:

[0588] 29-7 (50 mg, 1 eq) was dissolved in DMF, and HOBt (9.2 mg, 1.1 eq) was added. The mixture was stirred at room temperature for 15 min, followed by the addition of eribulin mesylate (56 mg, 1 eq) and DIEA (17.7 mg, 2 eq). The mixture was allowed to react at room temperature for 2 h. After completion of the reaction as determined by LC-MS, the product was purified by reverse-phase column chromatography and lyophilized to afford a white solid (50 mg, 55%). LC-MS (ESI): m / z found [M+H] + =1320.6.

[0589] Synthesis of compound 29:

[0590] At room temperature, 29-5 (2.5 mg, 0.0078 mmol), 29-8 (10.3 mg, 0.0078 mmol), copper sulfate pentahydrate (1.9 mg, 0.0078 mmol), and vitamin C (1.4 mg, 0.0078 mmol) were dissolved in dry tetrahydrofuran (2 mL) and ethanol (6 mL). The atmosphere was purged with nitrogen three times and the reaction was maintained at room temperature for 2 hours. LCMS monitored the reaction completion, and the product was concentrated under reduced pressure, dissolved in a small amount of DMF, and purified by pre-HPLC to obtain a yellow solid product (7.02 mg, 55%). LC-MS (ESI): m / z found [M / 2+H] + =822.05.

[0591] Example 30:

[0592] Synthesis route:

[0593] Synthesis of intermediate 30-1:

[0594] On an ice bath, 29-5 (24 mg, 0.075 mmol) was dissolved in DCM (5 mL), and 11-4 (34 mg, 0.149 mmol) and DIPEA (26 μL, 0.149 mmol) were added. The mixture was reacted on ice for half an hour, then warmed to room temperature and reacted for 2 hours. LC-MS monitored the reaction. Upon completion, the reaction solution was concentrated under reduced pressure to remove the solvent, dissolved in a small amount of methanol, and purified by reverse-phase column chromatography (ACN:H2O=30:70). Drying gave a golden solid (45 mg, 98%). LC-MS (ESI): m / z found [M+H] + =607.0.

[0595] Synthesis of compound 30:

[0596] At room temperature, 30-1 (5 mg, 0.0082 mmol), 29-8 (11 mg, 0.0082 mmol), copper sulfate pentahydrate (2.1 mg, 0.0082 mmol), and vitamin C (1.5 mg, 0.0082 mmol) were dissolved in dry tetrahydrofuran (2 mL) and ethanol (6 mL). The atmosphere was purged with nitrogen three times and the reaction was maintained at room temperature for 2 hours. After completion of the reaction, the product was concentrated under reduced pressure and dissolved in a small amount of DMF, purified by pre-HPLC, and lyophilized to afford a yellow solid (7.56 mg, 63%). LC-MS (ESI): m / z found [M / 2+H] + =964.70.

[0597] Examples 31-35:

[0598] Except for replacing the corresponding reaction raw materials (for example, the payload used in Example 36 was monomethyl auristatin E (MMAE), purchased from MCE (MedChemExpress)), the compounds of Examples 31-36 were synthesized according to the synthetic route of Example 11, and their structural formulas are shown in the table below.

[0599] Table 6 Structural formulas and LC-MS of the compounds of Examples 31-36

[0600] Example 37:

[0601] Synthesis route:

[0602] Synthesis of intermediate 37-2:

[0603] 37-1 (5 g, 1.0 eq) was dissolved in 50 mL of DCM, and ethylene glycol (8.4 g, 10 eq) and PPTS (6.82 g, 2.1 eq) were added sequentially. The reaction was allowed to react at room temperature overnight. TLC monitored the reaction to be complete. The product was concentrated under reduced pressure and dissolved in DMF. The product was purified by reverse-phase column chromatography and lyophilized to obtain a white solid (4.68 g, 93%).

[0604] Synthesis of intermediate 37-3:

[0605] 37-2 (650 mg) was dissolved in DCM (10 mL), DEA (1 mL) was added, and the mixture was allowed to react at room temperature for 1.5 h. The reaction was monitored by TLC and concentrated under reduced pressure to give 662 mg of a crude pale yellow oil, which was used directly in the next step. LC-MS (ESI): m / z found [M+H] + =148.2.

[0606] Synthesis of intermediate 37-6:

[0607] At room temperature, 37-4 (1 g, 1.7 mmol) was dissolved in DMF (4 mL), and HOSU (215.2 mg, 1.87 mmol) and EDCI (358 mg, 1.87 mmol) were added. The mixture was allowed to react at room temperature for 6 hours. Compound 37-5 (578 mg, 1.7 mmol) and DIEA (444.3 μL, 2.55 mmol) were then added and allowed to react at room temperature for 2 hours. LCMS confirmed the complete reaction of the starting material. The product was purified by reverse-phase column chromatography and concentrated under reduced pressure to yield a white oil (1.142 g, 73.77%). LC-MS (ESI): m / z found [M+H] + =911.8.

[0608] Synthesis of intermediate 37-7:

[0609] At room temperature, 37-6 (1.142 g, 1.25 mmol) was dissolved in ACN (10 mL), and HOSU (216.4 mg, 1.88 mmol) and DCC (388 mg, 1.88 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then filtered, and the filtrate was collected and dried under reduced pressure. The crude product was dissolved in DMF (5 mL), and DIEA (327.5 μL, 1.88 mmol) and glycylglycyl-L-phenylalanine (420 mg, 1.5 mmol) were added. The reaction was allowed to react at room temperature for 2 hours. LCMS analysis confirmed the complete reaction of the starting material. The product was purified by reverse-phase column chromatography and concentrated under reduced pressure to afford a white oil (1.076 g, 73.22%). MS (ESI): m / z found [M+H / 2] + =587.2.

[0610] Synthesis of intermediate 37-8:

[0611] At room temperature, 37-7 (400 mg, 0.34 mmol) was dissolved in DMF (2 mL), and piperidine (337 μL, 3.41 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. LC-MS confirmed the complete reaction. The reaction solution was purified by pre-HPLC and lyophilized to obtain a white oil (159.3 mg, 49.14%). LC-MS (ESI): m / z found [M+H] + =950.7.

[0612] Synthesis of intermediate 37-9:

[0613] At room temperature, 37-8 (45 mg, 0.0474 mmol) was dissolved in DMF (2.5 mL). Azidoacetic acid NHS ester (18.8 mg, 0.0947 mmol) and DIEA (16.5 μL, 0.0947 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1.5 hours. After the reaction was complete, the reaction solution was purified by pre-HPLC and lyophilized to obtain a white oil (19.4 mg, 39.65%). LC-MS (ESI): m / z found [M+H] + =1033.75.

[0614] Synthesis of intermediate 37-10:

[0615] At room temperature, 37-9 (50 mg, 0.048 mmol) was dissolved in THF (2 mL), and DCC (12 mg, 0.058 mmol) and HOSU (7 mg, 0.058 mmol) were added and allowed to react at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered, concentrated, and dissolved in DMF. DIEA (10 μL, 0.058 mmol) and 37-3 (11 mg, 0.073 mmol) were added and allowed to react for 2 h. The reaction was monitored for completion by LCMS. Pre-HPLC preparation and lyophilization gave the product as a white oil (15 mg, 26.8%). LC-MS (ESI): m / z found [M+H] + =1163.3.

[0616] Synthesis of intermediate 37-11:

[0617] At room temperature, 37-10 (286 mg, 0.246 mmol) was dissolved in DMF (4 mL). Di(p-nitrobenzene) carbonate (523 mg, 1.72 mmol) was added, followed by dropwise addition of DIEA (128 μL, 0.74 mmol). The temperature was raised to 50°C and the reaction was allowed to proceed overnight under nitrogen. LCMS monitored the reaction completion. The reaction solution was filtered, and the filtrate was purified by reverse-phase column chromatography and lyophilized to afford a colorless solid (148 mg, 44.7%). LC-MS (ESI): m / z found [M+H] + =1345.6.

[0618] Synthesis of intermediate 37-12:

[0619] At room temperature, 37-11 (170 mg, 0.214 mmol) was dissolved in DMSO (5 mL), and 11-10 (283 mg, 0.26 mmol), copper sulfate pentahydrate (54 mg, 0.214 mmol), and Vc (39 mg, 0.214 mmol) were added. The mixture was reacted at room temperature under nitrogen for 1 h. TLC monitored the reaction completion. Purification by reverse phase column chromatography and lyophilization afforded a yellow solid (278 mg, 62.3%). LC-MS (ESI): m / z found [M+H] + =2122.2.

[0620] Synthesis of compound 37:

[0621] 37-2 (1 eq) was dissolved in DMA, and eribulin mesylate (1 eq) and DIEA (2 eq) were added sequentially. The mixture was allowed to react at room temperature for 2 h. LC-MS monitored the reaction to be complete. The mixture was purified by Pre-HPLC and lyophilized to obtain a yellow solid.

[0622] Experimental Example 1: Preparation of Antibody-Drug Conjugates

[0623] Antibody 1 of the present disclosure is AGSM6 prepared with reference to Example 2 of WO2012047724, and its heavy chain and light chain amino acid sequences are shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively.

[0624] AGSM6 heavy chain (SEQ ID NO: 1)

[0625] AGSM6 light chain (SEQ ID NO: 2)

[0626] Antibody 2 of the present invention is hH2L1, which was prepared with reference to the sequence of Example 1 of CN117942409A. The amino acid sequences of its heavy chain and light chain are shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

[0627] hH2L1 heavy chain (SEQ ID NO: 5)

[0628] hH2L1 light chain (SEQ ID NO: 6)

[0629] The anti-nectin-4 antibody A heavy chain selected in the present invention is SEQ ID NO: 3

[0630] The light chain of Nectin-4 antibody A selected in the present invention is SEQ ID NO: 4

[0631] The CDRs of the antibody A are shown in SEQ ID NOs: 7-12

[0632] HCDR1: SEQ ID NO: 7

[0633] HCDR2: SEQ ID NO: 8

[0634] HCDR3: SEQ ID NO: 9

[0635] LCDR1: SEQ ID NO: 10

[0636] LCDR2: SEQ ID NO: 11

[0637] LCDR3: SEQ ID NO: 12

[0638] Heavy chain variable region: SEQ ID NO: 13

[0639] Light chain variable region: SEQ ID NO: 14

[0640] 1.1 Cysteine ​​coupling based on partial reduction

[0641] The antibody was diluted to 5 mg / mL in 1 mM EDTA-PBS buffer. 5 mM TCEP was added at a 2-fold molar equivalent ratio for cleavage, and the mixture was shaken at 37°C for 2 hours. After cleavage, 5 mg / mL of Linker-Payload was added at a 4-fold molar equivalent ratio. DMSO was also added to the system to a 10% DMSO content. After mixing at room temperature for 2 hours, the sample was centrifuged, the precipitate was removed, and desalting was performed. The final sample was subjected to quantification, SEC, and HIC analysis.

[0642] The antibody-drug conjugates shown in Table 7 were prepared, wherein the antibodies conjugated to NECTIN 4-ADC-1 to NECTIN 4-ADC-4, NECTIN 4-ADC-7-1, NECTIN 4-ADC-8, NECTIN 4-ADC-9-1, and NECTIN 4-ADC-10 were designated as positive control antibody 1, and the antibodies conjugated to NECTIN 4-ADC-7-2, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-22 to NECTIN 4-ADC-24 were designated as antibody A.

[0643] Table 7 Numbers and structures of partially reduced cysteine-conjugated ADCs

[0644] Note: m or m1 is the drug-to-antibody ratio (DAR).

[0645] 1.2 Coupling based on double conjugated bridges

[0646] The antibody was diluted to 5 mg / mL in 1 mM EDTA-PBS buffer. 5 mM TCEP was added at an 8-fold molar equivalent ratio for cleavage, and the mixture was shaken at 37°C for 2 hours. After cleavage, 5 mg / mL of Linker-Payload was added at a 6-fold molar equivalent ratio. DMSO was also added to the system to a 10% DMSO content. After mixing at room temperature for 2 hours, the sample was centrifuged, the precipitate was removed, and desalting was performed. The final sample was subjected to quantification, SEC, and HIC analysis.

[0647] The antibody-drug conjugates shown in Table 8 were prepared, wherein the 9MW2821 and NECTIN 4-ADC-29 conjugated antibodies were the positive control antibody 2hH2L1, the NECTIN 4-ADC-5-1, NECTIN 4-ADC-6, and NECTIN 4-ADC-28 conjugated antibodies were the positive control antibody 1AGSM6, and the NECTIN 4-ADC-5-2, NECTIN 4-ADC-11 to NECTIN 4-ADC-21, NECTIN 4-ADC-25, NECTIN 4-ADC-26, and NECTIN 4-ADC-27 conjugated antibodies were antibody A.

[0648] Table 8 ADC numbers and structural formulas based on double conjugated bridges

[0649] Note: m is the drug-antibody ratio;

[0650] The maleimide ring of the double conjugated bridge part ADC has two forms: open ring and closed ring. During the preparation process, the maleimide of the linker part of ADC is hydrolyzed to form (Closed loop) becomes (open loop).

[0651] LC-MS was used to detect the ratio of closed-loop structure to open-loop structure in the ADC of the present invention, as shown in Table 8-1 below:

[0652] Table 8-1

[0653] Conclusion: The ADCs listed in Table 8-1 of the present invention exist in both open-ring and closed-ring forms. The maleimide hydrolysis rate in nectin 4-ADC-14, nectin 4-ADC-15, nectin 4-ADC-14, and nectin 4-ADC-20 ADCs exceeded 80%, with nectin 4-ADC-11 completely hydrolyzed. This demonstrates that the introduction of aromatic groups can effectively control the hydrolysis of the maleimide moiety and improve ADC stability.

[0654] 1.3 ADC Purity and DAR Value Testing

[0655] HPLC-HIC analysis was used to determine whether the coupling was successful and to detect the DAR value; SEC-HPLC was used to detect the purity of ADC.

[0656] Table 9 HIC and SEC results of the disclosed ADC

[0657] The HIC analysis results of the control ADC (Enfortumab vedotin) and the ADC of the present disclosure are shown in Figures 11, 12, 13, and 14.

[0658] Conclusion: Based on the results in Figures 11-14, the antibody-drug conjugates disclosed herein (such as NECTIN 4-ADC-11, NECTIN 4-ADC-18, NECTIN 4-ADC-26, etc.) have better DAR value uniformity than Enfortumab vedotin.

[0659] Experimental Example 2: In vitro inhibition test of tumor cell proliferation by the disclosed ADC

[0660] 1. MDA-MB-468 cell activity inhibition experiment

[0661] MDA-MB-468 (breast cancer cells, Kebai, CBP60387) was used. This cell line is a cell line that highly expresses nectin 4.

[0662] Fresh cell culture medium containing 10% FBS was used to prepare cell suspensions at densities of 5×10 4 cells / mL, 100 μL per well was added to a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium to 4 μM. Using this initial concentration, 10-fold serial dilutions were made in PBS for a total of nine concentrations. 50 μL of culture medium was aspirated from each well and 50 μL of the ADC solution was added, resulting in an initial ADC concentration of 2 μM in a final volume of 100 μL per well. Cultures were incubated at 37°C in 5% CO2 for 5 days. The supernatant was discarded, and 100 μL of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark), and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.

[0663] 2. MDA-MB-453 cell activity inhibition experiment

[0664] MDA-MB-453 (breast cancer cells, Kebai, CBP60386) was used. This cell line is a cell line with high expression of nectin 4.

[0665] Fresh cell culture medium containing 10% FBS was used to prepare cell suspensions at densities of 5×10 4cells / mL, 100 μL per well was added to a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium to 0.8 μM. Using this initial concentration, 5-fold serial dilutions were performed in PBS, resulting in a total of nine concentrations. 50 μL of culture medium was aspirated from each well and 50 μL of the ADC solution was added, resulting in an initial ADC concentration of 0.4 μM in a final volume of 100 μL per well. Cultures were incubated at 37°C in 5% CO2 for 5 days. The supernatant was discarded, and 100 μL of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark), and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.

[0666] 3. HT1376 cell activity inhibition experiment

[0667] HT1376 (bladder cancer cell line, Kebai, CBP60310) was used. This cell line is a cell line with high expression of nectin 4.

[0668] Fresh cell culture medium containing 10% FBS was used to prepare cell suspensions at densities of 3×10 4 cells / mL, 100 μL per well was added to a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium at 0.4 μM, 2 μM, and 7 μM concentrations, respectively. Using these initial concentrations, 50 μL of the ADC solution was serially diluted fivefold in PBS, for a total of nine concentrations. 50 μL of culture medium was aspirated from each well and 50 μL of the ADC solution was added, resulting in a 5 μM ADC concentration in the initial well, with a final volume of 100 μL per well. Culture was continued at 37°C in 5% CO2 for 3 days. The supernatant was discarded, and 100 μL of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark), and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.

[0669] 4. T47D cell activity inhibition experiment

[0670] T47D (ductal breast carcinoma cell line, Kebai, CBP60397) was used. This cell line is a cell line with high expression of nectin 4.

[0671] Fresh cell culture medium containing 10% FBS was used to prepare cell suspensions at densities of 1×10 5cells / mL, 100 μL per well was added to a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium at 0.4 μM, 2 μM, and 7 μM concentrations, respectively. Using these initial concentrations, 50 μL of the ADC solution was serially diluted fivefold in PBS, for a total of nine concentrations. 50 μL of culture medium was aspirated from each well and 50 μL of the ADC solution was added, resulting in a 5 μM ADC concentration in the initial well, with a final volume of 100 μL per well. Culture was continued at 37°C in 5% CO2 for 3 days. The supernatant was discarded, and 100 μL of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark), and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.

[0672] Table 10: IC values ​​of some antibody drug conjugates of the present disclosure in different cell lines 50 value

[0673] Note: “-” means not tested.

[0674] Conclusion: The above data demonstrate that the antibody-drug conjugates prepared in this disclosure exhibit excellent inhibitory activity in various cells expressing Nectin 4 (e.g., breast cancer and bladder cancer cells), and their inhibitory activity is significantly superior to that of the control drug, enfortumab vedotin. Furthermore, using the same antibody and linker, the ADC with eribulin as the payload (Nectin 4-ADC-11) exhibits superior tumor inhibitory activity compared to the ADC with MMAE as the payload (Nectin 4-ADC-27).

[0675] Experimental Example 3: In vivo efficacy experiment of the ADC compound of the present invention

[0676] The experimental data were statistically analyzed using Excel 2016 software: the mean was calculated as average; the SD was calculated as STDEV; and the SEM was calculated as STDEV / SQRT. The calculation formulas for each indicator are as follows:

[0677] Tumor volume (V): V = 1 / 2L long diameter × (L short diameter) 2

[0678] Relative tumor volume (RTV): RTV = VT / V0

[0679] Relative tumor proliferation rate T / C (%) = TRTV / CRTV × 100%

[0680] Tumor inhibition rate (%) = (CRTV-TRTV) / CRTV (%)

[0681] Tumor weight inhibition rate (%) = (1-average tumor weight of the treatment group / average tumor weight of the control group) * 100%

[0682] V0 and VT are the tumor volumes at the beginning and end of the experiment, respectively. CRTV and TRTV are the relative tumor volumes of the blank control group (PBS) and the experimental group, respectively, at the end of the experiment.

[0683] 1. In vivo efficacy evaluation in MDA-MB-468 cell CDX model mice

[0684] BALB / c-Nude nude mice were subcutaneously inoculated with human triple-negative breast cancer cells MDA-MB-468 (Kebai) (1*10^7 / 200μL / mouse, with 50% low-growth factor artificial basement membrane) in the right rib cage. After cell inoculation, the tumor grew for 7 days and the tumor volume reached 135mm. 3 After the experiment, the animals were randomly divided into groups (D0), with 6 animals in each group.

[0685] Patients were administered via tail vein injection at multiple doses of 2 mg / kg, 1 mg / kg, and 0.5 mg / kg, with single injections administered, and observed for 21 days. Tumor volume and body weight were measured twice weekly, and the data were recorded and used to calculate the tumor volume inhibition rate. Data were analyzed using Excel 2016 statistical software: mean was calculated as average; SD was calculated as STDEV; and SEM was calculated as STDEV / SQRT.

[0686] The results are shown in Figure 1.

[0687] Table 11 MDA-MB-468 tumor volume inhibition rate

[0688] Conclusion: In the triple-negative breast cancer MDA-MB-468 CDX model, the exemplary compound NECTIN 4-ADC-11 of the present disclosure exhibited significant tumor growth inhibitory effects at doses of 0.5-2 mg / kg. Its tumor growth inhibitory effect was significantly superior to that of enfortumab vedotin. In fact, the tumor inhibitory effect of 0.5 mg / kg NECTIN 4-ADC-11 was superior to that of 2 mg / kg enfortumab vedotin. The TGI of 2 mg / kg NECTIN 4-ADC-11 was as high as 100%.

[0689] 2. In vivo efficacy evaluation in MDA-MB-453 cell CDX model mice

[0690] BALB / c-Nude nude mice were subcutaneously inoculated with human breast cancer cells MDA-MB-453 (Kebai) (1*10^7 / 200μL / mouse, with 50% low-growth factor artificial basement membrane) in the right rib cage. After cell inoculation, the tumor grew for 7 days and the tumor volume reached 120mm. 3 After 48 hours, the animals were randomly divided into groups (D0), with 5 animals in each group.

[0691] The drug was administered via tail vein injection, with a single dose of 1 mg / kg administered in parallel, and observation was continued for 20 days. Tumor volume and body weight were measured twice a week and the data were recorded.

[0692] The results are shown in Figure 2:

[0693] Conclusion: In the breast cancer MDA-MB-453 CDX model, the exemplary antibody-drug conjugates NECTIN 4-ADC-11 and NECTIN 4-ADC-22 disclosed herein have significant tumor growth inhibitory effects, and have better tumor inhibitory effects than Enfortumab vedotin.

[0694] 3. In vivo efficacy evaluation in HT1376 cell CDX model mice

[0695] BALB / c-Nude nude mice were subcutaneously inoculated with human breast cancer cells HT1376 (Kebai) (1*10^7 / 200μL / mouse, with 50% low growth factor artificial basement membrane) in the right rib cage. After cell inoculation, the tumor grew for 8 days and the tumor volume reached 120mm. 3 After 48 hours, the animals were randomly divided into groups (D0), with 5 animals in each group.

[0696] The drug was administered by tail vein injection, with multiple doses of 8 mg / kg and 4 mg / kg administered in parallel, and single injection administered, for 21 days. Tumor volume and body weight were measured twice weekly and the data were recorded.

[0697] The results are shown in Figures 3 and 4.

[0698] Conclusion: In the HT1376 CDX model, the exemplary antibody-drug conjugates NECTIN 4-ADC-7-2, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-11 disclosed herein have significant tumor growth inhibitory effects, and their tumor inhibitory effects are superior to or equivalent to Enfortumab vedotin.

[0699] 4. In vivo efficacy evaluation in HT1376-CDX model mice

[0700] BALB / c-Nude nude mice were subcutaneously inoculated with human breast cancer cells HT1375 (Kebai) (1*10^7 / 200μL / mouse, with 50% low growth factor artificial basement membrane) in the right ribs. After cell inoculation, the tumor grew for 8 days and the tumor volume reached 120mm. 3 After the experiment, the animals were randomly divided into groups (D0), with 6 animals in each group.

[0701] The drug was administered by tail vein injection, with multiple doses of 5 mg / kg, 2.5 mg / kg, and 1 mg / kg administered in parallel, and observed for 21 days. Tumor volume and body weight were measured twice weekly, and the data were recorded to calculate the tumor volume inhibition rate.

[0702] The results are shown in Figure 5.

[0703] Table 12 HT1376 tumor volume inhibition rate

[0704] Conclusion: The experimental results show that in the HT1376 CDX model, the exemplary antibody-drug conjugate NECTIN 4-ADC-11 of the present disclosure has an excellent inhibitory effect on tumor growth at different dosages, and the efficacy at a dosage of 2.5 mg / kg is better than that of the 5 mg / kg Enfortumab vedotin group.

[0705] 5. In vivo efficacy evaluation in the RT4 / Nectin 4 cell CDX mouse model

[0706] Human bladder transitional cell papilloma RT4 / Nectin 4 (Kebai) cells (9*10^6 / 200μL / mouse, with 50% low-growth factor artificial basement membrane) were subcutaneously inoculated in the right flank of BALB / c-Nude nude mice. After cell inoculation, the tumors grew to 110-120 mm in size over 7 days. 3 After 48 hours, the animals were randomly divided into groups (D0), with 5 animals in each group.

[0707] The animals were injected via tail vein at a single dose of 5 mg / kg and observed for 21 days. Tumor volume and body weight were measured twice weekly and the data were recorded.

[0708] The results are shown in Figure 6.

[0709] Conclusion: The exemplary antibody-drug conjugate NECTIN 4-ADC-11 disclosed herein has a significant tumor growth inhibitory effect in the RT4 / Nectin 4 CDX model, and its tumor inhibitory effect is significantly better than that of Enfortumab vedotin.

[0710] 6. In vivo efficacy evaluation in MDA-MB-453 cell CDX model mice

[0711] a. Human breast cancer cells MDA-MB-453 (Kebai) (1×10 7 / 200μL / mouse, with 50% low growth factor artificial basement membrane). After cell inoculation, the tumor grew for 6 days and the tumor volume grew to 135mm 3 After the experiment, the animals were randomly divided into groups (D0), with 6 animals in each group.

[0712] b. Administer the drug via tail vein injection at doses of 2 mg / kg, 1 mg / kg, and 0.5 mg / kg, respectively, as a single injection. Measure tumor volume and body weight twice weekly, record the data, and calculate the tumor volume inhibition rate.

[0713] The results are shown in Figure 15.

[0714] Table 13 MDA-MB-453 tumor volume inhibition rate

[0715] Conclusion: The exemplary antibody-drug conjugate NECTIN 4-ADC-11 disclosed herein can effectively inhibit the growth of MDA-MB-453 xenografts in tumor-bearing nude mice at doses of 0.5-2 mg / kg in a dose-dependent manner, and its efficacy is significantly better than that of positive drugs.

[0716] 7. Efficacy in MDA-MB-468 tumor-bearing nude mice

[0717] a. Human triple-negative breast cancer cells MDA-MB-468 (Kebai) (1×10 7 / 200μL / mouse, with 50% low growth factor artificial basement membrane). After cell inoculation, the tumor grew for 10-11 days and the tumor volume grew to 115-135mm 3 After 48 hours, the animals were randomly divided into groups (D0), with 5 animals in each group.

[0718] b. Administer the drug via tail vein injection at doses of 2 mg / kg and 1 mg / kg, respectively, as a single injection. Measure tumor volume and body weight twice weekly, record the data, and calculate the tumor volume inhibition rate.

[0719] The results are shown in Figure 16.

[0720] Table 14 MDA-MB-468 tumor volume inhibition rate

[0721] Conclusion: The exemplary antibody-drug conjugate NECTIN 4-ADC-11 disclosed herein can effectively inhibit the growth of MDA-MB-468 xenografts in tumor-bearing nude mice at doses of 1 mg / kg and 2 mg / kg in a dose-dependent manner, and its efficacy is significantly better than that of the positive drug 9MW2821.

[0722] Test Example 4: ADC drug toxicology experiment

[0723] 1. Acute toxicity test in BALB / c mice

[0724] Acute toxicity studies were conducted in 6-8 week-old BALB / c mice. Enfortumab vedotin, NECTIN 4-ADC-9-2, NECTIN 4-ADC-11, and NECTIN 4-ADC-22 were administered via tail vein injection at a dose of 100 mg / kg in a volume of 200 μL per group. Four experimental groups (6 mice each, 3 males and 3 females) were administered, respectively.

[0725] Detection indicators:

[0726] Cage observation was performed twice a day (including observation of death and dying), and a survival curve was drawn based on the survival status;

[0727] Detailed clinical observation: 2 times / week;

[0728] Body weight: Record once before administration and twice a week after administration; the recording time is Day 0, Day 4, Day 7, Day 12 and Day 14.

[0729] 2. Long-term toxicity experiment in BALB / c mice

[0730] Acute toxicity studies were conducted in 6-8 week old BALB / c mice treated with Vital River. Enfortumab vedotin, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-11 were administered via tail vein injection at a dose of 60 mg / kg in a volume of 200 μL per group. The mice were administered twice (day 0 and day 7) for 14 days. The solvent control group (PBS group) consisted of 4 mice (2 males and 2 females); the experimental groups consisted of 6 mice (3 males and 3 females) in each group. Enfortumab vedotin, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-11 were administered to the mice.

[0731] Detection indicators:

[0732] Cage observation was performed twice a day (including observation of death and dying), and a survival curve was drawn based on the survival status;

[0733] Detailed clinical observation: 2 times / week;

[0734] Body weight: once before administration, once a week after administration, and once before autopsy (twice a week in this experiment)

[0735] The results of acute toxicity tests and long-term toxicity tests are shown in Figures 7-10.

[0736] Conclusion: The exemplary antibody-drug conjugates NECTIN 4-ADC-9-2, NECTIN 4-ADC-11, and NECTIN 4-ADC-22 disclosed herein had survival rates comparable to those of the vehicle group during the observation period, had good safety, and were significantly superior to Enfortumab vedotin in terms of mouse survival rate.

[0737] 3. Toxicological Maximum Tolerated Dose (MTD) Experiment in Humanized Mice

[0738] (1) Experimental groups

[0739] Table 15

[0740] (2) Experimental methods

[0741] Administration route and frequency: Tail vein injection, once a week, with the day of administration being Day 0. The results are shown in Figures 17 and 18.

[0742] Conclusion: The exemplary antibody drug conjugate NECTIN 4-ADC-11 disclosed in the present invention (with an MTD of up to 80 mg / kg) is well tolerated and has a better safety profile than the positive control enfortumab vedotin (MTD < 70 mg / kg).

[0743] 4. Repeated-dose toxicity study of humanized Nectin4 in mice

[0744] Experimental groups

[0745] Table 16

[0746] TK: toxicokinetics, ADA is anti-drug antibody.

[0747] (2) Experimental methods

[0748] Administration route: Tail vein injection, once a week, the day of administration is Day 1, and the drug is administered on Day 1, 8, 15, and 22, for a total of 4 doses.

[0749] Dosing frequency: Multiple doses, once a week;

[0750] Experimental duration: 4 weeks.

[0751] Daily toxicity observations, including mouse survival, weight changes, skin toxicity, etc.

[0752] Detection indicators:

[0753] The results are shown in Figures 19 and 20.

[0754] Table 17 Incidence of skin toxicity

[0755] Conclusion: The exemplary antibody-drug conjugate NECTIN 4-ADC-11 of this application is well tolerated and has a higher tolerated dose than the active drug Enfortumab vedotin. The degree of weight loss at the same dose is lower than that of the active drug, and it can reduce the severe side effects of Nectin 4 target skin toxicity to a certain extent.

[0756] Test Example 5: Pharmacokinetic Test

[0757] 1. Pharmacokinetics in BALB / c mice

[0758] Instruments and reagents:

[0759] Table 18

[0760] Experimental steps:

[0761] NECTIN 4-ADC-11 and control were administered as a single injection via the tail vein of mice, and their basic pharmacokinetic characteristics in mice were observed.

[0762] a. Groups, doses, and administration volumes are shown in Table 19 below:

[0763] Table 19

[0764] b. Dosage frequency and method: Single administration via tail vein.

[0765] c. Blood collection points: 5 min, 1 h, 4 h, 8 h, 24 h, 48 h, 96 h (Day 4), 168 h (Day 7), 240 h (Day 10), 336 h (Day 14), 504 h (Day 21), 672 h (Day 28)

[0766] d. Blood Collection Method: The first blood draw from each animal was done via the orbital venous plexus; the blood volume was 0.15 mL / time point. The second blood draw was done by enucleation of the eyeball; the blood volume was 0.5 mL / time point. For each of the eight test substances, three mice were used as a cohort, with each cohort consisting of 24 mice.

[0767] e. Blood Sample Processing and Testing: After serum collection, allow to stand for 1 hour. Once the serum is clearly separated, centrifuge at 4000 rpm for 10 minutes and collect the supernatant. The resulting serum samples were frozen in two aliquots at -80°C. Following completion of the experiment, free small molecules, ADC, and total antibody assays were performed.

[0768] The results are shown in Figures 21 and 22.

[0769] Table 20 Pharmacokinetic results of plasma ADC in BALB / c mice

[0770] Conclusion: Experimental results show that at doses of 1 mg / kg, 2.5 mg / kg, 5 mg / kg, or 10 mg / kg, the in vivo release of both drugs, ADC, and total antibody was dose-dependent in mouse pharmacokinetics. Furthermore, the antibody-drug conjugate NECTIN 4-ADC-11 of the present invention exhibited lower free payload shedding, lower clearance, and a longer half-life. This suggests that the antibody-drug conjugate NECTIN 4-ADC-11 of the present invention has greater stability and is expected to reduce premature release of free payload in the circulation and off-target toxicity.

[0771] 2. Pharmacokinetics of HT1376 tumor-bearing mice

[0772] (1) Instruments and reagents

[0773] (2) Experimental steps

[0774] a. Human breast cancer cells HT1376 (Kebai) (1×10 7 After cell inoculation, the tumors grew for 17 days and the tumor volume reached 250-300 mm. 3 After about 24 days, the animals were randomly divided into groups (D0), with 3 animals in each group, for a total of 24 groups. (PBS, Enfortumab vedotin, NECTIN 4-ADC-11, a total of 3 drugs)

[0775] b. The drug was administered by tail vein injection, with a single dose of 6 mg / kg.

[0776] c. Blood collection point design: 1h, 6h, 24h, 48h, 72h, 168h, 240h, 336h.

[0777] d. Remove the eyeball and collect 800 μL of blood. Dissect and remove the tumor, grind it, centrifuge it, and collect the supernatant. Detect TAB and ADC content by ELISA, and detect the content of free small molecules by LC-MS.

[0778] The results are shown in Figure 23.

[0779] Conclusion: The antibody-drug conjugate NECTIN 4-ADC-11 of the present invention specifically accumulates in tumors, has lower payload exposure in serum than the positive control drug Enfortumab vedotin, and has higher safety in vivo.

[0780] The present invention has been described through the above-described embodiments. However, it should be understood that the above-described embodiments are for illustrative and illustrative purposes only and are not intended to limit the present invention to the described embodiments. Furthermore, it will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments and that further variations and modifications may be made based on the teachings of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound as shown in Formula 1-1 or a pharmaceutically acceptable salt thereof, T-M-L1——L 23 -L4-L5-G Formula 1-1 in, T is a linker unit; preferably T is selected from R at each occurrence is independently selected from halogen and -S-Ar; preferably, R at each occurrence is independently selected from F, Cl, Br, I and -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl, M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, and a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, and heterocycloalkylene group are unsubstituted or optionally substituted by one or more R a replace; L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a replace; When L 23 When L5 is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, L5 is a spacer unit having a side chain comprising a hydrophilic unit; wherein the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof, preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; provided that when L 23 When it is a single bond, L5 does not contain a triazole ring; or When L5 is any spacer unit, L 23 Selected from -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-, and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group, or the heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a Replacement; provided that, when T is When L1 contains an alkynylene group, L5 is a spacer unit having a side chain containing a hydrophilic unit; n7, and n10 are each independently selected from 0, 1, 2, 3, 4, 5 and 6; n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; M, L1, and L 23 Not all are single bonds; L4 is a peptide residue consisting of amino acids or -NR a -alkylene-NR a -, wherein the alkylene, and amino acid are unsubstituted or optionally substituted with one or more R a replace; G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and R a Each occurrence is independently selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, carboxyl, -NH-C 1-6 Alkyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-NHC(O)-C 1-6 Alkyl, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, 6-10 membered aryl and 5-13 membered heteroaryl, wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkylamino, aryl and heteroaryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein When L5 is selected from a single bond, -N(R b )-(CH2) g -O-(CH2) g -OC(O)-、-N(R b )-(CH2) g -O-(CH2-CH2-O) g -C(O)-, When L 23 Selected from -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-, and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group or a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group or the heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R b The hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, L 23 Selected from -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -C(O)-, -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -C(O)-, 1, 2, 3 or more of; or When L 23 Selected from single bond, -(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -(OCH2CH2) n1 -、-C(O)-、-Cy1-C 1-10 Alkylene-C(O)-, -Cy1-C(O)-, and -Cy1-(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -C(O)-, when there is one, two, three or more of them, L5 is a spacer unit having a side chain comprising a hydrophilic unit; the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; in, Each occurrence of Cy1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted by one or more R a substituted; preferably, Cy1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Substitution; preferably, Cy1 is selected from Preferably, Cy1 is selected from n1, n2 and n3 are each independently selected from an integer from 0 to 30; preferably, n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28; n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence; n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 at each occurrence; and n12 and n15 are not both 0; Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; j is independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence; Each occurrence of Cy3 is independently selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substitution; preferably, Cy3 is selected from Preferably, Cy3 is X1 is g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6; and R a and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 The aryl group and the 5-13 membered heteroaryl group are substituted by 1, 2, 3 or more substituents.

3. A compound as shown in Formula 1 or a pharmaceutically acceptable salt thereof, TM-L1-L2-L3-L4-L5-G Formula 1 in, T is a linker unit; preferably T is selected from R is selected from halogen and -S-Ar; preferably, R is selected from F, Cl, Br, I and -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl, M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, and a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, and heterocycloalkylene group are unsubstituted or optionally substituted by one or more R a replace; L1 is selected from a single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 2-10 Alkylene, and C 1-10 wherein said alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a replace; L2 is a single bond, -(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -, or -(CH2) n3 -(OCH2CH2) n1 -; L3 is selected from a single bond, -C(O)-, -Cy1-C 1-10 Alkylene-C(O)-, -Cy1-C(O)-, and -Cy1-(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -C(O)-; Cy1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, or heterocycloalkylene being unsubstituted or optionally substituted with one or more R a Preferably, the arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a Preferably, each occurrence of Cy1 is independently selected from Preferably, Cy1 is M, L1, L2 and L3 are not single bonds at the same time; L4 is a peptide residue composed of amino acids or -NR a -C 1-6 Alkylene-NR a -; wherein the amino acid and alkylene are unsubstituted or optionally substituted with one or more R a replace; L5 is a spacer unit having a side chain comprising a hydrophilic unit; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamate glucosamine, glycosyl, phosphate, sulfonate and combinations thereof; G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; n1, n2, and n3 are each independently selected from an integer from 0 to 30; preferably, n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28; and R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 The aryl group and the 5-13 membered heteroaryl group are substituted by 1, 2, 3 or more substituents.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: in, L5 is L a Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-10 Alkylene and C 2-10 wherein the alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a Substituted; preferably, L a Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a replace; Cy2 is selected from 6-13 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally further substituted by one or more R a Preferably, Cy2 is selected from 6-10 membered arylene, 5-10 membered heteroarylene, 3-12 membered cycloalkylene and 3-12 membered heterocycloalkylene, wherein the arylene, heteroarylene, cycloalkylene and heterocycloalkylene are unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace; L b Selected from single bond, alkynylene, alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with one or more R a Substituted; preferably, L b Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a replace; L c Selected from CR a R s , R s is a side chain comprising 1-30 hydrophilic units, wherein the hydrophilic units are selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic units are selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate, one or a combination of two or more; preferably, R s Selected from More preferably, Rs is selected from j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6; Each occurrence of n is independently selected from any integer between 1 and 30; preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; L d Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-、C 1-10 Alkylene and C 1-10 wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a Substituted; preferably, L d Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein said alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a replace; R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 aryl and 5-13 membered heteroaryl 1, 2, 3 or more substituents; preferably, R a Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl, and C1-C3 alkoxy; Preferably, L5 is selected from Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 aryl and 5-13 membered heteroaryl 1, 2, 3 or more substituents; preferably, R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein The compound is shown in Formula 4: T-M-L1——M a -L6-L7-G Formula 4 wherein T is a linker unit; preferably T is selected from R is selected from halogen and -S-Ar; preferably, R is selected from F, Cl, Br, I and -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl, M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group and a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group and heterocycloalkylene group are unsubstituted or optionally substituted by one or more R b replace; L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR b -、-O-、-C(O)-、-NR b -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with one or more R b replace; M a Selected from and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group or a 3-15 membered heterocycloalkylene group; the arylene group, heteroarylene group, cycloalkylene group or heterocycloalkylene group being unsubstituted or optionally further substituted with one or more R b Substitution; the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; L6 is a peptide residue composed of amino acids or -NR b -alkylene-NR b -; wherein the alkylene and amino acid are unsubstituted or optionally further substituted with one or more R b replace; L7 is a spacer unit; provided that, when T is When L1 contains an alkynylene group, L7 is a spacer unit having a side chain containing a hydrophilic unit; G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; R a and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 10 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 10 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 10 substituted by one, two, three or more substituents selected from aryl and 5-13 membered heteroaryl; and n17 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein M a Selected from -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -C(O)-、 -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -C(O)-、 -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -C(O)-、-(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-、 1, 2, 3 or more combinations of; ； n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence; n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, and n12 and n15 are not 0 at the same time; j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6; Each occurrence of Cy3 is independently selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Preferably, each occurrence of Cy3 is independently selected from Preferably, Cy3 is and / or L7 is selected from a single bond, -N(R b )-(CH2) g -O-(CH2) g -OC(O)-、-N(R b )-(CH2) g -O-(CH2-CH2-O) g -C(O)-, X1 is selected from g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6; Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; R a and R b selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkyl-C(O)NH-, C1-C6 alkyl-OC(O)-NH-, C1-C6 alkyl-NHC(O)-NH-, C6-C 15 Aryl and 5-15 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-15 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 alkylamino, C6-C 15 aryl and 5-15 membered heteroaryl are substituted with one or more substituents; preferably, R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: T is selected from R is independently selected from halogen and -S-Ar at each occurrence; preferably, R is independently selected from F, Cl, Br, I and -S-Ar at each occurrence; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 0, 1, 2, 3 or 4 R a Substituted; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl group, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted with 1, 2 or 3 R a Substituted; W is selected from amino, -NR a -C 1-6 alkyl, Preferably, T is selected from and / or, M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group and a 3-15 membered heterocycloalkylene group, said arylene group, heteroarylene group, cycloalkylene group and heterocycloalkylene group being unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a substituted; preferably, M is selected from a single bond, a phenylene group, a 5-7 membered heteroaryl group, a 3-7 membered cycloalkylene group and a 3-7 membered heterocycloalkylene group, wherein the arylene group, the heteroaryl group, the cycloalkylene group and the heterocycloalkylene group are unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, M is selected from a single bond, and / or, L1 is selected from a single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L1 is selected from a single bond, C 2-3 Alkynylidene, C 2-3 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-3 Alkylene and C 1-3 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L1 is selected from a single bond, O, and / or, L 23 and M a Each independently selected from wherein each occurrence of n17 is independently selected from 6, 8, 12, and 24; L4 and L6 are each independently a peptide residue consisting of 2, 3, 4, 5, 6 or 7 amino acids or -NR b -C 1-6 Alkylene-NR b -, wherein the amino acid is selected from D-alanine, L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine and asparagine, and the alkylene group and the amino acid are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Preferably, L4 and L6 are each independently selected from -NH-CH2CH2-NH-, and / or L5 and L7 are each independently selected from: a single bond, and / or, G is selected from hydrogen, halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; preferably, G is selected from hydrogen, F, Cl, Br, I, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and / or, R a and R b is selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 aryl and 5-13 membered heteroaryl 1, 2, 3 or more substituents; preferably, R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

8. A compound as shown in Formula 1-5 or a pharmaceutically acceptable salt thereof, T-M-L1——L 23 -L4-L5-G Formula 1-5 in, T is the connector unit; M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace; L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a replace; L 23 It is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; L4 is a peptide residue composed of amino acids or -NRa-alkylene-NRa-; wherein the alkylene group and the amino acid are unsubstituted or optionally further substituted with one or more Ra; L5 is any spacer unit, or L5 is a spacer unit having a side chain comprising a hydrophilic unit; the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; G is a leaving group; Each occurrence of n1, n2, and n3 is independently selected from a natural number between 0 and 30; R a Selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocyclic group, -NH-C 1-6 Alkyl, C 1-6 Alkyl NH2, -C 1-6 Alkyl NHCOC 1-6 Alkyl, -C 1-6 AlkylCONH2, C 1-6 Alkyl O-CONH, -C 1-6 AlkylNHCONH2, 6-10 membered aryl and 5-13 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl; The conditions are: When L5 is any spacer unit, L 23 for or L 23 It is a chemically linked structure comprising 1 to 30 hydrophilic units and simultaneously comprises a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace; Each occurrence of n17 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28; Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6.

9. A compound as shown in formula 1-5-2 or a pharmaceutically acceptable salt thereof, TM-L1-L2-L3-L4-L5-G Formula 1-5-2 in, T is the connector unit; M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace; L1 is selected from a single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 2-10 Alkylene, and C 1-10 1, 2, 3 or more combinations of heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a replace; L2 is a single bond or -(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -(OCH2CH2) n1 -; L3 is selected from a single bond, -C(O)-, -Cy1-C 1-10 Alkylene-C(O)-, -Cy1-C(O)-, and -Cy1-(CH2) n3 -(OCH2CH2) n1 -O-(CH2) n2 -C(O)-; Cy1 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a Preferably, the arylene, heteroarylene, cycloalkylene, heterocycloalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Substitution; preferably, Cy1 is selected from Preferably, Cy1 is selected from L4 is a peptide residue consisting of amino acids; wherein the amino acids are not substituted or are optionally further substituted with one or more R a replace; L5 is a spacer unit having a side chain comprising a hydrophilic unit; G is a leaving group; Each occurrence of n1, n2, and n3 is independently selected from a natural number between 0 and 30; R a Selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocyclic group, -NH-C 1-6 Alkyl, C 1-6 Alkyl NH2, -C 1-6 Alkyl NHCOC 1-6 Alkyl, -C 1-6 AlkylCONH2, C 1-6 Alkyl O-CONH, -C 1-6 AlkylNHCONH2, 6-10 membered aryl and 5-13 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl.

10. The compound according to claim 7 or 8 or a pharmaceutically acceptable salt thereof, wherein L5 is L a Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-10 Alkylene, and C 2-10 1, 2, 3 or more combinations of heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by one or more R a Substituted; preferably, L a Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace; Cy2 is selected from 6-13 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, wherein the arylene, heteroarylene, cycloalkylene, heterocycloalkylene is unsubstituted or optionally further substituted with one or more R a Preferably, Cy2 is selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene, unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace; L b Selected from single bond, alkynylene, alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by one or more R a Substituted; preferably L b Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace; L c Selected from CR a R s , R s is a side chain comprising 1-30 hydrophilic units, wherein the hydrophilic units are selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic units are selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, R s Selected from Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6; Each occurrence of n is independently selected from any integer between 1 and 30. Preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; L d Selected from single bond, C 2-10 Alkynylidene, C 2-10 Alkenylene, -NR a -、O、-C(O)-、-NR a -C(O)-、C1 -10 Alkylene, and C 1-10 1, 2, 3 or more combinations of heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by one or more R a Substituted; preferably L d Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a replace.

11. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, T-M-L1——M a -L6-L7-G Formula 1-5-4 in, T is the connector unit; M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R b replace; L1 is selected from a single bond, an alkynylene group, an alkenylene group, -NR b -、-O-、-C(O)-、-NR b -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R b replace; M a for or M a It is a chemically linked structure comprising 1 to 30 hydrophilic units and simultaneously comprises a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace;; L6 is a peptide residue composed of amino acids or -NR b -alkylene-NR b -; wherein the alkylene group, amino acid is unsubstituted or optionally further substituted with one or more R b replace; L7 is a spacer unit; G is a leaving group; R b selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an aryl group and a heteroaryl group.

12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein M a Selected from -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -CO-, -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -CO-、 -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -CO-、 -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -CO-、 Each occurrence of n7, n9, n10, n10, n11, n13, and n14 is independently selected from 0, 1, 2, 3, 4, 5, and 6; Each occurrence of n8 and n17 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28; Each occurrence of n12 and n15 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15; n12 and n15 are not 0 at the same time; Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6; Cy3 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5, or 6 R a Substitution; preferably, Cy3 is selected from Preferably, Cy3 is selected from and / or L7 is selected from X1 is selected from Each occurrence of g is independently selected from 1, 2, 3, 4, 5, and 6; R b selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkylCONH2, C1-C6 alkylOCONH2, C1-C6 alkylNHCONH2, C6-C 15 Aryl and 5-15 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-15 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 aryl and 5-15 membered heteroaryl are substituted with one or more substituents; preferably, R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

13. The compound according to any one of claims 8 to 11 or a pharmaceutically acceptable salt thereof, wherein: T is selected from R is selected from halogen, -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, wherein W is selected from amino, -NR a -C 1-6 alkyl, The phenyl group, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl may be optionally substituted with 0, 1, 2, 3, or 4 R a Replace; and / or M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or L1 is selected from a single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or L4 is -NR b -C 1-6 Alkylene-NR b -, or 2-7 amino acid residues, wherein the amino acids are selected from D / L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine, asparagine, which are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L4 is selected from -NH-C2H4-NH-, and / or G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and / or n1, n2, n3 each occurrence are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; and / or R a selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C6 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C6 15 substituted by one or more substituents in aryl and 5-13 membered heteroaryl; preferably, R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; Preferably, T is selected from R is selected from halogen, -S-Ar; Ar is selected from phenyl, C 1-6 Alkylphenyl, C 1-6 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, wherein W is selected from amino, -NR a -C 1-6 alkyl, and / or M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or L1 is selected from a single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene, and C 1-6 1, 2, 3 or more combinations of alkynylene, alkenylene, alkylene, heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a Replace; and / or Cy1 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted by 1, 2, 3, 4, 5, or 6 R a Substitution; preferably, Cy1 is selected from Preferably, Cy1 is selected from and / or L4 is a peptide residue consisting of 2-7 amino acids, wherein the amino acids are selected from D / L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine, and asparagine, which are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L4 is selected from and / or G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO2; and / or n1, n2, n3 each occurrence are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; and / or R a selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C6 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C6 15 substituted by one or more substituents in aryl and 5-13 membered heteroaryl; preferably, R a Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy.

14. The compound according to any one of claims 9, 10 or 13, or a pharmaceutically acceptable salt thereof, wherein: R s Selected from Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6; Each occurrence of n is independently selected from any integer between 1 and 30. Preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.

15. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: wherein, n and n1 are each independently selected from any integer between 1 and 30 at each occurrence; preferably, n and n1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 at each occurrence.

16. A compound as represented by Formula 2-1, 2-2 or 2-3 or a pharmaceutically acceptable salt thereof, in, T, M, L1, L2, L3, L4, L5, M a , L6, L7 and L 23 As defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; D is selected from the group consisting of cytotoxic drug moieties, drug moieties for treating autoimmune diseases, and anti-inflammatory drug moieties; preferably, D is selected from the group consisting of cytotoxic drug moieties; preferably, D is selected from the group consisting of topoisomerase I (TOP1) inhibitor moieties, tubulin polymerization inhibitor moieties, topoisomerase II (TOP2) inhibitor moieties, dihydrofolate reductase inhibitor moieties, DNA alkylating agent moieties, thymidine synthetase inhibitor moieties, purine nucleoside synthetase inhibitor moieties, ribonucleotide reductase inhibitor moieties, DNA polymerase inhibitor moieties, RNA polymerase II inhibitor moieties, and other compound moieties capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of The wavy line indicates the connection point between D and L.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: n8 and n5, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; and n and n1 are each independently selected from any integer between 1 and 30; preferably, n and n1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.

18. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein: The ligand-drug conjugate is shown in Formula 3-1, Wherein, Ab is a ligand, and the ligand is an antibody or an antigen-binding fragment thereof; m is any integer or decimal from 1 to 12; D is selected from the group consisting of a cytotoxic drug moiety, a drug moiety for treating autoimmune diseases, and an anti-inflammatory drug moiety; preferably, D is a cytotoxic drug moiety; preferably, D is selected from the group consisting of a topoisomerase I (TOP1) inhibitor moiety, a tubulin polymerization inhibitor moiety, a topoisomerase II (TOP2) inhibitor moiety, a dihydrofolate reductase inhibitor moiety, a DNA alkylating agent moiety, a thymidine synthetase inhibitor moiety, a purine nucleoside synthetase inhibitor moiety, a ribonucleotide reductase inhibitor moiety, a DNA polymerase inhibitor moiety, an RNA polymerase II inhibitor moiety, and other moieties capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of The wavy line indicates the connection point between D and L; L is Where T a at represents the connection point with the antibody or antigen-binding fragment thereof, L 5c at Indicates the connection point with D; T a Selected from wherein T a On the left side of the structure Indicates the connection point with the antibody or antigen-binding fragment thereof, the T a On the right side of the structure Indicates that c connection points; M c is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group and a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group and the heterocycloalkylene group are unsubstituted or optionally substituted by one or more R a replace; L 1c Selected from single bond, alkynylene, alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more R a replace; L 2c Selected from single bond, -(CH2) n7 -(OCH2CH2) n8 -O-(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -(CH2CH2O) n8 -(CH2) n9 -Cy3-(CH2) n10 -C(O)-, -(CH2) n7 -Cy3-(CH2CH2O) n8 -(CH2) n9 -C(O)-, -(CH2) n11 -(OCH2CH2) n12 -O-(CH2) n13 -Cy3-(CH2) n14 -(OCH2CH2) n15 -C(O)-, -(CH2) n7 -(OCH2CH2) n8 -(CH2) n10 -C(O)-, 1, 2, 3 or more combinations of; n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence; n8 and n17, at each occurrence, are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, and n12 and n15 are not 0 at the same time; j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6; Each occurrence of Cy3 is independently selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a replace; M c 、L 1c , and L 2c Not all are single bonds; L 4c is a peptide residue consisting of amino acids or -NRa-alkylene-NRa-, wherein the alkylene, and amino acid are unsubstituted or optionally further substituted with one or more Ra; L 5c Selected from single bond, -N(R b )-(CH2) g -O-(CH2) g -OC(O)-、-N(R b )-(CH2) g -O-(CH2-CH2-O) g -C(O)-, And when L 2c When selected from single bonds, L 5c Not for When T a for and L 1c When containing an alkynylene group, L 5c for Each occurrence of n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28; X1 is selected from g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6; R a and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C1-C6 alkyl-C(O)-, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-NHC(O)-, -C 1-6 Alkylene-C(O)-NH2, C 1-6 Alkyl OC(O)NH-, -C 1-6 Alkylene-NHC(O)-NH2, C1-C6 alkyl-NHC(O)-NH-, C6-C 15 Aryl and 5-13 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 Aryl and 5-13 membered heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C6-C 15 The aryl group and the 5-13 membered heteroaryl group are substituted by 1, 2, 3 or more substituents.

19. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 18, wherein: m is any integer or decimal from 1 to 10; preferably, m is any integer or decimal from 2 to 8; preferably, m is any integer or decimal from 2 to 6; and / or D is selected from the group consisting of a topoisomerase I (TOP1) inhibitor portion, a tubulin polymerization inhibitor portion, a topoisomerase II (TOP2) inhibitor portion, a dihydrofolate reductase inhibitor portion, a DNA alkylating agent portion, a thymidine synthetase inhibitor portion, a purine nucleoside synthetase inhibitor portion, a ribonucleotide reductase inhibitor portion, a DNA polymerase inhibitor portion, an RNA polymerase II inhibitor portion, and other compound portions capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of The wavy line indicates the point where D and L connect; and / or M c is selected from a single bond, a phenylene group, a 5-7 membered heteroarylene group, a 3-7 membered cycloalkylene group and a 3-7 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group and the heterocycloalkylene group are unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, M c Selected from single bonds, and / or L 1c Selected from single bond, C 2-6 Alkynylidene, C 2-6 Alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-、C 1-6 Alkylene and C 1-6 wherein the alkynylene, alkenylene, alkylene and heteroalkylene groups are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L 1c Selected from single bond, C 2-3 Alkynylidene, C 2-3 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-3 Alkylene and C 1-3 wherein said alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L 1c Selected from single bond, O, and / or Cy3 is selected from Preferably, Cy3 is selected from and / or L 4c is a peptide residue consisting of 2, 3, 4, 5, 6 or 7 amino acids or -NRa-C 1-6 Alkylene-NRa-, wherein the amino acid is selected from D-alanine, L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine and asparagine, and the alkylene and amino acid are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L 4c Selected from -NH-CH2CH2-NH-, and / or L 5c Selected from: single bond, and / or R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 18 or 19, wherein D is selected from The wavy line indicates the point where D and L connect; and / or M c Selected from single bonds, and / or L 1c Selected from single bond, C 2-3 Alkynylidene, C 2-3 Alkenylene, -NR a -、-C(O)-、-NR a -C(O)-、C 1-3 Alkylene and C 1-3 wherein said alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a Substituted; preferably, L 1c Selected from single bond, O, and / or L 2c Selected from single bonds, in, n17 is independently selected from 6, 8, 12 and 24 at each occurrence; and / or L 4c Selected from -NH-CH2CH2-NH-, and / or L 5c Selected from: single bond, and or R a and R b Each occurrence is independently selected from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1-C3 alkylamino, C1-C3 alkyl and C1-C3 alkoxy.

21. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 18, wherein: L is Among them, T a As defined in claim 10, M, L1, L2, L3, L4, L5, M a , L6, L7 and L 23 As defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

22. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 21, wherein: L is selected from the following structures: wherein n and n1 are each independently selected from any integer between 1 and 30; preferably, n and n1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.

23. [Corrected 18.02.2025 according to Rule 91] A ligand-drug conjugate of formula 3-1 or 3-2, or a pharmaceutically acceptable salt thereof, in, Ab is a ligand; preferably, the ligand is an antibody or antigen-binding fragment capable of binding to nectin-4; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 1; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 2; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 4; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 3; m is any integer or decimal from 1 to 10; D as defined in claim 16; L is a chemical linking structure; Preferably, L is T a Selected from M c is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a replace; L 1c Selected from single bond, alkynylene, alkenylene, -NR a -、-O-、-C(O)-、-NR a -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a replace; L 2c It is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH2-CH2-O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2-CH2-O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; L 4c is a peptide residue composed of amino acids or -NRa-alkylene-NRa-; wherein the alkylene group and the amino acid are unsubstituted or optionally further substituted with one or more Ra; L 5c is any spacer unit; R a Selected from H, deuterium atoms, halogens, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 2-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-10 Alkoxy, hydroxy, nitro, cyano, amino, 3-15 membered cycloalkyl, 3-15 membered heterocyclic group, -NH-C 1-6 Alkyl, C 1-6 Alkyl NH2, -C 1-6 Alkyl NHCOC 1-6 Alkyl, -C 1-6 AlkylCONH2, C 1-6 Alkyl O-CONH, -C 1-6 AlkylNHCONH2, 6-10 membered aryl and 5-13 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl; More preferably, L is Among them, -M-, -L1-, -L2-, -L3-, -L4-, -L5-, -M a -, L6, L7 as defined in claim 8.

24. A ligand-drug conjugate as shown in Formula 3 or a pharmaceutically acceptable salt thereof, in, Ab is a ligand; preferably, the ligand is an antibody or antigen-binding fragment against nectin-4; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 1; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 2; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 4; and / or the antibody heavy chain sequence is as shown in SEQ ID NO: 3; m is any integer or decimal from 1 to 10; D as defined in claim 6; It is a chemically connected structure; Preferably, As defined in claim 6; preferably, T a is a linker portion for connecting ligands, preferably, T a Selected from 25. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 24, wherein: The ligand-drug conjugate is selected from the following structures: Wherein, Ab is a ligand, and the ligand is an antibody or an antigen-binding fragment thereof; m and m1 are each independently selected from integers or decimals from 1 to 12 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 1 to 10 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 2 to 8 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 2 to 6 at each occurrence; preferably, m and m1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 at each occurrence; and n1, n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8 at each occurrence.

26. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 18 to 25, wherein: The antibody is selected from the group consisting of a chimeric antibody, a humanized antibody and a fully human antibody; Preferably, the antibody or antigen-binding fragment thereof is selected from anti-nectin-4 antibody, anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 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-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody and antigen-binding fragments thereof; Preferably, the ligand is an anti-nectin-4 antibody or an antigen-binding fragment thereof; Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and / or a light chain, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDRs), wherein the amino acid sequence of heavy chain complementarity determining region 1 (HCDR1) is shown in SEQ ID NO: 7, the amino acid sequence of heavy chain complementarity determining region 2 (HCDR2) is shown in SEQ ID NO: 8, and the amino acid sequence of heavy chain complementarity determining region 3 (HCDR3) is shown in SEQ ID NO: 9; and / or the light chain comprises a light chain variable region, wherein the light chain variable region comprises three light chain complementarity determining regions (LCDRs), wherein the amino acid sequence of light chain complementarity determining region 1 (LCDR1) is shown in SEQ ID NO: 10, the amino acid sequence of light chain complementarity determining region 2 (LCDR2) is shown in SEQ ID NO: 11, and the amino acid sequence of light chain complementarity determining region 3 (LCDR3) is shown in SEQ ID NO: 12; Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and / or a light chain variable region, wherein the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 14; and / or the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 13; Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and / or a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 1, and / or the amino acid sequence of the light chain is shown in SEQ ID NO: 2; or, the amino acid sequence of the light chain is shown in SEQ ID NO: 4, and / or the amino acid sequence of the heavy chain is shown in SEQ ID NO: 3; or, the antibody light chain sequence is shown in SEQ ID NO: 6, and / or the antibody heavy chain sequence is shown in SEQ ID NO: 5; Preferably, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and / or a light chain, wherein the amino acid sequence of the light chain is shown in SEQ ID NO: 4, and / or the amino acid sequence of the heavy chain is shown in SEQ ID NO:

3.

27. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 16 or 17 or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate according to any one of claims 18 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. Use of the compound of claim 16 or 17 or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate of any one of claims 18 to 25 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27 in the preparation of a medicament for treating or preventing tumors; Preferably, the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer; preferably, the breast cancer is triple-negative breast cancer.

29. A method for preventing or treating tumors, comprising administering to a subject in need thereof an effective amount of the compound according to claim 16 or 17 or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate according to any one of claims 18 to 25 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27; Preferably, the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer; preferably, the breast cancer is triple-negative breast cancer.

30. The compound of claim 16 or 17 or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate of any one of claims 18 to 25 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27, for use in preventing or treating tumors; Preferably, the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer; preferably, the breast cancer is triple-negative breast cancer.

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