Ligand-drug conjugates of camptothecin analogs and uses thereof

Abstract

The present disclosure relates to conjugates of camptothecin analogs of the formula T-(L-D) m with a cell binding molecule. The present disclosure also provides methods for preparing conjugates of camptothecin analogs with cell binding agents, and methods of using the conjugates in tumor-targeted therapy.

Description

Technical Field

[0001] This invention provides conjugates of camptothecin analogues and cell surface receptor-binding molecules for targeted therapy, and pharmaceutical compositions containing the conjugates. This invention also provides intermediates for the camptothecin analogue conjugates and methods for their preparation. This invention further provides the use of camptothecin analogue-cell-binding molecule conjugates and pharmaceutical compositions containing the conjugates in targeted cancer therapy. Background Technology

[0002] Cancer is one of the leading causes of death worldwide. Surgery, chemotherapy, radiotherapy, and targeted therapy are currently the standard treatment options. Although chemotherapy is widely used, the use of most chemotherapeutic drugs is limited by unintended side effects—primarily stemming from the drug's effects on tumors and extracellular cells in their microenvironment, leading to systemic toxicity and a narrow therapeutic window. The discovery of the unique composition of cancer cell surfaces, and the understanding of the highly selective interactions between antibodies and cell surface antigens, have paved the way for developing antibodies as targeted delivery carriers for chemotherapeutic drugs, including highly toxic ones (Drago, JZ et al.). Nat.Rev.Clin.Oncol , 2021; Khongorzul, P. et al., Mol.Cancer Res , 2020, 18, 3-19; Joubert, N. et al., The Last Decade, Pharmaceuticals 2020, 13, 245; Ravi V.J. Chari et al., Angew.Chem.Int.Ed (2014, 53, 3796-3827). The resulting molecular entity, namely antibody-drug conjugates (ADCs), mainly consists of three parts: an antibody responsible for selectively recognizing cancer cell surface antigens that can mediate ADC endocytosis, a drug payload responsible for killing cancer cells after being released into the cell, and a linker connecting the antibody and the payload.

[0003] Antibody-drug conjugates, combining selective targeting of tumor cells through antigen-guided recognition with potent cell killing through cytotoxic payloads, have become an effective treatment for various cancers in recent years. Nature review Drug Discovery(2013, 12, 329-332). The first ADC (Mylotarg) was approved in 2000 (subsequently withdrawn in 2010, and reapproved in 2017), the second ADC (Adcetris) received accelerated approval in 2011 and full approval in 2015. The third (Kadcyla) and fourth (Besponsa) ADCs were approved in 2013 and 2017, respectively. Kadcyla was the first ADC approved for the treatment of solid tumors. Since 2019, more than ten ADCs have been approved, and more than one hundred ADCs are in clinical development.

[0004] It is known that the payload-connector components in an ADC play a crucial role in the ADC's uniformity, cyclic stability, pharmacokinetic profile, tolerability, and overall therapeutic efficacy (Acchionea, M. et al.). mAbs 2012, 4, 362; Zhao, RY, et al. J. Med. Chem .2011,54,3606). Although a great deal of research has been conducted to optimize the above features, most payloads used to date include DNA damaging agents (such as spicococcal, PBD, and pyruvic), microtubule disruptors (such as maytansines, e.g., DM1 or DM4; olprestatins, e.g., MMAE or MMAF; tubulolysins), and topoisomerase inhibitors (such as camptothecins, e.g., Dxd or SN-38) (Leung, D. et al., 2011, 54, 3606). Antibodies (Basel) 2020, 9, 2; Khongorzul, P. et al. Mol.Cancer.Res ., 2020, 18, 3; Chau, CH et al., Lancet 2019, 394, 793).

[0005] Among these payloads, camptothecins have proven to be a promising option for ADC construction with a broader therapeutic index than many other payloads. Two approved ADCs—Enhertu and Trodelvy, which use camptothecin payloads Dxd and SN-38, respectively—have demonstrated significant clinical benefit (progression-free survival, PFS, and overall survival, OS) in solid tumors in multiple clinical trials (Pondé, N. et al.). Curr Treat Options Oncol 2019, 20, 37; Kaplon, H. et al. Mabs (2020, 12, 1703531). Through interaction with the DNA enzyme topoisomerase I, a reversible enzyme-camptothecin-DNA ternary complex is subsequently formed, and camptothecin can induce cell death.

[0006] Camptothecin and most of its analogues are poorly soluble in physiological buffer solutions and have shown a high incidence of adverse drug reactions in preliminary clinical trials since the 1970s. The low solubility of camptothecin can lead to the aggregation of its ADC conjugates (Burke, P. et al.). Bioconjugate Chem (2009, 20, 6, 1242), which has an adverse impact on large-scale manufacturing and may cause systemic side effects due to aggregation. To date, the US FDA has only approved three water-soluble camptothecin analogues for cancer treatment: topotecan, irinotecan, and belletcan (Palakurthi, S., Expert Opin Drug Deliv. 2015, 12 (12), 1911). To date, most camptothecin-based payloads used in ADC development have suffered from low solubility, which further limits the drug-antibody ratio and leads to lower titers.

[0007] This application provides a series of ligand-drug conjugates of camptothecin analogues. Summary of the Invention

[0008] This disclosure provides camptothecin analog conjugates linked to cell-binding molecules, camptothecin analog-linker compounds, camptothecin analogs, and methods for their preparation and use.

[0009] Aspect 1: This disclosure provides a ligand-drug conjugate having the formula T-(LD). m , Or a pharmaceutically acceptable salt or solvate thereof, wherein: T represents the target or binding ligand; L represents the connection unit; m is an integer or fraction selected from 1 to 12; D is a drug unit with formula D1: ; in: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1aSelected from H or halogens; wherein the divalent group is independently selected from the group consisting of the following groups each time it appears: S-CH=N-, -O-CH=N-, -CH=CH-CH=CH-, -O(CH2)2-, -(CH2) p O(CH2) p -、-O-CH=CH-、 -(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; Each time p appears, it is independently selected from 1 or 2; R 1d Selected from H or halogens; R 2a and R 2b Each is independently selected from the group consisting of: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or R 2a With R 2b It combines with the carbon atom it is attached to to form C3-C6 cycloalkyl groups; Z is -R 3a -R 3b ; R 3b Selected from -OH, -SH and -NHR 3c ; R 3a Choose from the group consisting of the following groups: -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C0-C3 alkylene-C3-C 10 Cycloalkylene-C0-C3 alkylene-, -R 3g -C1-C6 alkylene-R 3g -C1-C6 alkylene-, -R 3g-C0-C3 alkylene-C5-C 12 arylene-C0-C3 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 Heteroaryl-C0-C3 alkylene-,-R 3g -C0-C3 alkylene-C3-C 10 Heterocyclic alkyl-C 0- C3 alkylene-, -N(C1-C8 alkyl)-C2-C8 alkylene-, and -NR 3d R 3e -R 3f ; R 3g It does not exist, or is selected from the group consisting of the following groups: O, S, S(O), S(O)2, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -NHC(=O)S-, -NHC(=S)NH- and -NHS(O)2-; R 3d and R 3e They combine with the nitrogen atoms to which they are attached to form 4-9 membered rings with optional substitutions, containing one or two nitrogen atoms; R 3f If not present, or selected from the group consisting of the following groups: -C(O)-N(C1-C3 alkyl)-C1-C8 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene(C1-C3 alkyl)-, -C1-C6 alkylene-, -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 Heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene-, and -C(O)-NH-C1-C8 alkylene-; R 3c Selected from H or C1-C6 alkyl groups; Wherein D is covalently linked to L through any suitable linking site on D, optionally wherein the hydrogen atom of the hydroxyl, mercapto, primary or secondary amine of D is replaced with a bond with L, or the tertiary amine of D is quaternized to form a bond with L. The condition is that when R 1a and R 1b Combine to form -O-CH=CH- and R 3a When choosing a group consisting of the following groups: -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C3-C 10 Cycloalkylene- and -R 3g -C1-C6 alkylene-R 3g When -C1-C6 alkylene-, R 3g Not -NHC(=O)-.

[0010] In some embodiments of aspect 1, wherein R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a and R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b and R 1c When R combines to form a divalent group, 1a It is selected from H or halogens; wherein, each time the divalent group appears, it is independently selected from the group consisting of the following groups: -O(CH2)2-, -(CH2) p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、 -S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; R 3fIt does not exist, or is selected from the group consisting of the following groups: -C1-C6 alkylene-, -C1-C6 alkylene (C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 Heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene-, and -C(O)-NH-C1-C8 alkylene.

[0011] In some embodiments of aspect 1, wherein R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a and R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b and R 1c When R combines to form a divalent group, 1a Selected from H or halogen; wherein each divalent group is independently selected from the group consisting of -S-CH=N-, -O-CH=N- and -CH=CH-CH=CH-, and wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen.

[0012] In some embodiments of aspect 1, wherein -NR 3d R 3e -R 3f -Has a structure similar to Formula I: ; in: X is -C(R) 5b - or -N-; R 5a Does not exist, or R 5a and R 8 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl; or R 5a and R 5bTogether with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; wherein the 5- to 6-membered aryl, 5- to 6-membered heteroaryl, each of the “3- to 6-membered cycloalkyl” and each of the “4- to 8-membered heterocycloalkyl” are each optionally and independently bound by 1 to 3 R 9 replace; R 4 R 5b R 6 R 7 and R 8 Independently selectable from H, halogen, hydroxyl, and C 1-8 Alkyl, C 3-6 The group consisting of cycloalkyl, aryl, and heteroaryl groups, wherein each C 1-8 Alkyl, C 3-6 Cycloalkyl, aryl, and heteroaryl groups are independently and optionally surrounded by 1 to 4 R groups. 9 Replace; or R 4 and R 5b Together with the atoms to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, provided that R 5a and R 5b Not forming a ring at the same time; or R 4 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 4 and R 6 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 7 and R 8 Together with the atoms to which they are attached, they form an oxo group, a 3- to 6-membered cycloalkyl group, or a 4- to 8-membered heterocycloalkyl group; wherein each 3- to 6-membered cycloalkyl group and each 4- to 8-membered heterocycloalkyl group is independently and optionally bonded by 1 to 4 R groups. 9 Replace; and R 4 R 5b R 6 R 7 and R 8 The remaining parts are independently selected from the group consisting of the following groups each time they appear: H, halogen, hydroxyl, C. 1-8 Alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, aryl, and heteroaryl groups are independently and optionally separated by one to four R groups. 9 replace; R9 Each time it appears, it is independently selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, and heteroaryl group; or, when two R groups appear, they are selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, 9 When a group is attached to an adjacent carbon atom, it forms a fused C3-C6 cycloalkyl group together with the carbon atoms to which they are attached; or, when two R groups are attached to adjacent carbon atoms, they form a fused C3-C6 cycloalkyl group. 9 When groups are attached to the same carbon atom, they together form a spirocyclic C3-C6 cycloalkyl group; wherein each C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, heteroaryl group, fused C3-C6 cycloalkyl group, and spirocyclic C3-C6 cycloalkyl group is independently and optionally substituted by one to three groups selected from fluorine, hydroxyl, and C1-C3 alkyl groups; n 1 and n 2 Each of the integers is independently chosen from 0, 1, 2, 3, and 4; provided that n is an integer. 1 + n 2 It can be 1, 2, 3, or 4.

[0013] In some embodiments of aspect 1, wherein -NR 3d R 3e -R 3f -Has a formula selected from the following: .

[0014] In some embodiments of aspect 1, wherein -NR 3d R 3e -R 3f -Has a formula selected from the following: .

[0015] In some embodiments of aspect 1, wherein RR 1a and R 1b They combine to form a divalent group, wherein the divalent group is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-; wherein each of the divalent groups is optionally substituted by at least one C1-C6 alkyl or halogen; p is independently selected from the group consisting of 1 and 2 each time it appears.

[0016] In some embodiments of aspect 1, wherein R 1c and R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC (=O)-CH2-O-, -OC (=O)-CH2-NH-, -OC (=O)-CH2-S-, -OC (=O)-CH2-CH2-, -(CH2) p S (=O)2(CH2) p The group consisting of -CH2C(=O)OCH2- and -OC(=O)-CH2-; and wherein each of the divalent groups is optionally substituted by at least one C1-C6 alkyl or halogen; p is independently selected from the group consisting of 1 and 2 each time it appears.

[0017] In some embodiments of aspect 1, wherein R 3f For the choice of freedom - C3 - C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 The group consisting of cycloalkylene-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene-, and -C(O)-NH-C1-C8 alkylene-.

[0018] In some embodiments of aspect 1, where D is transmitted via R 3b The oxygen, sulfur, or nitrogen atom is covalently bonded to L, where R... 3b -OH, -SH, or -NHR 3c One of the hydrogen atoms is replaced by a bond connected to L.

[0019] In some embodiments of aspect 1, wherein R 2a and R 2b It is independently selected from the group consisting of hydrogen, halogens and C1-C3 alkyl groups.

[0020] In some embodiments of aspect 1, wherein R 3b It is -OH.

[0021] In some embodiments of aspect 1, wherein R 3a Selected from -C1-C6 alkylene-, -S-C1-C6 alkylene-, -S(O)2-C1-C6 alkylene-, and -NR 3d R3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structural formula selected from the following: .

[0022] In some embodiments of aspect 1, wherein R 3a It is -C1-C6 alkylene- or -S-C1-C6 alkylene-.

[0023] In some embodiments of aspect 1, wherein R 3a For -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structural formula selected from the following: .

[0024] In some embodiments of aspect 1, wherein R 3f It does not exist, or is selected from -C1-C6 alkylene-, -NH-C(O)-C1-C6 alkylene- and -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-.

[0025] In some embodiments of aspect 1, D has D 1a D 1b D 1c D 1d D 1e D 1f D 1g D 1h D 1m D 1n D 1p or D 1q Structural formula: ; Where R 1e and R 1f Each time it appears, it is independently selected from H, halogens, and C1-C3 alkyl groups; R 1a R 1c R 1d R 2a R 2b Z is defined as in aspect 1 and in any of its implementations as in formula D1.

[0026] In some embodiments of aspect 1, the structural formula of D is selected from the group consisting of the following structural formulas: .

[0027] In some embodiments of aspect 1, the structural formula of D is selected from the group consisting of the following structural formulas: .

[0028] In some embodiments of aspect 1, the structural formula of D is selected from the group consisting of the following structural formulas: .

[0029] In some embodiments of aspect 1, D is covalently linked to L via the O atom of a substituent on the 7-carbon atom of camptothecin, wherein the hydrogen atom of -OH is replaced by a bond linked to L.

[0030] In some embodiments of aspect 1, L is a connection unit having the following formula: -L 1 -L 2 -L 3 -L 4 - Where L 1 For connecting subunits; L 2 It does not exist, or it is a separator; L 3 It is an amino acid unit; L 4 It does not exist, or it is a spacing element; and where L 1 Connect to T.

[0031] In some embodiments of aspect 1, wherein L 1 Selected from: ; Among them, Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5- to 6-arylene, and 5- to 6-heteroarylene; Y1 Choose from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heterocycloalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, -NHC(O) CH2-(OCH2CH2) p 6 -OC1-C6 alkyl and cycloalkyl groups; p 6 Each occurrence is independently selected from integers between 3 and 15; and each of the above L... 1 The left side of the group is attached to T; L 2 It does not exist, or is selected from the group consisting of the following groups: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p2 -(CH2) p 3 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、 -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5-to-6-heteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1-(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It is a group that does not exist or is selected from the following groups: ; Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Choose from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0032] In some embodiments of aspect 1, wherein, L 1 Choose from the group consisting of the following groups: ; Among them, Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5- to 6-arylene, and 5- to 6-heteroarylene; Y 1 Selected from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkylene and 5- to 10-membered heteroarylene; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1Each occurrence is independently selected from the group consisting of: C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, heteroalkylene, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroalkylene is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1 The left side of the group is attached to T; L 2 It does not exist, or is selected from the group consisting of the following groups: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2-(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2)p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O), and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an independent integer selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 3 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist, or is selected from the group consisting of the following groups: ; Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0033] In some embodiments of aspect 1, wherein L 1 Selected from the group consisting of the following groups: ; Among them, Z 1 Each occurrence is selected from C1-C8 alkylene, C1-C8 alkenylene, and C1-C8 ynylene. 3 Integers selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of: C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, heteroalkylene, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroalkylene is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteryl, alkoxy-NHC(O)CH2-(OCH2CH2) p 6 -OC1-C6 alkyl and cycloalkyl groups; p 6 Each occurrence is an independent integer selected from 3 to 15; and each of the above L... 1 The left side of the group is attached to T; L 2 The following groups are absent or selected from the group consisting of: -[NR] 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1-C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5-C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2-(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2-C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist or is selected from the group consisting of the following groups: ; Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Choose from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0034] In some embodiments of aspect 1, wherein: L 1 yes ;W 1 yes ;R 17 R 18 and R 19 Each time it appears, choose independently either H or -(CH2CH2O). p 7 The group consisting of -(C1-C6 alkyl), -SO3H, -PO(OH)2 and C1-C6 alkyl; R 20Each occurrence is independently a C1-C6 alkylene group; p 7 W is an integer selected from 1 to 15; W is selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heterocycloalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally and independently further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1 The left side of the group is attached to T; L 2 It does not exist, or is selected from the group consisting of the following groups: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2)p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4-O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L is an optionally substituted amino acid residue or an optionally substituted peptide residue consisting of 2 to 7 amino acids; wherein the L above 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L4 or R 3b ; L 4 It does not exist, or it is selected from the group consisting of the following groups: ; Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Choose from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0035] In some embodiments of aspect 1, wherein L 1 yes Z 1 Selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5- to 6-arylene, and 5- to 6-heteroarylene; Y 1 -O- or -CH2-; q 1 and q 2 Each of the integers is independently selected from 1, 2, 3, and 4.

[0036] In some embodiments of aspect 1, wherein L 2 Choose from the group consisting of the following groups: -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2)p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is independently selected from an integer from 3 to 15; "5- to 6-membered heteroaryl" each occurrence is independently selected from the group consisting of the following groups: .

[0037] In some embodiments of aspect 1, wherein L 3 The residue is an amino acid residue or a peptide residue consisting of 2 to 7 amino acids; wherein the amino acid is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N); wherein the amino acid residue and peptide residue may optionally be further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH 2、 -[N(CH3)-CH2-C(O)] g 1 -N(CH3)-CH2COOH, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 -NH-(CH2CH2O) g 1 -C1-C6 alkyl groups, -C(O)-(CH2CH2O) g 1 -(CH2) g-N[CH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]2、-NH-C[CH2OCH2CH2C(O)NHCH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]3; where g is an integer selected independently from 0 to 5 each time it appears; s is an integer selected from 0 to 3; Y 2 Y 3 and Y 4 Each time it appears, it is independently selected from the group consisting of -CH2-, -NH-, -S-, and -O-; g 1 Each occurrence is independently an integer selected from 3 to 15; optionally, it is a peptide residue composed of 1, 2 or more phenylalanine and glycine; optionally, it is a peptide residue composed of 4 amino acids; optionally, it is a peptide residue composed of GGFG; wherein the above L 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b .

[0038] In some embodiments of aspect 1, wherein L 3 The residue is an amino acid residue or a peptide residue consisting of 2 to 7 amino acids; wherein the amino acid is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N); wherein the amino acid residue and peptide residue may optionally be further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 Where g is an independent integer selected from 0 to 5 each time it appears; s is an integer selected from 0 to 3; Y 2 Y 3 and Y 4 Each time it appears, it is selected from groups composed of -CH2-, -NH-, -S-, and -O-; g 1 Each occurrence is an independent integer selected from 3 to 15; optionally, it is a peptide residue composed of 1, 2 or more phenylalanine and glycine; optionally, it is a peptide residue composed of 4 amino acids; optionally, it is a peptide residue composed of GGFG; wherein, the above L 3 The N-terminus of the group is connected to the L 1 or L2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3 .

[0039] In some embodiments of aspect 1, wherein L 4 Does not exist or is ;R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 16 Choose from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups.

[0040] In some embodiments of aspect 1, wherein Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, phenylene, and 5- to 6-heteroarylene.

[0041] In some embodiments of aspect 1, wherein Z 1 Each time it appears, it is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenyl, and C1-C8 ynylene.

[0042] In some embodiments of aspect 1, L is selected from the following structures: .

[0043] In some embodiments of aspect 1, L is selected from the following structures: .

[0044] In some embodiments of aspect 1, L is selected from the following structures: .

[0045] In some embodiments of aspect 1, L is selected from the following structures: .

[0046] In some embodiments of aspect 1, the ligand-drug conjugate includes, but is not limited to: ; Or its pharmaceutically acceptable salts or solvates.

[0047] In some embodiments of aspect 1, T is a targeting antibody or a ligand that binds to an antigen; wherein the antibody is selected from chimeric antibodies, humanized antibodies, and fully human antibodies.

[0048] In some embodiments of aspect 1, T is a monoclonal antibody.

[0049] In some embodiments of aspect 1, T is selected from anti-Her2 (ErbB2) antibody, anti-EGFR antibody, anti-B7H3 antibody, anti-c-MET antibody, anti-Her3 (ErbB3) antibody, anti-Her4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MICI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenosynovin C antibody, anti-SLC44A4 antibody, anti-mesothelin antibody, and anti-ROR1 antibody, or antigen-binding fragments thereof.

[0050] In some embodiments of aspect 1, T is selected from trastuzumab, pertuzumab, nimotuzumab, enoblituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, bivatuzumab, lorvotuzumab, cBR96, and glembatumumab, or an antigen-binding fragment.

[0051] In some embodiments of aspect 1, T is trastuzumab.

[0052] In some embodiments of aspect 1, m is an integer or fraction selected from 2 to 8.

[0053] In some embodiments of aspect 1, m is an integer or fraction selected from 3 to 8.

[0054] Aspect 2: This disclosure provides a compound having the formula LD, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: L represents the connection unit; D is a drug unit with formula D1: ; in, R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a Selected from H or halogens; each time the divalent group appears, it is independently selected from the group consisting of: -S-CH=N-, -O-CH=N-, -CH=CH-CH=CH-, -O(CH2)2-, -(CH2) p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2)p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or halogen; Each time p appears, it is independently selected from 1 or 2; R 1d Selected from H or halogen; R 2a and R 2b Independently selected from the group consisting of H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or R 2a and R 2b Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group; Z is -R 3a -R 3b ; R 3b Selected from -OH, -SH and -NHR 3c ; R 3a Choose Free-R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C0-C3 alkylene-C3-C 10 Cycloalkylene-C0-C3 alkylene-, -R 3g -C1-C6 alkylene-R 3g -C1-C6 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 arylene-C0-C3 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 Heteroaryl-C0-C3 alkylene-,-R 3g -C0-C3 alkylene-C3-C 10 Heterocyclic alkyl-C0-C3 alkylene-, -N(C1-C8 alkyl)-C2-C8 alkylene- and -NR 3d R 3e -R3f -A group; R 3g It does not exist, or you can choose the group consisting of O, S, S(O), S(O)2, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -NHC(=O)S-, -NHC(=S)NH- and -NHS(O)2-; R 3d and R 3e Together with the nitrogen atom to which it is attached, it forms an optionally substituted 4- to 9-membered ring containing one or two nitrogen atoms; R 3f It does not exist, or can be selected from -C(O)-N(C1-C3 alkyl)-C1-C8 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene(C1-C3 alkyl)-, -C1-C6 alkylene-, -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-; R 3c Selected from H or C1-C6 alkyl groups; D is covalently linked to L through any suitable linking site; optionally, the hydrogen atom on the hydroxyl, mercapto, primary or secondary amine of D is replaced with a bond linked to L, or the tertiary amine of D is quaternized to form a bond linked to L. The prerequisite is that when R 1a With R 1b Combine to form -O-CH=CH-, and R 3a Selected from -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C3-C 10 Cycloalkylene- and -R 3g -C1-C6 alkylene-R 3g When R is a group consisting of -C1-C6 alkylene-, 3gNot -NHC(=O)-.

[0055] In some embodiments of aspect 2, R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b When R¹ᶜ combines with R to form a divalent group, R 1a It is selected from H or halogens; the divalent group is independently selected from -O(CH2)2- or -(CH2) each time it appears. p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; R 3f It does not exist, or is selected from -C1-C6 alkylene-, -C1-C6 alkylene (C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

[0056] In some embodiments of aspect 2, R 1b With R 1a or R 1cCombine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a It is selected from H or halogen; wherein each divalent group is independently selected from the group consisting of -S-CH=N-, -O-CH=N- and -CH=CH-CH=CH-, and wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen.

[0057] In some embodiments of aspect 2, where -NR 3d R 3e -R 3f - Has the structure shown in Equation I: ; in: X is -C(R) 5b - or -N-; R 5a Does not exist, or R 5a and R 8 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl; or R 5a and R 5b Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; wherein, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, each "3- to 6-membered cycloalkyl" and each "4- to 8-membered heterocycloalkyl" are independently and optionally surrounded by 1 to 3 R 9 replace; R 4 R 5b R 6 R 7 and R 8 Independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein each C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl is independently and optionally surrounded by 1 to 4 R 9 Replace; or R 4 With R 5b Together with the atoms to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, provided that R is present. 5a With R 5b Do not form a ring at the same time; or R 4 and R 7Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 4 and R 6 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 7 With R 8 Together with the atoms to which they are attached, they form an oxo group, a 3- to 6-membered cycloalkyl group, or a 4- to 8-membered heterocycloalkyl group; wherein each of the 3- to 6-membered cycloalkyl groups and the 4- to 8-membered heterocycloalkyl groups is independently and optionally surrounded by 1 to 4 R groups. 9 Replace; and R 4 R 5b R 6 R 7 and R 8 The remaining parts, each time appearing, are independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein the C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl are independently and optionally separated by 1 to 4 R. 9 replace; R 9 Each time it appears, it is independently selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, and heteroaryl group; or two R groups. 9 When a group is attached to an adjacent carbon atom, it forms a fused C3-C6 cycloalkyl group together with the attached carbon atom; or two R groups... 9 When the group is attached to the same carbon atom, it forms a spirocyclic C3-C6 cycloalkyl group together with the carbon atom to which it is attached; wherein each C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, heteroaryl group, fused C3-C6 cycloalkyl group and spirocyclic C3-C6 cycloalkyl group is independently and optionally substituted by 1 to 3 substituents selected from fluorine, hydroxyl and C1-C3 alkyl groups; n 1 and n 2 Each is an independent integer selected from 0, 1, 2, 3, and 4; the prerequisite is n. 1 + n 2 It can be 1, 2, 3 or 4.

[0058] In some embodiments of aspect 2, wherein -NR 3d R 3e -R 3f - Has a structure selected from the following: .

[0059] In some embodiments of aspect 2, wherein -NR 3d R 3e -R 3f - Has a structure selected from the following: .

[0060] In some embodiments of aspect 2, R 1a With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; and each occurrence of p is independently selected from the group consisting of 1 and 2.

[0061] In some embodiments of aspect 2, R 1c With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; p is independently selected from the group consisting of 1 and 2 each time it appears.

[0062] In some embodiments of aspect 2, R 3f Choose Free - C3 - C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10The group consisting of cycloalkylene-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

[0063] In some embodiments of aspect 2, where D is transmitted via R 3b The O, S, or N atoms are covalently bonded to L; where R 3b -OH, -SH or -NHR 3c The hydrogen atoms on the L atom are replaced with bonds attached to the L atom.

[0064] In some embodiments of aspect 2, R 2a and R 2b It is independently selected from H, halogens and C1-C3 alkyl groups.

[0065] In some embodiments of aspect 2, R is -OH.

[0066] In some embodiments of aspect 2, R 3a Selected from -C1-C6 alkylene-, -S-C1-C6 alkylene-, -S(O)2-C1-C6 alkylene- and -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structure selected from the following: and .

[0067] In some embodiments of aspect 2, R 3a It is -C1-C6 alkylene- or -S-C1-C6 alkylene-.

[0068] In some embodiments of aspect 2, R 3a For -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structure selected from the following: and .

[0069] In some embodiments of aspect 2, R 3f It does not exist, or is selected from -C1-C6 alkylene-, -NH-C(O)-C1-C6 alkylene- and -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-.

[0070] In some embodiments of aspect 2, D has D 1a D 1b D 1c D 1d D 1e D 1f D 1g D 1h D 1m D 1n D 1p or D 1q The structure shown: ; Where R 1e and R 1f Each occurrence is independently selected from H, halogens, and C1-C3 alkyl groups; R 1a R 1c R 1d R 2a R 2b Each time Z appears, it is as defined by equation D1 in aspect 2 and any of its implementations.

[0071] In some embodiments of aspect 2, D has a structural formula selected from the group consisting of: .

[0072] In some embodiments of aspect 2, the structural formula of D is selected from the group consisting of the following structural formulas: .

[0073] In some embodiments of aspect 2, D is covalently linked to L via the O atom of a substituent on the 7-carbon atom of camptothecin, wherein the hydrogen atom of -OH is replaced by a bond linked to L.

[0074] In some embodiments of aspect 2, L is a connection unit having the following formula: L 1a -L 2 -L 3 -L 4 - Where L 1a For connecting subunits; L 2 It does not exist, or it is a separator; L 3It is an amino acid unit; L 4 It does not exist, or it is a spacing element; and where L 1 Connect to T.

[0075] In some embodiments of aspect 2, wherein L 1a Selected from: ; Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5-to-6-arylene, and 5-to-6-heteroarylene; Y 1 Choose from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, -NHC(O)CH2-(OCH2CH2). p 6 -OC1-C6 alkyl and cycloalkyl groups; p 6 Each occurrence is an independent integer selected from 3 to 15; and each of the above L... 1a The right side of the group is connected to L 2 or L 3 ; L 2 It does not exist, or is selected from the group consisting of the following groups: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2)p 1 -C(O)-、-CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10-C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2)p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence of L is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L is an optionally substituted amino acid residue or an optionally substituted peptide residue consisting of 2 to 7 amino acids; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist, or is selected from the group consisting of the following groups: ; Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0076] In some embodiments of aspect 2, wherein: L 1a Selected from the group consisting of the following groups: ; Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5-to-6-arylene, and 5-to-6-heteroarylene; Y1 Choose from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, heteroalkylene, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroalkylene is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1a The right side of the group is connected to L 2 or L 3 ; L 2 Not present, or selected from the group consisting of: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence of L is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist, or is selected from the group consisting of the following groups: ; Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0077] In some embodiments of aspect 2, wherein: L 1a Selected from the group consisting of the following groups: ; Z 1 Each occurrence is selected from C1-C8 alkylene, C1-C8 alkenylene, and C1-C8 ynylene. 3 For integers selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, -NHC(O)CH2-(OCH2CH2). p 6 -OC1-C6 alkyl and cycloalkyl groups; p 6 Each occurrence is an independent integer selected from 3 to 15; and each of the above L... 1a The right side of the group is connected to L 2 or L 3 ; L 2 Not present, or selected from the group consisting of: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-、-O-(CH2) p 1 -C(O)-、-S-(CH2) p 1 -C(O)-、-CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10-C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2)p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence of L is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist, or is selected from the group consisting of the following groups: ; Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0078] In some embodiments of aspect 2, wherein: L 1a yes ;W 1 yes ; Where R 17 R 18 and R 19 Each time it appears, it is independently selected from H and -(CH2CH2O). p 7 -(C 1 -C 6 The group consisting of alkyl groups, -SO3H, -PO(OH)2, and C1-C6 alkyl groups; R 20 Each occurrence is independently a C1-C6 alkylene group; p 7 W is an integer selected from 1 to 15; W is selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heterocycloalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally and independently further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1a The left side of the group is attached to T; L 2 It does not exist, or is selected from the group consisting of the following groups: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O)p 2 -(CH2) p 3 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2)p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1-(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence of L is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist, or is selected from the group consisting of the following groups: ; Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

[0079] In some embodiments of aspect 2, wherein L 1a for And Z 1 Selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5- to 6-arylene, and 5- to 6-heteroarylene; Y 1 -O- or -CH2-; q 1 and q 2 Each is an independent integer selected from 1, 2, 3, and 4.

[0080] In some embodiments of aspect 2, wherein L 2 Selected from the group consisting of the following groups: -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O)p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1-(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent selection from 3 to 15 integers: "5- to 6-membered heteroaryl" is each independently selected from the group consisting of the following groups: .

[0081] In some embodiments of aspect 2, wherein L 3 The residue is an amino acid residue or a peptide residue consisting of 2 to 7 amino acids; wherein the amino acid is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N); wherein the amino acid residue and peptide residue are optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2、-[N(CH3)-CH2-C(O)] g 1 -N(CH3)-CH2COOH, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 -NH-(CH2CH2O) g 1 -C1-C6 alkyl, -C(O)-(CH2CH2O)g 1 -(CH2) g -N[CH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]2, -NH-C[CH2OCH2CH2C(O)NHCH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]3, where g is an independent integer selected from 0 to 5 each time it appears; s is an integer selected from 0 to 3; Y 2 Y 3 and Y 4 Each time it appears, select the group consisting of -CH2-, -NH-, -S-, and -O-; g 1 Each occurrence is an independent integer selected from 3 to 15; optionally, it is a peptide residue composed of one, two, or more phenylalanine and glycine; optionally, it is a peptide residue composed of four amino acids; optionally, it is a peptide residue composed of GGFG; wherein the above L 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b .

[0082] In some embodiments of aspect 2, wherein L 3 The residue is an amino acid residue or a peptide residue consisting of 2 to 7 amino acids; wherein the amino acid is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N); wherein the amino acid residue and peptide residue may optionally be further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 And g is an independent integer selected from 0 to 5 each time it appears; s is an integer selected from 0 to 3; Y 2 Y 3 and Y 4 Each time it appears, select the group consisting of -CH2-, -NH-, -S-, and -O-; g 1 Each occurrence is an independent integer selected from 3 to 15; optionally, it is a peptide residue composed of one, two, or more phenylalanine and glycine; optionally, it is a peptide residue composed of four amino acids; optionally, it is a peptide residue composed of GGFG; wherein the above L3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b .

[0083] In some embodiments of aspect 2, wherein L 4 Does not exist or is ;where R 14 and R 15 Independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 16 Choose from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups.

[0084] In some embodiments of aspect 2, Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynynylene, phenylene, and 5- to 6-heteroaryl groups.

[0085] In some embodiments of aspect 2, Z 1 Each time it appears, it is selected from the group consisting of C1-C8 alkylene, C2-C8 alkenylene, and C2-C8 alkynylene.

[0086] In some embodiments of aspect 2, L is selected from the following structures: .

[0087] In some embodiments of aspect 2, L is selected from the following structures: .

[0088] In some embodiments of aspect 2, L is selected from the following structures: .

[0089] In some embodiments of aspect 2, L is selected from the following structures: .

[0090] In some embodiments of aspect 2, the compound includes, but is not limited to: ; Or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof.

[0091] Aspect 3: This disclosure provides a compound represented by formula D1: ; Or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a Selected from H or halogens; each time the divalent group appears, it is independently selected from the group consisting of: -S-CH=N-, -O-CH=N-, -CH=CH-CH=CH-, -O(CH2)2-, -(CH2) p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p-, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or halogen; Each time p appears, it is independently selected from 1 or 2; R 1d Selected from H or halogen; R 2a and R 2b Independently selected from the group consisting of H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or R 2a and R 2b Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group; Z is -R 3a -R 3b ; R 3b Selected from -OH, -SH and -NHR 3c ; R 3a Choose Free-R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C0-C3 alkylene-C3-C 10 Cycloalkylene-C0-C3 alkylene-, -R 3g -C1-C6 alkylene-R 3g -C1-C6 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 arylene-C0-C3 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 Heteroaryl-C0-C3 alkylene-,-R 3g -C0-C3 alkylene-C3-C 10 Heterocyclic alkyl-C0-C3 alkylene-, -N(C1-C8 alkyl)-C2-C8 alkylene- and -NR 3d R 3e -R 3f -A group; R 3gIt does not exist, or you can choose the group consisting of O, S, S(O), S(O)2, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -NHC(=O)S-, -NHC(=S)NH- and -NHS(O)2-; R 3d and R 3e Together with the nitrogen atom to which it is attached, it forms an optionally substituted 4- to 9-membered ring containing one or two nitrogen atoms; R 3f It does not exist, or can be selected from -C(O)-N(C1-C3 alkyl)-C1-C8 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene(C1-C3 alkyl)-, -C1-C6 alkylene-, -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-; R 3c Selected from H or C1-C6 alkyl groups; The prerequisite is that when R 1a With R 1b Combine to form -O-CH=CH-, and R 3a Selected from -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C3-C 10 Cycloalkylene- and -R 3g -C1-C6 alkylene-R 3g When R is a group consisting of -C1-C6 alkylene-, 3g Not -NHC(=O)-.

[0092] In some embodiments of aspect 3, R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1bWhen R combines to form a divalent group, 1c Selected from H or halogen; when R 1b When R¹ᶜ combines with R to form a divalent group, R 1a It is selected from H or halogens; the divalent group is independently selected from -O(CH2)2- or -(CH2) each time it appears. p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; R 3f It does not exist, or is selected from -C1-C6 alkylene-, -C1-C6 alkylene (C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

[0093] In some embodiments of aspect 3, R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1aIt is selected from H or halogen; wherein each divalent group is independently selected from the group consisting of -S-CH=N-, -O-CH=N- and -CH=CH-CH=CH-, and wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen.

[0094] In some embodiments of aspect 3, where -NR 3d R 3e -R 3f - Has the structure shown in Equation I: ; in: X is -C(R) 5b - or -N-; R 5a Does not exist, or R 5a and R 8 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl; or R 5a and R 5b Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; wherein, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, each "3- to 6-membered cycloalkyl" and each "4- to 8-membered heterocycloalkyl" are independently and optionally surrounded by 1 to 3 R 9 replace; R 4 R 5b R 6 R 7 and R 8 Independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein each C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl is independently and optionally surrounded by 1 to 4 R 9 Replace; or R 4 With R 5b Together with the atoms to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, provided that R is present. 5a With R 5b Do not form a ring at the same time; or R 4 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 4 and R 6Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 7 With R 8 Together with the atoms to which they are attached, they form an oxo group, a 3- to 6-membered cycloalkyl group, or a 4- to 8-membered heterocycloalkyl group; wherein each of the 3- to 6-membered cycloalkyl groups and the 4- to 8-membered heterocycloalkyl groups is independently and optionally surrounded by 1 to 4 R groups. 9 Replace; and R 4 R 5b R 6 R 7 and R 8 The remaining parts, each time appearing, are independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein the C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl are independently and optionally separated by 1 to 4 R. 9 replace; R 9 Each time it appears, it is independently selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, and heteroaryl group; or two R groups. 9 When a group is attached to an adjacent carbon atom, it forms a fused C3-C6 cycloalkyl group together with the attached carbon atom; or two R groups... 9 When the group is attached to the same carbon atom, it forms a spirocyclic C3-C6 cycloalkyl group together with the carbon atom to which it is attached; wherein each C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, heteroaryl group, fused C3-C6 cycloalkyl group and spirocyclic C3-C6 cycloalkyl group is independently and optionally substituted by 1 to 3 substituents selected from fluorine, hydroxyl and C1-C3 alkyl groups; n 1 and n 2 Each is an independent integer selected from 0, 1, 2, 3, and 4; the prerequisite is n. 1 + n 2 It can be 1, 2, 3 or 4.

[0095] In some embodiments of aspect 3, wherein -NR 3d R 3e -R 3f - Has a structure selected from the following: .

[0096] In some embodiments of aspect 3, wherein -NR 3d R 3e -R 3f - Has a structure selected from the following: .

[0097] In some embodiments of aspect 3, R 1a With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; and each occurrence of p is independently selected from the group consisting of 1 and 2.

[0098] In some embodiments of aspect 3, R 1c With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; p is independently selected from the group consisting of 1 and 2 each time it appears.

[0099] In some embodiments of aspect 3, R 3f Choose Free - C3 - C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 The group consisting of cycloalkylene-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

[0100] In some embodiments of aspect 3, R 2a and R 2b It is independently selected from H, halogens and C1-C3 alkyl groups.

[0101] In some embodiments of aspect 3, R is -OH.

[0102] In some embodiments of aspect 3, R 3a Selected from -C1-C6 alkylene-, -S-C1-C6 alkylene-, -S(O)2-C1-C6 alkylene- and -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structure selected from the following: and .

[0103] In some embodiments of aspect 3, R 3a It is -C1-C6 alkylene- or -S-C1-C6 alkylene-.

[0104] In some embodiments of aspect 3, R 3a For -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structure selected from the following: and .

[0105] In some embodiments of aspect 3, R 3f It does not exist, or is selected from -C1-C6 alkylene-, -NH-C(O)-C1-C6 alkylene- and -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-.

[0106] In some embodiments of aspect 3, D has D 1a D 1b D 1c D 1d D 1e D 1f D 1g D 1h D 1m D 1n D 1p or D 1q The structure shown: ; Or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, wherein R1e and R 1f Each occurrence is independently selected from H, halogens, and C1-C3 alkyl groups; R 1a R 1c R 1d R 2a R 2b Each time Z appears, it is as defined by equation D1 in aspect 2 and any of its implementations.

[0107] In some embodiments of aspect 2, D has a structural formula selected from the group consisting of: ; Or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof.

[0108] In another embodiment, the cell surface binding molecule T can be any cell-binding ligand currently known or to be discovered in the future, such as peptides and non-peptides. Typically, the cell-binding molecule T is: an antibody; a single-chain antibody; an antibody fragment capable of binding to target cells; a monoclonal antibody; a single-chain monoclonal antibody; a monoclonal antibody fragment capable of binding to target cells; a chimeric antibody; a chimeric antibody fragment capable of binding to target cells; a domain antibody; a domain antibody fragment capable of binding to target cells; adnectins or DARPins (antibody mimics); lymphokines; hormones; vitamins; growth factors; colony-stimulating factors; or nutrient transport molecules (such as transferrin); binding peptides, proteins, or antibodies; or small molecule affinity ligands attached to albumin, polymers, dendritic macromolecules, liposomes, nanoparticles, vesicles, or (viral) capsids. Preferably, the binding molecule T is a monoclonal antibody.

[0109] This article also provides the formula T-(LD). m The compounds shown in LD, D1 and any embodiments thereof, or pharmaceutically acceptable salts or solvates thereof, wherein the compounds are tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof.

[0110] Another aspect of this disclosure provides a preparative T-(LD) formulation. mMethods for the ligand-drug conjugates shown in LD, D1 and any embodiments thereof, or pharmaceutically acceptable salts or solvates thereof, and optionally their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof.

[0111] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of: 1) the ligand-drug conjugate or compound described in this disclosure, or a pharmaceutically acceptable salt or solvate thereof, and optionally its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof; and 2) one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0112] Another embodiment of this disclosure also relates to the use of the following: 1) the ligand-drug conjugate or compound described in this disclosure, or a pharmaceutically acceptable salt or solvate thereof, and optionally its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof; or 2) the use of a pharmaceutical composition of this disclosure comprising the substances described in 1) above in the preparation of a medicament for treating or preventing tumors; optionally, the tumor is cancer; optionally, the tumor is cancer associated with the expression of HER2, HER3, HER4, ROR1, TROP-2, B7-H3, c-MET, CD20, CD22, CD30, or EGFR.

[0113] Another aspect of this disclosure relates to a method of treating a tumor in a subject in need, comprising administering to the subject: 1) the ligand-drug conjugate or compound of this disclosure, or a pharmaceutically acceptable salt or solvate thereof, and optionally its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof; or 2) a pharmaceutical composition of this disclosure comprising the substance described in 1); optionally, the tumor is cancer; optionally, the tumor is cancer associated with the expression of HER2, HER3, HER4, ROR1, TROP-2, B7-H3, c-MET, CD20, CD22, CD30, or EGFR.

[0114] Another aspect of this disclosure relates to: 1) the ligand-drug conjugates or compounds described in this disclosure, or pharmaceutically acceptable salts or solvates thereof, and optionally tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof; or 2) pharmaceutical compositions comprising the foregoing substances described in this disclosure for the treatment of tumors; optionally, the tumor is cancer; optionally, the tumor is cancer associated with the expression of HER2, HER3, HER4, ROR1, TROP-2, B7-H3, c-MET, CD20, CD22, CD30, or EGFR. In some embodiments, the cancer is selected from the group consisting of: breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, or relapsed anaplastic large cell lymphoma).

[0115] The active compound may be formulated in a form suitable for administration via an appropriate route, preferably in a unit dose form or in a form that can be administered by the patient as a single dose. The unit dose form of the compounds or compositions disclosed herein may be tablets, capsules, sachets, bottled formulations, powders, granules, lozenges, suppositories, reconstituted powders, or liquid formulations.

[0116] In the treatment methods described in this disclosure, the dosage of the compound or composition typically varies depending on the severity of the disease, the patient's weight, and the relative efficacy of the compound. However, as a general guideline, a suitable unit dose may be from 0.1 to 1000 mg.

[0117] In addition to the active compound, the pharmaceutical compositions described herein may also contain one or more excipients, including fillers (diluents), binders, wetting agents, disintegrants, excipients, etc. Depending on the route of administration, the compositions may contain 0.1% to 99% by weight of the active compound.

[0118] The pharmaceutical compositions described in this disclosure may be in the form of an oil-in-water emulsion.

[0119] The pharmaceutical composition may be in the form of a sterile aqueous solution for injection. Acceptable carriers or solvents that can be used are water, Ringer's solution, or isotonic sodium chloride solution. The sterile injectable formulation may be a sterile water-in-oil microemulsion for injection, wherein the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin, and then the oil solution is added to a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion may be administered into the patient's bloodstream via local bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound disclosed herein. To maintain this constant concentration, a continuous intravenous delivery device may be used; an example of such a device is the DeltecCADD-PLUS™ 5400 intravenous pump.

[0120] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension prepared in a non-toxic, non-enteric-acceptable diluent or solvent. Furthermore, sterile fixative oils can be conveniently used as a solvent or suspension medium.

[0121] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound, the patient's age, the patient's weight, the patient's general health condition, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and combination therapy. Furthermore, optimal treatment regimens, such as the mode of treatment, the daily dose of compound (I) or the type of its pharmaceutically acceptable salt, can be validated against standard treatment protocols. Attached Figure Description

[0122] Figure 1 Results of ADC efficacy study in Capan-1 tumor-bearing nude mice (ADC-5).

[0123] Figure 2 : Body weight curve of Capan-1 tumor-bearing nude mice (ADC-5).

[0124] Figure 3 Results of ADC efficacy study in NCI-N87 tumor-bearing nude mice (ADC-4).

[0125] Figure 4 Body weight curves of NCI-N87 tumor-bearing nude mice (ADC-4).

[0126] Figure 5 Results of ADC efficacy study in NCI-N87 tumor-bearing nude mice (ADC-5 and ADC-8).

[0127] Figure 6Body weight curves of NCI-N87 tumor-bearing nude mice (ADC-5 and ADC-8).

[0128] Figure 7 Results of ADC efficacy study in JIMT-1 tumor-bearing nude mice (ADC-5).

[0129] Figure 8 Body weight curve of JIMT-1 tumor-bearing nude mice (ADC-5).

[0130] Figure 9 Drug loading concentrations in plasma, lung tissue, and tumor tissue 4 hours after intravenous administration.

[0131] Figure 10 Drug loading concentration in plasma, lung tissue, and tumor tissue 24 hours after intravenous administration.

[0132] Figure 11 Changes in body weight in rats after intravenous administration. Detailed Implementation

[0133] Unless otherwise stated, all technical and scientific terms used herein are consistent with the common understanding of one of ordinary skill in the art to which this disclosure pertains. While any methods and materials similar to or equivalent to those described herein may be used in implementing or testing this disclosure, preferred methods and materials are described herein. In describing and protecting this disclosure, the following terms shall be used as defined below.

[0134] Unless otherwise stated, the terms used in the specification and claims have the meanings described below.

[0135] Unless the context clearly indicates otherwise, the indefinite articles “an” and “a” used in this article refer to one or more.

[0136] A "ligand" is a compound that can recognize and bind to a target cell-associated antigen or receptor. The role of a ligand is to deliver a drug to the target cell population that has bound it. Such ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, peptides, or other molecules that can bind to cells. In one embodiment of this disclosure, the ligand is designated as T to represent trastuzumab. The ligand can form a bond with a linker via a heteroatom thereon. The ligand is preferably an antibody or its antigen-binding fragment. The antibody is selected from chimeric antibodies, humanized antibodies, fully humanized antibodies, or murine antibodies, preferably monoclonal antibodies.

[0137] The term "drug" refers to the cytotoxic drugs described herein, which are chemical molecules that can strongly disrupt the normal growth of tumor cells. In principle, all cytotoxic drugs can kill tumor cells at sufficiently high concentrations.

[0138] The terms "linker," "linker unit," "linker fragment," or "linker cell" refer to a chemical structural segment or bond that is linked at one end to a ligand and at the other end to a drug substance. Preferred embodiments of this disclosure use L and L... 1 To L 4 It means that L 1 The end connects to the ligand, L 4 The end is connected to the drug.

[0139] Linkers (including extension units, spacer units, and amino acid units) can be synthesized by methods known in the art, such as those described in US 2005-0238649A1. The linkers can be “cleavable linkers” or “release linkers” that facilitate the release of drugs into cells. For example, acid-labile linkers (e.g., hydrazone bonds), protease-sensitive linkers (e.g., peptidase-sensitive linkers), photostable linkers, dimethyl linkers, or linkers containing disulfide bonds can be used (Chari et al., *Cancer Research* 52:127-131 (1992); US Patent No. 5,208,020).

[0140] The term "ligand-drug conjugate" refers to a bioactive drug that is linked to a ligand as described herein via a stable linker. In this disclosure, "ligand-drug conjugate" is preferably an antibody-drug conjugate (ADC), i.e., a toxic drug that is linked to a bioactive monoclonal antibody or antibody fragment via a stable linker.

[0141] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem, Vol. 243, p. 3558 (1968).

[0142] The term "antibody" refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The antibodies described in this disclosure are preferably specific antibodies targeting cell surface antigens. Non-limiting examples include one or more of the following antibodies: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUC1 antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenosynovin C antibody, and anti-SLC44A4. Antibodies or anti-mesothelin antibodies, preferably trastuzumab (trade name: Herceptin), pertuzumab (also known as 2C4, trade name: Peijeta), nimotuzumab (trade name: Taixinsheng), enoblituzumab, emibetuzumab, inotuzumab (domestic generic name: Ointuzumab), pinatuzumab, brentuximab (domestic generic name: Brentuximab), gemtuzumab (domestic generic name: Gemtuzumab-Ozomicin), bivatuzumab, lorvotuzumab, cBR96, and glembatumumab.

[0143] The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. Fragments of full-length antibodies have been shown to be used to achieve antigen-binding functionality. Examples of binding fragments in the term "antigen-binding fragment" include: (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, which are bivalent fragments consisting of two Fab fragments linked by disulfide bonds in their hinge regions; (iii) Fd fragments, which consist of VH and CH1 domains; (iv) Fv fragments, which consist of VH and VL domains of a single-arm antibody; (v) single-domain or dAb fragments (Ward et al. (1989) Nature 341:544-546), which consist of a VH domain; and (vi) separate complementarity-determining regions (CDRs), or (vii) combinations of two or more separate complementarity-determining regions optionally linked by synthetic linkers. Furthermore, although the VL and VH domains of the Fv fragment are encoded by two separate genes, they can be linked using synthetic linkers via recombination methods, thereby generating a single protein chain of a monovalent molecule formed by the pairing of the VL and VH domains (referred to as a 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). This single-chain antibody is also intended to be included within the definition of an "antigen-binding fragment" of the antibody. Such antibody fragments can be obtained using conventional techniques known to those skilled in the art, and functional fragments can be screened using the same methods as for intact antibodies. Antigen-binding sites can be prepared using recombinant DNA technology or by enzymatic or chemical cleavage of intact immunoglobulins.

[0144] The term "CDR" refers to one of the six hypervariable regions within the antibody variable domain, which is primarily involved in antigen binding. One of the most commonly used definitions of the six CDRs is given by Kabat EA et al. (1991), "Sequences of proteins of immune interest," NIH Publication 91-3242. The Kabat definition of CDR used in this article applies only to CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domain, and CDR2 and CDR3 (CDR H2, CDR H3 or H2, H3) of the heavy chain variable domain.

[0145] The terms "specific binding," "selective binding," "selectively binding," and "specifically binding" refer to the binding of an antibody to a predetermined epitope of an antigen. Typically, this antibody binds at a concentration of less than 10... -7The affinity (KD) of M binds, for example, less than 10. -8 M, 10 -9 M or 10 -10 M or smaller.

[0146] Methods for the preparation and purification of antibodies and antigen-binding fragments are well-known in the art, such as Chapters 5-8 and 15 of the *Cold Spring Harbor Antibody Technical Guide*. Antigen-binding fragments can also be prepared using conventional methods. The antibodies or antigen-binding fragments disclosed herein are genetically engineered to introduce one or more human FR regions into non-human CDR regions. Human FR germline sequences can be obtained by alignment with the IMGT Human Antibody Variable Region Germplasm Database from the ImMunoGeneTics (IMGT) website (http: / / imgt.cines.fr) and MOE software, or obtained from *Journal of Immunoglobulins* 20011SBN012441351.

[0147] The term "peptide" refers to a compound segment that lies between amino acids and proteins, consisting of two or more amino acid molecules linked together by peptide bonds. Peptides are structural and functional segments of proteins. Hormones, enzymes, and other similar substances are essentially peptides.

[0148] The term "toxin" refers to any substance that can have a harmful effect on cell growth or proliferation. Toxins can be small molecule toxins and their derivatives derived from bacteria, fungi, plants, or animals.

[0149] The term "chemotherapy drug" refers to compounds that can be used to treat tumors. This definition also includes anti-hormonal drugs, which modulate, attenuate, block, or inhibit the effects of hormones that promote cancer growth, typically in the form of systemic or holistic therapy.

[0150] The number of carbon atoms in various hydrocarbon-containing groups is indicated by a prefix, which defines the minimum and maximum number of carbon atoms in the group, i.e., the prefix C. i -C j This indicates a group with an integer number of carbon atoms, from "i" to "j" (inclusive). For example, C1-C6 alkyl refers to alkyl groups with 1 to 6 carbon atoms (inclusive).

[0151] The term "camptothecin" refers to a potent natural alkaloid with cytotoxic properties. Camptothecin has a planar five-membered fused-ring system containing three fused rings: the pyrrolo-(3,4-β)-quinoline moiety (rings A, B, and C), which is fused to a pyridone (ring D). The active form of camptothecin contains a chiral center within the α-hydroxylactone ring (ring E), which has an (S)-configuration. The structure of camptothecin and the numbering of its carbon atoms are shown in Formula A. .

[0152] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon substituent (i.e., a substituent obtained by removing one hydrogen atom from a hydrocarbon); in one embodiment, it contains 1 to 8 carbon atoms, in another embodiment 1 to 6 carbon atoms, in yet another embodiment 2 to 4 carbon atoms, and in still another embodiment 1 to 3 carbon atoms. Non-limiting examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl, isopentyl, hexyl, heptyl, octyl, etc. In another embodiment, it is a group containing 1 to 3 carbon atoms, composed of methyl, ethyl, n-propyl, and isopropyl. The phrase "each 'C1-C8 alkyl' is optionally surrounded by 1 to 3 R..." 9 "Substitution" means that each "C1-C8 alkyl" in the listed group list can be replaced by one to three R groups. 9 Replace. For example, in the following list "C1-C 88 In the series “alkyl”, “(C1-C8 alkyl)NHC(O)O-”, “(C1-C8 alkyl)NH-”, and “(C1-C8 alkyl)C(O)O-”, each C1-C8 alkyl group can be divided by 1 to 3 R groups. 9 Substitution. In addition to the groups expressly listed in the various embodiments or claims, in some embodiments, the alkyl group may optionally be substituted with one to three substituents, said substituents being independently selected from halogens, -C1-C2, -C4, -C5, -C6, and -C5, -C6, -C7, -C6 ... 12 Alkyl (unsubstituted or substituted, in one embodiment substituted with 1, 2 or 3 halogens), aryl, -OH, -O-C1-C 12 Alkyl group, -S(O) n C1-C4 alkyl (where n is 0, 1, or 2), -C1-C4 alkylNH2, -NHC1-C4 alkyl, -C(=O)H, -C(=O)OR a -OC(=O)R b -OC(=O)NR a R c -OC(=O) heteroaryl and -OC(=O) (heterocyclic), where R a and R c Independently hydrogen or -C1-C4 alkyl, R b It is an alkyl group.

[0153] As used in this article, the term "alkylene" refers to a divalent alkyl group as defined herein.

[0154] The term "-(C0 alkylene)-" refers to a chemical bond. Therefore, the term "-(C0-C3 alkylene)-" includes a chemical bond (i.e., C0) and a -(C1-C alkylene)- group.

[0155] The term "acetylenic" refers to a hydrocarbon group containing at least one carbon-carbon triple bond. In one embodiment, it contains 2 to 6 carbon atoms; in another embodiment, it contains 4 to 6 carbon atoms (i.e., C4-C6 acetylenic). Exemplary acetylenic groups include -C≡C-, -CH2C≡C-, -C≡C-CH2-, -C≡C-CH2CH2-, -CH2-C≡C-CH2-, and -C≡CHCH2CH2CH2-.

[0156] The term "alkenyl" refers to a hydrocarbon group containing at least one carbon-carbon double bond. In one embodiment, it contains 2 to 6 carbon atoms; in another embodiment, it contains 4 to 6 carbon atoms (i.e., a C4-C6 alkenyl group). Exemplary alkenyl groups include -CH=CH-, -CH2CH=CH-, -CH=CH-CH2-, -CH=CH-CH2CH2-, -CH2CH=CHCH2-, and -CH=CHCH2-.

[0157] The term "-alkylene-cycloalkylene-" as used herein refers to a group formed by the attachment of an alkylene group as defined herein to a cycloalkylene group as defined herein.

[0158] The term "alkoxy" refers to an -OR group, where R is an alkyl group as defined herein, i.e., a substituent obtained by removing a hydrogen atom from the hydroxyl group of a hydrocarbon alcohol; in one embodiment, it contains 1 to 6 carbon atoms. Non-limiting examples of such substituents include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentoxy, hexoxy, etc. In another embodiment, it contains 1 to 3 carbon atoms and is composed of methoxy, ethoxy, n-propoxy, and isopropoxy. An alkoxy group attached to an alkyl group is called an alkoxyalkyl group, an example of which is methoxymethyl.

[0159] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group as defined herein.

[0160] The term "membered ring" can encompass any ring structure (e.g., spirocyclic, bridged, and fused rings). The term "member" is used to indicate the number of skeleton atoms that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran, and thioran are six-membered rings, while cyclopentyl, pyrrole, furan, and thiophene are five-membered rings.

[0161] The term "cycloalkyl" refers to a carbocyclic substituent obtained by removing a hydrogen atom from a saturated or partially unsaturated (but without an aromatic ring) carbocyclic molecule; in one embodiment, it contains 3 to 7 carbon atoms, and in another embodiment, it contains 5 to 6 carbon atoms. The term "cycloalkyl" includes monocyclic saturated carbocyclic rings. The term "C3-C7 cycloalkyl" refers to groups in three- to seven-membered ring systems, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups can also be bicyclic (including bridged and fused rings) or spirocyclic carbocyclic rings. For example, the term "C3-C7 cycloalkyl" refers to... 12 "Cycloalkyl" includes monocyclic carbocyclic and bicyclic or spirocyclic cycloalkyl structural moieties, such as bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, spiropentyl, spirohexyl, spiroheptyl, spiroctyl, and spirononyl. In addition to the groups expressly listed in the various embodiments or claims, in some embodiments, the cycloalkyl group is optionally substituted with 1 to 3 substituents, said substituents being independently selected from halogens, -C1-C64, and -C1-C64. 12 Alkyl (unsubstituted or substituted, in one embodiment substituted with 1, 2 or 3 halogens), aryl, -OH, -O-C1-C 12 Alkyl group, -S(O) n C1-C4 alkyl (where n is 0, 1, or 2), -C1-C4 alkylNH2, -NHC1-C4 alkyl, -C(=O)H, -C(=O)OR a -OC(=O)R b -OC(=O)NR a R c -OC(=O) heteroaryl and -OC(=O) (heterocyclic), where R a and R c Independently hydrogen or -C1-C4 alkyl, R b It is an alkyl group.

[0162] The term "cycloalkylene" refers to the divalent cycloalkyl group as defined herein.

[0163] In some cases, the number of atoms in a cyclic substituent (i.e., a heteroaryl or heterocyclic alkyl group) containing one or more heteroatoms is indicated by the prefix "x-to-y-membered," where x is the minimum number of atoms constituting the cyclic structure of the substituent, and y is the maximum number of atoms. For example, "4-to-6-membered heterocyclic alkyl" refers to a heterocyclic alkyl group whose cyclic structure contains 4-6 atoms (including 1-3 heteroatoms). Similarly, the phrase "5-to-6-membered heteroaryl" refers to a heteroaryl group containing 5-6 atoms, and "5-to-10-membered heteroaryl" refers to a heteroaryl group whose cyclic structure contains 5-10 atoms (each containing one or more heteroatoms). Furthermore, the phrases "5-membered heteroaryl" and "6-membered heteroaryl" refer to five-membered and six-membered heteroaryl ring systems, respectively. The heteroatoms contained in the above ring systems are selected from N, O, S(O), S(O)2, and S.

[0164] The term "hydroxyl" refers to -OH. When used in combination with other terms, the prefix "hydroxyl" indicates that the substituent attached to that prefix is ​​replaced by one or more hydroxyl substituents. Compounds with a carbon atom connected to one or more hydroxyl substituents include, for example, alcohols, enols, and phenols. The terms cyano and nitrile refer to -CN groups. The term "oxo" refers to an oxygen atom attached to a carbon atom via a double bond (i.e., when R...). 4 When it is an oxygen group, R 4 Together with the carbon atoms they are attached to, they form the C=O group.

[0165] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one, two, or three hydroxyl groups as defined herein.

[0166] The term “halogen” or “halogen” refers to fluorine (which can be represented as -F), chlorine (which can be represented as -Cl), bromine (which can be represented as -Br) or iodine (which can be represented as -I).

[0167] The term "haloalkyl" refers to an alkyl group substituted with one, two, three, four, five, or six halogen groups as defined herein. In some embodiments, haloalkyl includes chloroalkyl.

[0168] The term "heterocyclic alkyl" refers to a substituent obtained by removing one hydrogen atom from a saturated or partially saturated ring structure containing a specified total number of atoms, for example, containing 4 to 6 ring atoms or 4 to 12 ring atoms in one embodiment; wherein at least one ring atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Sulfur may be oxidized (i.e., S(O) or S(O)2) or not oxidized. In groups containing heterocyclic alkyl substituents, the ring atom to which the heterocyclic alkyl substituent is attached may be an nitrogen heteroatom or a cyclic carbon atom. Similarly, if the heterocyclic alkyl substituent itself is substituted by a group or substituent, the group or substituent may be attached to an nitrogen heteroatom or a cyclic carbon atom. It should be understood that heterocyclic groups may be monocyclic, bicyclic (including bridged and fused rings), polycyclic, or spirocyclic. In addition to the groups expressly listed in any embodiment or claim, in some embodiments, the heterocyclic alkyl group may optionally be substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, -C1-C 12 Alkyl (unsubstituted or substituted, in one embodiment substituted with 1, 2 or 3 halogens), aryl, -OH, -O-C1-C 12 Alkyl group, -S(O) n C1-C4 alkyl (where n is 0, 1, or 2), -C1-C4 alkylNH2, -NHC1-C4 alkyl, -C(=O)H, -C(=O)OR a -OC(=O)R b -OC(=O)NR a R c-OC(=O) heteroaryl and -OC(=O) (heterocyclic), where R a and R c Independently hydrogen or -C1-C4 alkyl, R b It is an alkyl group.

[0169] The term “heterocyclic alkylene” refers to a divalent heterocyclic alkyl group as defined herein.

[0170] The term "aryl" refers to a carbocyclic monocyclic or bicyclic system, wherein the monocyclic ring is an aromatic ring and the bicyclic ring comprises at least one aromatic ring. Optionally, one embodiment has 6 to 10 carbon atoms, and another embodiment has 6 to 8 carbon atoms. Examples of "aryl" include phenyl, tetrahydronaphthyl, and naphthyl. In addition to any group expressly listed in any embodiment or claim, in some embodiments, the aryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -C1-C... 12 Alkyl (unsubstituted or substituted, in one embodiment substituted with 1, 2 or 3 halogens), aryl, -OH, -O-C1-C 12 Alkyl group, -S(O) n C1-C4 alkyl (where n is 0, 1, or 2), -C1-C4 alkylNH2, -NHC1-C4 alkyl, -C(=O)H, -C(=O)OR a -OC(=O)R b -OC(=O)NR a R c -OC(=O) heteroaryl and -OC(=O) (heterocyclic), where R a and R c Independently hydrogen or -C1-C4 alkyl, R b It is an alkyl group.

[0171] As used in this article, the term "aryl" refers to a divalent aryl group as defined herein.

[0172] The term "heteroalkyl" refers to an alkyl group as defined herein, wherein one or more -CH2- groups are substituted with a group independently selected from -O-, -S-, -S(O)-, -S(O)2, and -NR- (where R is hydrogen or an alkyl group as defined herein); and / or one or more -CH3 groups are substituted with a group independently selected from -OH, -SH, and -NH2. Heteroalkyl groups include 2-thioethyl, 2-aminopropyl-1-yl, 2-hydroxyethyl-1-yl, N-methylaminoethyl, etc. Hydroxyalkyl is a subset of heteroalkyl groups.

[0173] The term "heteroalkylene" refers to the divalent heteroalkylene as defined herein.

[0174] The term "heteroaryl" refers to an aromatic ring structure containing a specified number of ring atoms, wherein at least one ring atom is a heteroatom (i.e., oxygen, nitrogen, and / or sulfur), and the remaining ring atoms are carbon. Optionally, one embodiment has 5 to 10 ring atoms, and another embodiment has 5 to 6 ring atoms. Examples of heteroaryl substituents include six-membered heteroaryl rings such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and five-membered heteroaryl rings such as triazolyl, imidazolyl, furanyl, thiophene, pyrazolyl, pyrroleyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and isothiazolyl. Heteroaryl groups can also be bicyclic heteroaryl groups, such as indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxazolel, benziisoxazolel, oxazolopyridyl, imidazopyridyl, imidazopyrimidinyl, etc. In groups containing a heteroaryl ring, the ring atom attached to the group can be a nitrogen atom or a ring carbon atom. Similarly, if the heteroaryl ring is further substituted by a group or substituent, the group or substituent can be attached to a nitrogen atom or a ring carbon atom. The term "heteroaryl" also includes pyridinyl N-oxide and groups containing a pyridinyl N-oxide ring. Furthermore, heteroaryl groups can contain oxo groups, such as the oxo groups present in pyridinone groups. Further examples include furanyl, thiopheneyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridinyl, pyrazinyl, pyridin-2(1H)-keto, pyridin-2(1H)-keto, pyrimidin-2(1H)-keto, pyrazin-2(1H)-keto, imidazole[1,2-a]pyridinyl, and pyrazo[1,5-a]pyridinyl. Heteroaryl groups may be further substituted as defined herein.

[0175] Examples of monocyclic heteroaryl and heterocyclic alkyl groups include furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, dihydrothienyl, tetrahydrothienyl, pyrroliyl, isopyrroliyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isimidazole, imidazolinyl, imidazoalkyl, pyrazolyl, pyrazolinyl, pyrazolyl, thiazolyl, tetrazolyl, dithioheteropenenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolylalkyl, isothiazolalkyl, thiazolyldiazole, oxadiazole, oxadiazole (including oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole or 1,3,4-oxadiazole) Pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridyl, piperidinyl, diazinyl (including pyridazinyl, pyrimidinyl, piperazinyl, triazinyl (including mesazinyl, asymmetric triazinyl, and triazinyl), oxazinyl (including 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, or 2H-1,4-oxazinyl), isoxazinyl (including o-isooxazinyl or p-isooxazinyl), oxazolidinyl, isoxazolidinyl, oxothiazinyl (including 1,2,5-oxothiazinyl or 1,2,6-oxothiazinyl), oxadiazinyl (including 2H-1,2,4-oxadiazinyl or 2H-1,2,5-oxadiazinyl), and morpholinyl.

[0176] When defined as such, the term "heteroaryl" may also include cyclic systems having two rings, wherein the rings may be fused, and one ring is an aromatic ring, while the other ring is not an integral part of the conjugated aromatic system (i.e., the heteroaryl ring may be fused to a cycloalkyl or heterocycloalkyl ring). Non-limiting examples of such cyclic systems include: 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopentano[b]pyridyl, 6,7-dihydro-5H-cyclopentano[c]pyridyl, 1,4,5,6-tetrahydrocyclopentano[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopentano[c]pyrazolyl, 5,6-dihydro-4H-pyrazolyl... The compounds are pyrrolizo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydropyrazolo[1.5-a]pyridyl, 4,5,6,7-tetrahydro-1H-indazoleyl, and 4,5,6,7-tetrahydro-2H-indazoleyl.

[0177] If the carbocyclic or heterocyclic portion is attached to a specified group by bonding with different ring atoms or otherwise, without specifying a particular attachment point, it means all possible attachment points, whether via a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, the term "thiophenyl" means 2-, or 3-thiophenyl, and so on.

[0178] The term "heteroaryl" as used in this article refers to the divalent heteroaryl as defined in this article.

[0179] The term "amino protecting group" refers to a group that prevents the amino group from reacting when the rest of the molecule reacts and can be easily removed. Non-limiting examples include 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, etc. These groups may optionally be substituted with one to three substituents selected from halogens, alkoxy groups, and nitro groups. The amino protecting group is preferably 9-fluorenylmethoxycarbonyl.

[0180] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0181] In the context of cycloalkyl, cycloalkylene, and heterocyclic compounds, the term "unsaturated" refers to a partially unsaturated but non-aromatic ring.

[0182] The term "fused" refers to a bicyclic, tricyclic, or polycyclic structure consisting of at least two carbon rings or heterocyclic structures that share at least one chemical bond.

[0183] If a substituent is described as having multiple variables "independently," then each example of a substituent is selected independently from the list of available variables, separate from the other substituents. Therefore, each substituent may be the same as or different from the other substituents. If a substituent is described as being "independently selected" from a set of groups, then each example of a substituent is selected independently from the other substituents. Therefore, each substituent may be the same as or different from the other substituents.

[0184] "Optional" or "optionally" means that an event or situation described below may occur but is not required to occur, and the description includes examples of the event or situation occurring as well as examples of it not occurring. For example, "aryl group optionally substituted with one or two alkyl groups" means that an alkyl group may be present but is not required to be present, and the description includes cases where the aryl group is substituted with one or two alkyl groups, as well as cases where the aryl group is not substituted with an alkyl group.

[0185] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently replaced by a corresponding number of substituents. Clearly, substituents exist only at their possible chemical positions. Those skilled in the art can determine the feasibility of such substitution without excessive experimentation or theoretical deduction. For example, a combination of an amino or hydroxyl group with free hydrogen and a carbon atom having an unsaturated bond (such as an olefinic bond) may be unstable.

[0186] As used herein, the term "compound of formula (I)" (or other formula designations) is defined to include all forms of compounds of formula (I), including their hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, and metabolites. For example, the compounds disclosed herein, or their pharmaceutically acceptable salts, may exist in both non-solventized and solvated forms. When the solvent or water is tightly bound, the complex will have a definite stoichiometric ratio independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water / solvent content will depend on humidity and drying conditions. In this case, a non-stoichiometric ratio will be the norm. Compounds having the same molecular formula but differing in the nature or order of atomic bonding, or in the spatial arrangement of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers."

[0187] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center (e.g., bonded to four different groups), a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described according to the R- and S-sequence rules of Cahn and Prelog, or characterized by the way the molecule rotates to the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0188] The compounds described herein may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)- or (S)- stereoisomers, or mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in the specification and claims is intended to include individual enantiomers and mixtures thereof in racemic or other forms. Methods for stereochemical determination and stereoisomer separation are well known in the art (see discussion in Chapter 4 of *Advanced Organic Chemistry*, 4th Edition, by J. March, John Wiley and Sons, New York, 1992).

[0189] Hydrogen (H) or carbon (C) substitution in compounds of formula I includes substitution with any isotope of the corresponding atom. Therefore, hydrogen (H) substitution includes... 1 H, 2 H (deuterium) or 3 H (tritium) isotope substitution, for example, can be used as needed for specific therapeutic or diagnostic therapies, metabolic research applications, or to enhance metabolic or chemical stability. Optionally, the compounds disclosed herein may be incorporated with radioisotopes or radionuclides known in the art, such as3 H, 15 O、 12 C or 13 Ni isotopes were used to obtain the corresponding radiolabeled compounds of formula I.

[0190] "Pharmaceutically acceptable carrier" means a carrier that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, and has no undesirable effects in a biological or other respect, including carriers that can be used for veterinary and human pharmaceutical purposes. The term "pharmaceutically acceptable carrier" as used in the specification and claims includes one or more such carriers.

[0191] A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and possesses the pharmacological activity required by the parent compound. Such salts include: (1) acid addition salts formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or formed from organic acids (such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, etc.); or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (such as alkali metal ions, alkaline earth metal ions, or aluminum ions); or salts formed by coordination with organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.).

[0192] The “treating”, “treatment”, or “therapy” of a disease includes: (1) preventing the disease, that is, preventing the development of clinical symptoms of the disease in mammals that may be exposed to or susceptible to the disease but have not yet developed or exhibited symptoms of the disease; (2) suppressing the disease, that is, stopping or slowing the development of the disease or its clinical symptoms; or (3) alleviating the disease, that is, causing the disease or its clinical symptoms to subside.

[0193] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, and other components such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism, which is beneficial for the absorption of the active ingredient, thereby enabling it to exert its biological activity.

[0194] The term "solvent" refers to a pharmaceutically acceptable solvate formed by the ligand-drug conjugate of this disclosure and one or more solvent molecules. Non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0195] As used in the compositions disclosed herein, the term "carrier" refers to a system that can alter the manner and distribution of a drug into the body, control the drug release rate, and deliver the drug to target organs. Drug carrier release and targeting systems can reduce drug degradation and loss, decrease side effects, and improve bioavailability.

[0196] The term "excipient" refers to auxiliary components in pharmaceutical preparations other than the active pharmaceutical ingredient. Examples include binders, fillers, disintegrants, and lubricants in tablets; the base portion in semi-solid preparations such as ointments and creams; and preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, osmotic pressure regulators, and colorants in liquid preparations.

[0197] The term "diluent," also known as a filler, is primarily used to increase the weight and volume of tablets. Adding diluents ensures a certain volume, reduces dosage deviation of the main ingredient, and improves the compressibility of the drug. When tablets contain oily components, absorbents are added to absorb the oily substances, thereby maintaining a "dry" state to facilitate tableting. Examples of diluents include starch, lactose, inorganic salts of calcium, and microcrystalline cellulose.

[0198] The pharmaceutical composition can be formulated as a sterile aqueous solution for injection. Acceptable carriers or solvents include water, Ringer's solution, or isotonic sodium chloride solution. The sterile injectable formulation can be a sterile water-in-oil microemulsion for injection, wherein the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. This oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injectable solution or microemulsion can be administered into the patient's bloodstream via local bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous infusion device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0199] The pharmaceutical composition can be formulated as a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents described above, according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension prepared in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any mixed fixative oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids (such as oleic acid) can also be used in the preparation of the injectable formulation.

[0200] The term "drug loading" refers to the average number of cytotoxic drugs loaded on each ligand in a compound of formula (I), and can also be expressed as the ratio of the number of drugs to the number of antibodies. The drug loading ranges from 0 to 12, preferably with 1 to 10 cytotoxic drugs loaded on each ligand. In one embodiment of this disclosure, the drug loading is expressed as n, and exemplary values ​​may be averages of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The average number of drugs on each ADC molecule after the coupling reaction can be determined by conventional methods, such as UV / Vis spectroscopy, mass spectrometry, ELISA detection, and HPLC characterization.

[0201] The term "tumor" refers to all tumorous cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues.

[0202] The term "cancer" refers to a disease characterized by the uncontrolled (and often rapid) growth of abnormal cells. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. This article describes examples of a variety of cancers, including but not limited to: breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, or relapsed anaplastic large cell lymphoma), including metastatic forms of these cancers.

[0203] "Therapeutic effective amount" refers to the amount of a compound that is sufficient to achieve a therapeutic effect when administered to a mammal to treat a disease. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and factors such as the age and weight of the mammal to be treated.

[0204] The term "mammal" refers to all mammals, including humans, livestock, and pets.

[0205] The compounds described herein are generally named according to the IUPAC or CAS nomenclature system. Abbreviations well known to those skilled in the art may be used (e.g., “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour, and “rt” or “RT” for room temperature).

[0206] Option I: A method for preparing a compound of formula (D1) of this disclosure or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: ; Optionally, the compound of formula (B1) can be reacted with the compound of formula (B2) under alkaline conditions to give the compound of formula (D1); Where: X, R 1a R 1b R 1c R 1d R 2a R 2b R 3b R 3f R 4 R 5a R 6 R 7 R 8 n 1 and n 2 As defined in formula (D1) and any of its implementations.

[0207] Reagents that provide alkaline conditions include organic and inorganic bases. Organic bases include, but are not limited to: triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, and potassium tert-butoxide. Inorganic bases include, but are not limited to: sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0208] Option II: A method for preparing the compound of formula (B7) of this disclosure (according to formula: LD) or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: ; Step 1: Compound (B1) and compound (B3) are optionally reacted under basic conditions to give compound (B4); Step 2: Deprotect the compound of formula (B4) to obtain the compound of formula (B5); Step 3: The compound of formula (B5) reacts with the compound of formula (B6) in the presence of a condensing agent or under basic conditions, and optionally under basic conditions, to give the compound of formula (B7). Wherein: Pg is an amino protecting group, preferably benzyloxycarbonyl (Cbz). R 3b’ For -O-, -S- and -N (R) 3c )-; n is an integer 1; X, R 1a R1b R 1c R 1d R 2a R 2b R 3c R 3f R 4 R 5a R 6 R 7 R 8 R 11 R 14 R 15 q 1 q 2 p 2 p 3 L 3 n 1 and n 2 As defined in formula LD and any of its implementations.

[0209] Reagents that provide alkaline conditions include organic and inorganic bases. Organic bases include, but are not limited to, triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, and potassium tert-butoxide. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0210] The condensing agent is selected from the group consisting of: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and benzotriazole-1-yloxytris(dimethylamino) Phosphorus hexafluorophosphate and benzotriazole-1-yloxytripyrrolidinyl phosphorus hexafluorophosphate; preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0211] Option III: Preparation of this disclosure according to formula T-(LD) n The ligand-drug conjugate shown, any embodiment thereof, or a pharmaceutically acceptable salt or solvate thereof, includes the following steps: ; After reduction, T is coupled with compound B7 to obtain the ligand-drug conjugate shown in formula (B8); the reducing agent is preferably TCEP. in: T is a ligand; n is an integer 1; X, R 1a R 1b R 1c R 1d R 2a R 2b R 3c R 3f R 4 R 5a R 6 R 7 R 8 R 11 R 14 R 15 q 1 q 2 p 2 p 3 L 3 n 1 n 2 And m as in formula T-(LD) m As defined in any of its implementations.

[0212] This disclosure will be further described through the following embodiments, but these embodiments should not be considered as limiting the scope of this disclosure.

[0213] Experimental methods not specified in this disclosure were performed under conventional conditions or conditions recommended by the material or product manufacturer; reagents not specified in their source were all commercially available conventional reagents.

[0214] Example 1: .

[0215] To a solution of benzothiophene-5-amine (1-1, 10.0 g, 67.0 mmol) in AcOH (200 mL), Br2 (9.64 g, 60.3 mmol) was added dropwise at 25 °C, and the mixture was stirred at RT for 12 h. LCMS showed that the starting material (SM) was completely consumed and the target MS was detected; TLC (PE / EA = 5 / 1) showed a main spot. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent PE / EA = 50 / 1 to 5 / 1) to give 1-2 (8.50 g, 37.3 mmol, yield 55.6%) as a brown solid.

[0216] To a solution of trichloroborane (17.5 mL) in DCE (50.0 mL), 1–2 (5.00 g, 21.9 mmol) were added at 0 °C, and the mixture was stirred for 10 min. Subsequently, chloroacetonitrile (1.66 mL, 26.3 mmol) and AlCl3 (3.80 g, 28.495 mmol) were added at 0 °C, and the mixture was stirred for another 20 min. The mixture was degassed and purged three times with N2, followed by stirring at 80 °C for 12 h. LC-MS showed that the SM was completely consumed and the target MS was detected. The reaction mixture was cooled to RT, quenched with ice water (100 mL), and extracted with DCM (50 mL * 3). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 180 * 70 mm # 10 μm; mobile phase: [A: H2O (1M NH4HCO3); B: ACN]; B%: 45.00%-85.00%, 20.00 min) to give 1-3 (1.50 g, 4.93 mmol, 22.5%) as a white solid.

[0217] LC-MS: 303.8, 305.8 [M+H]⁺.

[0218] To a mixture of 1-3 (500 mg, 1.64 mmol) and MRB-WX-014 (432 mg, 1.64 mmol) in toluene (10.0 mL), TosOH (565 mg, 3.28 mmol) was added at 25 °C under N2. The reaction mixture was stirred at 110 °C for 12 h. LC-MS showed that the SM was completely consumed and the target MS was detected. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was slurried with EtOAc (20 mL) to give 1-4 (1.00 g, 1.88 mmol, crude) as a brown solid.

[0219] LC-MS: 452.1 [M+H]⁺.

[0220] To a mixture of 1–4 (1.00 g, 1.88 mmol) and (3S)-piperidin-3-ol (0.230 g, 2.26 mmol) in DMF (6.00 mL), DIEA (1.0 mL, 0.730 g, 5.64 mmol) was added at 25 °C, and the reaction mixture was stirred at RT for 10 min. LC-MS showed that the SM was completely consumed and the target MS was detected. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 15 μm); mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 15.00% - 45.00%, 22.00 min) to give 1–5 (35.0 mg, 0.059 mmol, 3.12%) as a yellow solid.

[0221] LC-MS: 596.2, 598.2 [M+H]⁺.

[0222] Pd / C (10%, 0.890 mg, 0.001 mmol) was added to a DMF (1.00 mL) solution of 1–5 (25.0 mg, 0.042 mmol) under N2. The suspension was degassed under vacuum, purged several times with H2, and then stirred at 25 °C for 5 min under H2 (15 psi). LC-MS showed half of the SM remaining, and the target MS was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 80 * 30 mm * 3 µm; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 5.00% - 35.00%, 8.00 min) to give 1 (4.81 mg, 0.009 mmol, 22.1%) as a yellow solid.

[0223] LC-MS: 518.3 [M+H] + .

[0224] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.29 - 9.11 (m, 1H), 8.82 (br s, 1H), 8.21- 8.02 (m, 1H), 7.84 - 7.66 (m, 1H), 7.48 - 7.35 (m, 1H), 6.69 - 6.49 (m,1H), 5.58 - 5.33 (m, 4H), 5.22 - 4.99 (m, 1H), 4.25 - 3.59 (m, 1H), 3.57 -3.42 (m, 2H), 3.26 - 2.83 (m, 3H), 2.02 - 1.75 (m, 4H), 1.73 - 1.49 (m, 2H),0.93 - 0.87 (m, 3H).

[0225] Example 2: .

[0226] At 0 °C, 1-1 (10.0 g, 67.0 mmol) was added to a solution of trichloroborane (53.6 mL) in 100 mL of DCE and stirred for 10 min. After adding chloroacetonitrile (5.090 mL, 80.424 mmol) and AlCl3 (11.6 g, 87.1 mmol), the mixture was stirred at 0 °C for 20 min. The reaction mixture was degassed and purged three times with N2, followed by stirring at 80 °C for 12 h. TLC (PE / EA = 3 / 1) and LCMS showed that SM was completely consumed and the target MS was detected. The reaction mixture was cooled to RT, quenched with ice water (100 mL), and extracted with DCM (50 mL * 3). The organic phases were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 10 / 1) in two batches to obtain 2-1 (3.00 g, 26.6 mmol, 9.92%) as a brown solid.

[0227] LC-MS: 226.0 [M+H]⁺.

[0228] At 25 °C, MRB-WX-014 (1.75 g, 6.65 mmol) and TosOH (0.060 g, 0.332 mmol) were added to a 20.0 mL solution of 2-1 (1.50 g, 6.65 mmol) in toluene. The mixture was degassed and purged with N2 three times, followed by stirring at 110 °C for 12 h. LC-MS showed that SM was completely consumed and the target MS was detected. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was milled with EtOAc (20 mL) at 25 °C for 0.5 h to give 2-2 (2.50 g, 5.52 mmol, 83.1%) as a brown solid.

[0229] LC-MS: 453.1 [M+H]⁺.

[0230] At 25 °C, DIEA (62 μL, 45.7 mg, 0.353 mmol) was added to a DMF (3.00 mL) solution of 2-2 (80.0 mg, 0.177 mmol) and (3S)-hexahydropyridine-3-ol (21.4 mg, 0.212 mmol), and the mixture was stirred at RT for 15 min. LC-MS showed that SM was completely consumed and the target MS was detected. The reaction mixture was purified by prep-HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 10.00% - 40.00%, 20.00 min) to give compound 2 (6.85 mg, 0.013 mmol, 7.49%) as a yellow solid.

[0231] LC-MS: 518.1 [M+H] + .

[0232] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.25 (br d, J = 8.9 Hz, 1H), 8.13 (br d, J = 5.4 Hz, 1H), 8.00 (br d, J = 8.9 Hz, 1H), 7.93 (br d, J= 5.1 Hz, 1H), 7.54(s, 1H), 5.54 - 5.46 (m, 1H), 5.37 (s, 2H), 5.29 (d, J = 16.3 Hz, 1H), 4.65(br s, 2H), 3.96 - 3.73 (m, 1H), 3.28 (br dd, J = 1.9, 6.3 Hz, 1H), 3.16 -3.07 (m, 1H), 1.96 - 1.71 (m, 3H), 1.69 - 1.42 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0233] The following compounds were synthesized according to the steps described in Example 1:

[0234] The following compounds were synthesized according to the steps described in Example 2:

[0235] Example A1:

[0236] A1-1 (0.50 g, 0.92 mmol) in a solution of diethylamine (5.00 mL) and DCM (10.00 mL) was stirred at 25 °C for 12 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was analyzed by prep-HPLC (column: WePure Biotech XP tC18 250). 70 10 μm; mobile phase: [H2O (10 mm NH4HCO3)-ACN]; B%: 10%-40%, 20 min), yielded Al-2 (0.24 g, 0.75 mmol, 81.19% yield), a colorless oil.

[0237] LC-MS: 322.0 [M+H]⁺.

[0238] At 20 °C, TEA (0.22 mL, 1.56 mmol) was added to a mixture of A1-2 (0.25 g, 0.78 mmol) and DCM (10 mL). At 0 °C, a solution of 2-(trimethylsilyl)ethyl[(2,5-dioxotetrahydro-1H-pyrrole-1-yl)oxy]carbamate (242.08 mg, 0.93 mmol) in DCM (10 mL) was added to the mixture, and the mixture was stirred at 20 °C for 2 h. The reaction was shown to be complete by LCMS. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give A1-3 (0.20 g, 0.43 mmol, yield 55.22%) as a yellow oil.

[0239] LC-MS: 488.2 [M+Na]⁺.

[0240] Under N2, Pd / C (10%, 45.71 mg, 0.04 mmol) was added to a mixture of A1-3 (0.20 g, 0.43 mmol) and TFE (10.00 mL). The suspension was degassed under vacuum, purged several times with H2, and then stirred at 25 °C for 2 h under an H2 (15 Psi) atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give A1-4 (0.14 g, crude product) as a yellow oil.

[0241] LC-MS: 332.1 [M+H]⁺.

[0242] To a mixture of A1-4 (0.14 g, 0.36 mmol) and DMF (5.00 mL), 2-2 (162.59 mg, 0.36 mmol) and DIEA (125 µL, 92.80 mg, 0.72 mmol) were added, and the mixture was stirred at 25 °C for 10 min. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 40%-85%, 8 min) to give A1-5 (37.00 mg, 0.05 mmol, 13.78% yield) as a yellow solid.

[0243] LC-MS: 770.4 [M+Na]⁺.

[0244] A1-5 (17.00 mg, 0.023 mmol) was reacted with a mixture of DCM (1.00 mL) and TFA (0.20 mL) at 0–10 °C for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 10%–40%, 8 min) to give A1-6 (6.00 mg, 0.01 mmol, 43.73% yield) as a yellow solid.

[0245] LC-MS: 604.2 [M+H]⁺.

[0246] To a solution of A1-7 (0.14 mg, 0.46 mmol) in t-BuOH (4.00 mL) and H2O (4.00 mL), A1-8 (253.84 mg, 0.46 mmol), CuSO4·5H2O (22.90 mg, 0.09 mmol), and sodium L-ascorbate (36.33 mg, 0.18 mmol) were added. The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The residue was analyzed by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 µm; mobile phase: [water(FA)-ACN]; B%: 25%-55%, 8 min). A1-9 (0.20 g, 0.23 mmol, 50.78% yield) was obtained as a yellow oil. LC-MS: 859.4 [M+H]⁺.

[0247] A1-9 (0.20 g, 0.23 mmol) was mixed with 5.00 mL of DCM and 1.00 mL of TFA and stirred at 25 °C for 2 h. TLC (petroleum ether: ethyl acetate = 1:1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A1-10 (0.18 mg, 0.22 mmol, 96.29% yield) as a yellow oil.

[0248] A1-11 (83.55 mg, 0.25 mmol), NMM (0.11 mL, 0.99 mmol), and DMTMMT (78.23 mg, 0.25 mmol) were added to a DMF (5.00 mL) solution of A1-10 (0.20 g, 0.25 mmol). The mixture was stirred at 25 °C for 12 h. LC-MS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 8 min) to give A1-12A (0.20 g, 0.18 mmol, 71.67% yield) as a yellow solid. LC-MS: 1120.4 [M+H]⁺.

[0249] TFA (1.00 mL, 13.06 mmol) was added to a DCM (5.00 mL) solution of A1-12A (50.00 mg, 0.05 mmol), and the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether: ethyl acetate = 1:1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A1-12 (45.00 mg, 0.04 mmol, crude product) as a yellow oil.

[0250] A1-6 (5.67 mg, 0.01 mmol), NMM (0.004 mL, 0.04 mmol), and DMTMMT (2.95 mg, 0.01 mmol) were added to a DMF (2.00 mL) solution of A1-12 (10.00 mg, 0.01 mmol). The mixture was stirred at 25 °C for 12 h. The reaction was completed by LCMS. The residue was purified by prep-HPLC (column: 3-Phenomenex Luna C18 75*30 mm*3 µm; mobile phase: [water (0.2% FA)-ACN]; B%: 5%-35%, 8 min) to give A1 (5.02 mg, 0.003 mmol, 32.38% yield) as a yellow solid.

[0251] LC-MS: 825.9 [1 / 2M+H] + 。

[0252] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 2H), 8.45 (d, J = 8.8 Hz, 2H),8.39 - 8.32 (m, 2H), 8.29 (br t, J = 5.8 Hz, 1H), 8.17 - 8.03 (m, 4H), 7.93 -7.86 (m, 2H), 7.35 (s, 1H), 7.27 - 7.12 (m, 5H), 6.55 (s, 1H), 5.43 (br d, J = 14.3 Hz, 4H), 4.58 (br t, J = 6.1 Hz, 2H), 4.49 (br t, J = 5.2 Hz, 3H),4.30 (d, J = 5.6 Hz, 2H), 4.24 (br d, J = 13.2 Hz, 1H), 4.12 (br d, J = 13.4Hz, 1H), 3.92 (s, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.75 (br d, J = 5.6 Hz, 2H),3.71 - 3.67 (m, 2H), 3.61 - 3.58 (m, 2H), 3.57 - 3.55 (m, 2H), 3.54 - 3.44(m, 32H), 3.41 (s, 3H), 3.15 - 3.07 (m, 1H), 3.03 (br dd, J = 4.4, 13.8 Hz,1H), 2.77 (br dd, J = 13.6, 9.7 Hz, 1H), 2.68 (br dd, J= 3.4, 1.6 Hz, 1H),2.58 - 2.54 (m, 2H), 2.32 - 2.28 (m, 2H), 2.23 (br s, 1H), 1.93 - 1.79 (m,5H), 1.64 - 1.57 (m, 1H), 1.32 - 1.18 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

[0253] Example A2:

[0254] A1-6 were prepared using the same method as in Example A1.

[0255] Under N2, 22139-3 (3.12 g, 24.38 mmol), TEA (6.78 mL, 48.76 mmol), CuI (0.46 g, 2.44 mmol), and Pd(PPh3)4 (1.4 g, 1.22 mmol) were added to a solution of A2-1 (5.00 g, 24.38 mmol) in DMF (50.00 mL). The mixture was stirred at 80 °C for 12 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that the reaction was complete. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (200 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give A2-2 (4.00 g, 15.86 mmol, 65.03% yield) as a yellow solid.

[0256] LiOH·H2O (1.50 g, 35.67 mmol) was added to a solution of A2-2 (3.00 g, 11.89 mmol) in H2O (10.00 mL) and THF (30.00 mL), and the mixture was stirred at 25 °C for 3 h. TLC (petroleum ether: ethyl acetate = 1:1) showed that the reaction was complete. The reaction mixture was extracted with EtOAc (20 mL), and the aqueous layers were combined. The pH of the aqueous phase was adjusted to 2-3 with 2 N HCl, and then extracted with EtOAc (40 mL * 3). The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give A2-3 (2.10 g, 8.81 mmol, crude product) as a yellow solid.

[0257] To a solution of A2-3 (1.50 g, 6.29 mmol) and propargyl-1-amine (0.35 g, 6.29 mmol) in DCM (20.00 mL), DIEA (3.1 mL, 2.44 g, 18.89 mmol) and HATU (3.59 g, 9.44 mmol) were added, and the mixture was stirred at 25 °C for 12 h. TLC (petroleum ether: ethyl acetate = 2:1) showed that the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (40 mL * 3). The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give A2-4 (1.20 g, 4.6 mmol, 69.23% yield) as a white solid.

[0258] To a solution of A2-4 (1.20 g, 4.36 mmol) in DCM (15.00 mL), m-CPBA (1.65 g, 9.59 mmol) was added, and the mixture was stirred at 25 °C for 12 h. TLC (petroleum ether: ethyl acetate = 3:1) showed the reaction was complete. The reaction mixture was quenched with 20 mL of aqueous Na2SO3 solution and extracted with DCM (40 mL * 3). The combined organic layers were washed with 100 mL of aqueous NaHCO3 solution, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give A2-5 (0.90 g, 2.93 mmol, 67.19% yield) as a white solid.

[0259] A1-8 (0.18 g, 0.33 mmol), CuSO4·5H2O (16.25 mg, 0.07 mmol), and sodium L-ascorbate (25.79 mg, 0.13 mmol) were added to a solution of A2-5 (0.10 g, 0.33 mmol) in t-BuOH (2.00 mL) and H2O (2.00 mL). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 µm; mobile phase: [water(FA)-ACN]; B%: 25%-55%, 8 min) to give A2-6 (0.14 g, 0.16 mmol, 49.97% yield) as a colorless oil. LC-MS: 861.3 [M+H]⁺.

[0260] A solution of A2-6 (0.14 g, 0.16 mmol) in DCM (6.00 mL) and TFA (2.00 mL) was stirred at 25 °C for 0.5 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A2-7 (0.13 g, 0.16 mmol, crude), a yellow oil. LC-MS: 805.3 [M+H]⁺.

[0261] A1-11 (54.17 mg, 0.16 mmol), NMM (0.07 mL, 0.65 mmol), and DMTMMT (50.72 mg, 0.16 mmol) were added to a DMF (5.00 mL) solution of A2-7 (0.13 g, 0.16 mmol). The mixture was stirred at 25 °C for 12 h. LC-MS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*5 µm; mobile phase: [water(FA)-ACN]; B%: 20%-55%, 8 min) to give A2-8 (0.13 mg, 0.12 mmol, 71.72% yield) as a yellow oil. LC-MS: 1122.4 [M+H]⁺.

[0262] TFA (0.40 mL) was added to a 2.00 mL solution of A2-8 (50.00 mg, 0.05 mmol) in DCM, and the mixture was stirred at 25 °C for 1 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A2-9 (47.00 mg, 0.04 mmol, 98.95% yield) as a yellow oil. LC-MS: 1066.5 [M+H]⁺.

[0263] A1-6 (13.59 mg, 0.02 mmol), NMM (0.01 mL, 0.09 mmol), and DMTMMT (7.36 mg, 0.02 mmol) were added to a DMF (2.00 mL) solution of A2-9 (25.00 mg, 0.02 mmol). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Luna 3_PhenomenexLuna Phenomenex Luna C18 75*30mm*3µm; mobile phase: [water(FA)-ACN]; B%: 15%-45%, 8 min) to give A2 (16.19 mg, 0.01 mmol, 42.42% yield).

[0264] Example A21: .

[0265] To a DCE (10.0 mL) solution of compound 22-1 (149 mg, 0.400 mmol), compound 22 (100 mg, 0.200 mmol) and PPTS (10.2 mg, 0.04 mmol) were added at 25 °C. The mixture was heated to 70 °C and stirred for 12 h. LC-MS showed that most of compound 22 and compound 22-1 had been consumed and the target MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to give A21-1 (100 mg, 0.120 mmol, 61.6% yield) as a yellow solid. LC-MS: 803.4 [M+H]⁺.

[0266] A21-1 (100 mg, 0.120 mmol) was mixed in DCM (2.00 mL) and diethylamine (1.00 mL) and stirred at 25 °C for 1 h. LC-MS showed that SM was completely consumed and MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters xbridge 150 * 25 mm 10 μm; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 23.00% - 45.00%, 8.00 min) to give A21-2 (15.0 mg, 0.03 mmol, 20.7% yield) as a yellow solid. LC-MS: 581.1 [M+H]⁺. At 25 °C, A1-12 (42.8 mg, 0.02 mmol), NMM (0.01 mL, 0.09 mmol), and DMTMMT (7.95 mg, 0.03 mmol) were added to a DMF (3.00 mL) solution of A21-2 (14.0 mg, 0.020 mmol). The mixture was stirred under N2 for 2 h. LC-MS showed that the SM was completely consumed and the target MS was detected. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 25.00% - 55.00%, 20.00 min) to give A21 (3.02 mg, 0.002 mmol, 7.65% yield) as a white solid.

[0267] LC-MS: 814.5 [M / 2+H]⁺。

[0268] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 2H), 8.65 (br t, J = 6.3 Hz, 1H),8.51 - 8.42 (m, 2H), 8.40 - 8.32 (m, 2H), 8.18 - 8.02 (m, 4H), 7.95 - 7.85(m, 2H), 7.36 (s, 1H), 7.26 - 7.18 (m, 4H), 7.18 - 7.12 (m, 1H), 6.55 (s,1H), 5.47 (br s, 4H), 4.73 - 4.64 (m, 4H), 4.53 - 4.46 (m, 3H), 4.30 (d, J =5.5 Hz, 2H), 3.92 (s, 2H), 3.80 - 3.73 (m, 8H), 3.62 - 3.58 (m, 3H), 3.56 -3.54 (m, 2H), 3.52 - 3.46 (m, 28H), 3.41 (s, 3H), 3.04 (br dd, J [[ID=IS]] = 13.7, 4.6Hz, 1H), 2.97 (br t, J = 6.2 Hz, 2H), 2.84 - 2.72 (m, 2H), 2.58 - 2.56 (m,2H), 2.30 (t, J = 7.4 Hz, 2H), 1. 93 - 1.78 (m, 4H), 0.93 - 0.87 (m, 3H)。

[0269] Example A34:

[0270] To a solution of A34-1 (0.40 g, 0.83 mmol) in DCM (10.00 mL), (Boc)₂O (189.95 mg, 0.87 mmol) and TEA (0.03 mL, 0.21 mmol) were added. The mixture was stirred at 25 °C for 2 h. TLC (DCM: MeOH = 15:1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give A34-2 (0.45 g, 0.77 mmol, 93.17% yield) as a yellow oil.

[0271] Under N2 atmosphere, Pd / C (10%, 80.36 mg, 0.08 mmol) was added to a THF (10.00 mL) solution of A34-2 (0.44 g, 0.76 mmol). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25 °C for 2 h under H2 (15 psi) atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give A34-3 (0.40 g, crude), a yellow oil. LC-MS: 557.4 [M+H]⁺.

[0272] Add 6-[2-(methyldioxo-λ)] to a mixture of A34-3 (0.10 g, 0.18 mmol) and DMF (5.00 mL). 6 [-sulfonyl]pyrimidin-5-yl]hex-5-alkynyl acid (48.19 mg, 0.180 mmol), NMM (0.06 mL, 0.53 mmol), and DMTMMT (56.41 mg, 0.18 mmol). The mixture was stirred at 25 °C for 12 h. LC-MS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-50.00%, 8.00 min) to give A34-4 (45.00 mg, 0.06 mmol, 31.04% yield) as a yellow oil. LC-MS: 829.6 [M+Na]⁺.

[0273] TFA (0.40 mL, 5.22 mmol) was added to a mixture of A34-4 (45.00 mg, 0.06 mmol) and DCM (2.00 mL), and the mixture was stirred at 25 °C for 2 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A34-5 (39.00 mg, crude product) as a yellow oil. LC-MS: 707.5 [M+H]⁺.

[0274] DIEA (0.52 mL, 385.00 mg, 2.98 mmol) was added to a DCM (3.00 mL) solution of A1-11 (0.50 g, 1.49 mmol). After adding ethyl 2-chloro-2-oxoethyl acetate (223.00 mg, 1.64 mmol) to the mixture at 0 °C, the mixture was stirred at 25 °C for 2 h. TLC (PE:EA = 1:1) and LCMS showed that the starting material had been consumed and a main peak with the target MS was detected. The reaction mixture was diluted with H2O (5.00 mL) and extracted with DCM (5.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 100:1 to 0:1) to give A34-6 (0.30 g, 0.62 mmol, 41.7% yield) as a red oil. LC-MS: 458.1 [M⁺+55]⁺.

[0275] At 0 °C, LiOH·H₂O (67.40 mg, 1.60 mmol) was added to a solution of A34-6 (0.35 g, 0.80 mmol) in MeOH (5.00 mL). The reaction mixture was stirred at 0 °C for 2 h. LC-MS showed that the starting material was completely consumed and a main peak with the target MS was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The aqueous phase was acidified to pH 6-7 with 2N HCl aqueous solution and extracted with EtOAc (40 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 5.00%–45.00%, 8.00 min) to give A34-7 (70.0 mg, 0.12 mmol, 14.5% yield) as a white solid. LC-MS: 352.2 [M-55]⁺.

[0276] Under N2, p-toluenesulfonic acid (0.08 g, 0.490 mmol) was added to a DMF (60 mL) solution of 214-1 (3 g, 9.792 mmol) and 214-2 (4.82 g, 19.584 mmol). The mixture was stirred at 60 °C for 12 h. LC-MS showed that 214-1 was completely consumed. The reaction mixture was cooled to RT, diluted with H2O (100 mL), and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 214-3 (4 g, 5.684 mmol, 58.05% yield) as a white solid. LC-MS: 493.5 [M+H]⁺.

[0277] At 25 °C, Pd / C (10%, 0.2 g, 0.203 mmol) was added to a 20 mL TFE solution of 214-3 (2 g, 4.060 mmol). The suspension was degassed and purged with H2 three times, then stirred at 25 °C for 1 h under H2 atmosphere. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Without purification, 214-4 (1.4 g, 3.906 mmol, crude product) was obtained as a white solid. LC-MS: 359.4 [M+H]⁺.

[0278] At 25 °C, 214-4 (593.56 mg, 1.656 mmol) and DIEA (577 μL, 428.07 mg, 3.312 mmol) were added to a 10 mL solution of 2-2 (500 mg, 1.104 mmol). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed that 214-4 was completely consumed. Without post-treatment, the mixture was purified by prep-HPLC (FA conditions) to give A34-8 (70 mg, 0.090 mmol, 8.18% yield) as a brown solid. LC-MS: 775.5 [M+Na]⁺.

[0279] TFA (0.5 mL) was added to a 2.5 mL solution of A34-8 (50 mg, 0.065 mmol) in DCM at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure at 0 °C. Without purification, A34-9 (40 mg, 0.059 mmol, crude product) was obtained as a yellow oil. LC-MS: 675.4 [M+H]⁺.

[0280] NMM (0.01 mL, 0.12 mmol) and DMTMMT (12.44 mg, 0.04 mmol) were added to a mixture of A34-5 (28.00 mg, 0.04 mmol) and A34-7 (16.14 mg, 0.04 mmol) in DMF (1.00 mL). The reaction mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex LunaC18 75*30 mm*3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-50.00%, 8.00 min) to give A34-10 (25.00 mg, 0.02 mmol, 57.56% yield) as a yellow solid. LC-MS: 1118.7[M+Na]⁺.

[0281] TFA (0.30 mL, 3.92 mmol) was added to a mixture of A34-10 (25.00 mg, 0.02 mmol) and DCM (1.00 mL), and the mixture was stirred at 25 °C for 1 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A34-11 (23.00 mg, 0.02 mmol, 96.96% yield) as a yellow oil. LC-MS: 1040.5 [M+H]⁺.

[0282] NMM (0.01 mL, 0.09 mmol) and DMTMMT (6.94 mg, 0.02 mmol) were added to a DMF (2.00 mL) solution of A34-11 (23.00 mg, 0.02 mmol) and A34-9 (14.92 mg, 0.02 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-50.00%, 2.00 min) to give A34 (4.37 mg, 0.003 mmol, 11.65% yield) as a yellow solid.

[0283] LC-MS: 1697.8 [M+H] + .

[0284] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 2H), 8.76 (s, 1H), 8.62 (br t, J = 5.9 Hz, 1H), 8.59 - 8.51 (m, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.32 (br d, J =5.4 Hz, 2H), 8.17 - 8.05 (m, 4H), 7.92 (br t, J = 5.1 Hz, 1H), 7.35 (s, 1H),7.26 - 7.18 (m, 5H), 7.16 - 7.11 (m, 1H), 6.54 (s, 1H), 5.49 - 5.39 (m, 4H),4.63 - 4.54 (m, 2H), 4.53 - 4.45 (m, 1H), 4.21 - 4.14 (m, 2H), 4.07 (s, 1H),3.80 - 3.69 (m, 5H), 3.49 (s, 3H), 3.47 (br s, 2H), 3.40 (s, 4H), 3.20 (brd, J = 5.6 Hz, 2H), 3.07 - 2.98 (m, 3H), 2.82 - 2.73 (m, 1H), 2.63 (br d, J =11.5 Hz, 4H), 2.56 (br s, 2H), 2.40 - 2.36 (m, 2H), 2.26 (br t, J = 7.3 Hz,3H), 1.87 (br dd, J = 15.5, 8.3 Hz, 3H), 1.83 - 1.74 (m, 3H), 1.66 - 1.53 (m,3H), 1.50 - 1.37 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0285] Example A36: .

[0286] Add A1-11 (105.80 mg, 0.32 mmol), NMM (0.05 mL, 0.42 mmol), and DMTMMT (33.02 mg, 0.11 mmol) to a DMF (5.00 mL) solution of A36-1 (0.10 g, 0.11 mmol). The mixture was stirred at 25 °C for 12 h. LC-MS showed the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 40.00%–55.00%, 8.00 min) to give A36-2 (60.00 mg, 0.05 mmol, 44.99% yield) as a yellow solid. LC-MS: 1268.8 [M+H]⁺.

[0287] At 25 °C, a mixture of A36-2 (60.00 mg, 0.05 mmol) in DCM (2.00 mL) and diethylamine (1.00 mL) was stirred for 3 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 10.00%-40.00%, 8.00 min) to give A36-3 (35.00 mg, 0.03 mmol, 70.72% yield) as a colorless oil. LC-MS: 1046.4 [M+H]⁺.

[0288] NMM (0.01 mL, 0.10 mmol) and DMTMMT (11.56 mg, 0.04 mmol) were added to a mixture of A36-3 (35.00 mg, 0.03 mmol) and 6-[2-(methyldioxo-λ6-sulfonyl)pyrimidin-5-yl]hex-5-ethynic acid (13.46 mg, 0.05 mmol) in DMF (3.00 mL). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3µm; mobile phase: [A: H2O (0.2%FA); B: ACN]; B%: 10.00%-50.00%, 8.00 min) to give A36-4 (15.00 mg, 0.01 mmol, 34.59% yield) as a yellow solid. LC-MS: 1318.8 [M+Na]⁺.

[0289] The mixture of A36-4 (15.00 mg, 0.01 mmol) in DCM (1.00 mL) and TFA (0.20 mL) was stirred at 20 °C for 0.5 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude A36-5 (14.00 mg) as a yellow oil. LC-MS: 1262.7 [M+Na]⁺.

[0290] A36-5 (5.44 mg, 0.008 mmol), NMM (0.004 mL, 0.04 mmol), and DMTMMT (2.53 mg, 0.01 mmol) were added to a DMF (2.00 mL) solution of A34-9 (10.00 mg, 0.01 mmol). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-45.00%, 20.00 min) to give A36 (2.06 mg, 0.001 mmol, 13.47% yield) as a yellow solid.

[0291] LC-MS: 1897.0 [M+H]⁺.

[0292] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (br d, J = 6.1 Hz, 2H), 8.63 - 8.51(m, 1H), 8.46 (br d, J = 8.5 Hz, 1H), 8.32 (br d, J = 4.9 Hz, 2H), 8.24 -8.12 (m, 2H), 8.11 - 7.99 (m, 3H), 7.35 (s, 1H), 7.22 (br s, 5H), 6.54 (s,1H), 5.44 (br s, 4H), 4.58 (br d, J = 5.5 Hz, 2H), 4.50 (dt, J= 4.7, 2.3 Hz,1H), 4.33 (br s, 5H), 4.19 (br s, 6H), 4.12 - 4.05 (m, 5H), 4.03 - 3.98 (m,3H), 3.96 - 3.87 (m, 4H), 3.82 - 3.67 (m, 6H), 3.40 (br s, 3H), 3.03 - 2.82(m, 22H), 2.80 - 2.70 (m, 13H), 2.66 - 2.60 (m, 5H), 1.94 - 1.75 (m, 5H),1.66 - 1.54 (m, 3H), 1.51 - 1.39 (m, 2H), 1.25 (br d, J = 11.9 Hz, 3H), 0.89(br t, J = 7.1 Hz, 3H).

[0293] Example A37: .

[0294] Under N2 protection, Pd / C (10%, 92.26 mg, 0.087 mmol) was added to a THF (10 mL) solution of A1-8 (480 mg, 0.867 mmol). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25 °C for 2 h under H2 (15 psi) atmosphere. LC-MS showed that A1-8 was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude A37-1A (450 mg, 0.853 mmol), a yellow oil, which was used directly in the next step without purification. LC-MS: 528.5 [M+H]⁺.

[0295] To a mixture of A37-1 (146.75 mg, 0.768 mmol) and A37-1A (450 mg, 0.853 mmol) in DMF (5 mL), DIEA (0.45 mL, 330.69 mg, 2.559 mmol) and HATU (421.57 mg, 1.109 mmol) were added. The reaction mixture was stirred at 25 °C for 2 h. LC-MS showed that A37-1 was completely consumed. The residue was purified by prep-HPLC (FA conditions) to give A37-2 (300 mg, 0.428 mmol, 50.19% yield) as a yellow oil. LC-MS: 701.5 [M+H]⁺.

[0296] At -78 °C, A37-22 (diethyl phosphorus chloride, 116.16 mg, 0.742 mmol) was added to a THF (10 mL) solution of A37-21 (ethynyl magnesium chloride, 0.5 N, 1.484 mL, 0.742 mmol). The mixture was stirred at -78 °C for 0.5 h, then heated to 25 °C and stirred for another 1.5 h. A37-2 (130 mg, 0.185 mmol) was added at 25 °C, and the mixture was stirred at 25 °C for 12 h. LCMS showed that A37-2 was completely consumed. The pH of the mixture was adjusted to 5–6 with FA in MeCN solution, and the residue was purified by prep-HPLC (FA conditions) to give A37-3 (35 mg, 0.044 mmol, 23.86% yield) as a yellow oil. LC-MS: 735.5 [M-55]⁺.

[0297] TFA (1 mL) was added to a 5 mL solution of A37-3 (35 mg, 0.044 mmol) in DCM, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give crude A37-4 (32 mg, 0.044 mmol), a yellow oil. LC-MS: 735.4 [M+H]⁺.

[0298] NMM (0.019 mL, 0.174 mmol) and DMTMMT (27.35 mg, 0.087 mmol) were added to a DMF (3 mL) mixture of A37-4 (32 mg, 0.044 mmol) and A1-11 (16.07 mg, 0.048 mmol), and the mixture was stirred at 25 °C for 2 h. LC-MS showed that A37-4 was completely consumed, and the residue was purified by prep-HPLC (FA conditions) to give A37-5 (25 mg, 0.024 mmol, 54.56% yield) as a yellow oil. LC-MS: 1052.4 [M+H]⁺.

[0299] TFA (0.5 mL) was added to a 2.5 mL solution of A37-5 (25 mg, 0.024 mmol) in DCM. The mixture was stirred at 20 °C for 2 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give crude A37-6 (20 mg, 0.020 mmol), a yellow oil. LC-MS: 996.3 [M+H]⁺.

[0300] NMM (0.009 mL, 0.080 mmol) and DMTMMT (12.61 mg, 0.040 mmol) were added to a mixture of A37-6 (20 mg, 0.020 mmol) and A34-9 (13.55 mg, 0.020 mmol) in DMF (3 mL). The mixture was stirred at 25 °C for 2 h. LCMS showed that the starting material was completely consumed. The residue was purified by prep-HPLC (FA conditions) to give A37 (5.02 mg, 0.003 mmol, 14.76% yield, 97.6% purity) as a yellow solid.

[0301] LC-MS: 1653.0 [M+H]⁺.

[0302] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.93 (br t, J = 6.8 Hz, 1H), 8.67 (br d, J = 4.4 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.73 (br d, J = 5.6 Hz, 2H), 7.61 -7.51 (m, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.20 (br s,1H), 5.95 - 5.85 (m, 1H), 5.32 - 5.21 (m, 1H), 5.18 - 5.04 (m, 3H), 4.45 (brd, J = 5.1 Hz, 2H), 4.34 - 4.14 (m, 3H), 4.11 - 3.90 (m, 2H), 3.82 (br s,1H), 3.56 (s, 1H), 3.21 - 3.12 (m, 2H), 3.06 - 2.89 (m, 2H), 2.69 (s, 3H),1.98 (s, 2H), 1.91 (s, 2H), 1.64 - 1.36 (m, 4H), 1.17 (t, J = 7.1 Hz, 1H).

[0303] Example A38: .

[0304] To a solution of A38-1 (30.00 mg, 0.07 mmol) in i-PrOH (2.00 mL), tert-butyl acrylate (17.94 mg, 0.14 mmol) was added, and the mixture was stirred at 60 °C for 12 h. LC-MS showed that the reaction was complete and the target MS was detected. The reaction mixture was concentrated under reduced pressure to give A38-2 (38.00 mg, crude product), a yellow oil, which was used directly for the next step without purification. LC-MS: 556.5 [M+H]⁺.

[0305] To A38-2 (30.00 mg, 0.05 mmol) and 6-[2-(methyldioxo-λ) 6 [-sulfonyl]pyrimidin-5-yl]hex-5-alkynyl acid (21.73 mg, 0.08 mmol) was dissolved in DMF (2.00 mL) with NMM (0.006 mL, 0.054 mmol) and DMTMMT (16.95 mg, 0.05 mmol). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete and the target MS was detected. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-50.00%, 8.00 min) to give A38-3 (18.00 mg, 0.02 mmol, 41.37% yield) as a colorless oil. LC-MS: 806.5 [M+H]⁺.

[0306] A mixture of A38-3 (18.00 mg, 0.02 mmol) in DCM (1.00 mL) and TFA (0.20 mL, 1.44 mmol) was stirred at 25 °C for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A38-4 (17.00 mg, crude), a yellow oil, which was used directly for the next step without purification. LC-MS: 750.5 [M+H]⁺.

[0307] NMM (0.01 mL, 0.09 mmol) and DMTMMT (7.12 mg, 0.02 mmol) were added to a mixture of A38-4 (17.00 mg, 0.02 mmol) and 2-methylpropyl-2-yl N-{2-[(2-aminoacetyl)amino]acetyl}-L-phenylalanine tert-butyl ester (11.41 mg, 0.03 mmol) in DMF (1.00 mL). The mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 μm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-50.00%, 8.00 min) to give A38-5 (16.00 mg, 0.02 mmol, 66.13% yield), as a yellow oil. LC-MS: 1067.7 [M+H]⁺.

[0308] TFA (0.08 mL, 0.02 mmol) was added to a DCM (1.00 mL) solution of A38-5 (17.00 mg, 0.02 mmol), and the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give A38-6 (16.00 mg, crude product) as a yellow oil.

[0309] NMM (0.007 mL, 0.06 mmol) and DMTMMT (4.97 mg, 0.02 mmol) were added to a DMF (2.00 mL) solution of A38-6 (16.00 mg, 0.02 mmol) and A34-9 (10.68 mg, 0.02 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00%-45.00%, 20.00 min) to give A38 (6.47 mg, 0.004 mmol, 24.51% yield) as a yellow solid.

[0310] LC-MS: 1689.8 [M+Na]⁺.

[0311] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 2H), 8.63 - 8.51 (m, 1H), 8.47(br d, J = 8.8 Hz, 1H), 8.32 (br d, J = 4.8 Hz, 2H), 8.26 - 8.18 (m, 1H),8.12 - 8.06 (m, 2H), 7.36 (br s, 1H), 7.22 (br d, J = 2.1 Hz, 5H), 7.09 (s,1H), 6.96 (s, 1H), 6.56 (br s, 1H), 5.46 (br s, 4H), 4.65 - 4.56 (m, 2H),4.54 - 4.45 (m, 1H), 4.36 - 4.26 (m, 1H), 4.23 - 4.11 (m, 2H), 4.08 (s, 1H),3.82 - 3.64 (m, 8H), 3.61 - 3.54 (m, 4H), 3.52 - 3.47 (m, 32H), 3.40 (d, J =2.3 Hz, 8H), 3.10 - 2.98 (m, 3H), 2.88 - 2.75 (m, 2H), 2.69 - 2.60 (m, 5H),2.39 - 2.30 (m, 3H), 1.94 - 1.86 (m, 2H), 1.84 - 1.75 (m, 3H), 1.72 - 1.54(m, 3H), 1.49 - 1.41 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H).

[0312] Example A40: .

[0313] At 25 °C, A1-11 (1.23 g, 2.57 mmol), DIEA (1.23 mL, 0.910 g, 7.00 mmol), and HATU (1.15 g, 3.03 mmol) were added to a DMF (10.0 mL) solution of A40-1 (1.00 g, 2.33 mmol). The mixture was stirred at 25 °C for 12 h. LC-MS showed that A40-1 had been consumed and the target MS was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (30.0 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was ground with EtOAc (25.0 mL) at 25 °C for 0.5 hours and then filtered. The solid was purified by silica gel column chromatography (SiO2, DCM / MeOH = 20 / 1 to 1 / 1) to give A40-2 (1.17 g, 1.57 mmol, 67.2% yield) as a pale yellow solid. LC-MS: 690.4 [M-55]⁺.

[0314] A solution of A40-2 (0.95 g, 1.27 mmol) in DCM (10.0 mL) and diethylamine (5.00 mL) was stirred at 25 °C for 3 h. LC-MS showed that A40-2 had been consumed and the target MS was detected. The reaction mixture was concentrated under reduced pressure at 25 °C, then diluted with DMF (1 mL), and purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10 μm; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 30.00% - 70.00%, 10.00 min) to give A40-3 (440 mg, 0.840 mmol, 66.0% yield) as a pale yellow solid. LC-MS: 524.3 [M+H]⁺.

[0315] At 25 °C, NMM (0.462 mL, 4.20 mmol), A40-10 (372 mg, 0.840 mmol), and DMTMMT (264 mg, 0.840 mmol) were added to a DMF (5.00 mL) solution of A40-3 (440 mg, 0.840 mmol). The mixture was stirred at 25 °C for 2 h. LC-MS showed that A40-3 had been consumed and the target MS was detected. The mixture was poured into H2O (8.00 mL) and extracted with DCM (5.00 mL * 5). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude A40-4 (950 mg, 1.002 mmol), a yellow oil, which was used directly for the next step without further purification. LC-MS: 948.4 [M+H]⁺.

[0316] At -65 °C, A37-22 (165 mg, 1.06 mmol) was added to a 2.00 mL solution of A37-21 (2.32 mL, 1.16 mmol, 0.5 M) in THF. The mixture was stirred at -65 °C for 0.5 h. The mixture was then heated to 25 °C and stirred for 1.5 h, followed by the addition of a 1.00 mL solution of A40-4 (200 mg, 0.211 mmol) in THF. The reaction mixture was stirred at 25 °C for 12 h. LCMS showed that A40-4 had been consumed and the target MS was detected. The pH of the mixture was adjusted to 5 with FA, and then purified by prep-HPLC (column: 3-Phenomenex Luna C18 75 * 30 mm * 3 µm; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 25.00% - 45.00%, 8.00 min) to give A40-5 (70.0 mg, 0.067 mmol, 32.0% yield) as a brown oil. LC-MS: 519.9 [M / 2+H]⁺.

[0317] The solution of A40-5 (60.0 mg, 0.058 mmol) in DCM (3.00 mL) and TFA (1.00 mL) was stirred at 25 °C for 1.5 h. LC-MS showed that A40-5 had been consumed and the target MS was detected. The reaction mixture was concentrated under reduced pressure to give crude A40-6 (57.0 mg, 0.058 mmol), a yellow oil, which was used directly in the next step without further purification. LC-MS: 982.4 [M+H]⁺.

[0318] At 25 °C, NMM (0.010 mL, 0.092 mmol), A34-9 (24.7 mg, 0.018 mmol), and DMTMMT (5.76 mg, 0.018 mmol) were added to a 2.00 mL solution of A40-6 (18.0 mg, 0.018 mmol) in DCM. The mixture was stirred at 25 °C for 2 h. LCMS showed that A40-6 had been consumed and the target MS was detected. The reaction mixture was diluted with DMF (1 mL) and purified by prep-HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00% - 60.00%, 20.00 min) to give A40 (2.50 mg, 0.002 mmol, 8.32% yield) as a yellow solid.

[0319] LC-MS: 820.2 [M / 2+H]⁺.

[0320] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.62 - 8.43 (m, 2H), 8.40 - 8.27 (m, 4H), 8.21 - 7.99 (m, 4H), 7.67 - 7.59 (m, 1H), 7.38 - 7.30 (m, 1H), 7.27 - 7.13(m, 5H), 7.10 - 7.01 (m, 2H), 6.98 - 6.87 (m, 2H), 6.55 (s, 1H), 5.49 - 5.38(m, 3H), 4.72 - 4.46 (m, 4H), 4.39 - 4.27 (m, 1H), 4.25 - 4.14 (m, 2H), 4.13- 3.99 (m, 3H), 3.89 - 3.62 (m, 9H), 3.53 - 3.47 (m, 29H), 3.24 - 3.23 (m,3H), 3.12 - 2.94 (m, 5H), 2.86 - 2.73 (m, 3H), 2.64 (br d, J = 11.4 Hz, 4H), 2.38 (br dd, J= 6.6, 4.0 Hz, 2H), 1.96 - 1.82 (m, 2H), 1.70 - 1.52 (m, 3H), 1.50 - 1.33 (m, 2H), 1.31 - 1.23 (m, 4H), 0.95 - 0.85 (m, 3H).

[0321] Example A41: .

[0322] 22-1 (75.33 mg, 0.16 mmol) and PPTS (8.19 mg, 0.03 mmol) were added to a solution of 19 (60.00 mg, 0.16 mmol) in DCE (5.00 mL). The mixture was stirred at 80 °C for 16 h. LC-MS showed detection of the target MS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H2O (30 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 19-1 (110.00 mg, 0.04 mmol, crude), a brown solid, which was used directly for the next step. LC-MS: 771.5 [M+H]⁺.

[0323] Diethylamine (0.05 mL, 0.47 mmol) was added to a 2.00 mL solution of 19-1 (110.00 mg, 0.04 mmol, crude) in DMF. The mixture was stirred at 25 °C for 12 h. The target MS was detected by LC-MS. Without post-treatment, the mixture was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 µm; mobile phase: [A: H2O (10 mMNH4HCO3); B: ACN]; B%: 20.00%–50.00%, 8.00 min) to give 19-2 (12 mg, 0.02 mmol, 46.45% yield) as a white solid. LC-MS: 549.4 [M+H]⁺.

[0324] Pd / C (10%, 26.9 mg, 0.025 mmol) was added to a 2.00 mL TFE solution of A40-4 (240 mg, 0.253 mmol) at 25 °C. The mixture was degassed and purged three times with H2, followed by stirring at 25 °C for 2 h. LC-MS showed that A40-4 had been consumed and the target MS was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude A41-1 (230 mg, 0.249 mmol) as a yellow oil, which was used directly in the next step without further purification. LC-MS: 922.4 [M+H]⁺.

[0325] At 25 °C, furan-2,5-dione (23.4 mg, 0.239 mmol) was added to a solution of A41-1 (100 mg, 0.108 mmol) in acetone (5.00 mL). The mixture was stirred at 60 °C for 15 min, followed by the addition of NaOAc (62.3 mg, 0.759 mmol) and acetic anhydride (0.500 mL) at 60 °C. The reaction mixture was stirred at 60 °C for 12 h. LC-MS showed that A41-1 had been consumed and the target MS was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 25.00% - 60.00%, 8.00 min) to give A41-2 (38.0 mg, 0.038 mmol, 35.0% yield) as a brown oil. LC-MS: 1002.4 [M+H]⁺.

[0326] The solution of A41-2 (43.0 mg, 0.043 mmol) in DCM (0.300 mL) and TFA (0.100 mL) was stirred at 25 °C for 2 h. LC-MS showed that A41-2 had been consumed and the target MS was detected. The reaction mixture was concentrated under reduced pressure to give crude A41-3 (41.0 mg, 0.043 mmol), a yellow oil, which was used directly in the next step without further purification. LC-MS: 946.5 [M+H]⁺.

[0327] At 25 °C, NMM (0.038 mL, 0.347 mmol), 19-2 (23.8 mg, 0.043 mmol), and DMTMMT (13.6 mg, 0.043 mmol) were added to a 1.00 mL DMF solution of A41-3 (41.0 mg, 0.043 mmol). The mixture was stirred at 25 °C for 12 h. LCMS showed that A41-3 had been consumed and the target MS was detected. The reaction mixture was diluted with DMF (1 mL) and purified by prep-HPLC (column: Phenomenex Gemini-NX 80 * 30 mm * 3 µm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 20.00% - 50.00%, 20.00 min) to give A41 (6.55 mg, 0.004 mmol, 10.2% yield) as a white solid.

[0328] LC-MS: 739.3 [M / 2+H]⁺.

[0329] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.61 (br t, J = 6.4 Hz, 1H), 8.49 - 8.33(m, 4H), 8.22 - 8.04 (m, 4H), 7.76 (br d, J = 8.3 Hz, 1H), 7.38 - 7.28 (m,3H), 7.28 - 7.12 (m, 8H), 6.54 (s, 1H), 5.44 (br d, J = 11.4 Hz, 4H), 4.73 -4.63 (m, 3H), 4.57 - 4.49 (m, 1H), 3.82 - 3.73 (m, 7H), 3.67 (br s, 2H), 3.49(br d, J = 4.8 Hz, 34H), 3.24 - 3.20 (m, 3H), 3.18 - 3.02 (m, 3H), 2.96 -2.77 (m, 3H), 2.02 (br s, 2H), 1.95 - 1.80 (m, 2H), 0.90 (br t, J = 7.3 Hz, 3H).

[0330] Example A43:

[0331] At 0 °C, Ag₂CO₃ (5.55 g, 20.1 mmol) was added fractionally to a DCM (20 mL) solution of A43-1 (2 g, 5.0 mmol) and benzyl glycolate (1.26 g, 7.6 mmol). The reaction mixture was stirred at RT for 4 h. Target MS was detected by LC-MS. The mixture was filtered and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:3) to give A43-2 (0.84 g, 1.741 mmol, yield: 34.58%) as a white solid. LC-MS: m / z = 505.32 [M+Na]⁺.

[0332] At room temperature, Pd / C (10%, 84 mg, 0.788 mmol) was added to a 20 mL THF solution of A43-2 (760 mg, 1.575 mmol). The suspension was degassed and purged three times with H2, followed by stirring at room temperature for 1 hour under H2 atmosphere. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give A43-3 (710 mg, crude product) as a colorless solid, which was used directly in the next step without purification. LC-MS: m / z = 415.18 [M+Na]⁺.

[0333] K₂CO₃ (496 mg, 3.6 mmol) was added to a DMF (9 mL) solution of A43-4 (900 mg, 1.8 mmol) and allyl bromide (369 mg, 3.1 mmol). The reaction mixture was stirred at room temperature (RT) for 4 h. LC-MS showed that the starting material was completely consumed and the target MS was detected. The mixture was extracted with EA (10 mL * 3). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give A43-5 (1.7 g, 1.726 mmol, yield: 96.20%) as a yellow oil, which was used directly for the next step without purification. LC-MS: m / z = 542.03 [M+H]⁺.

[0334] DEA (0.5 mL) was added to a DMF (5 mL) solution of A43-5 (1.4 g, 2.6 mmol), and the reaction mixture was stirred at room temperature for 1 h. LC-MS showed that most of the starting material had been consumed and the target MS was detected. The mixture was purified by rapid chromatography (using a water-CH3CN system containing 0.1% TFA, eluting from 0% to 100% gradient) to give A43-6 (600 mg, 1.879 mmol, yield: 72.68%) as a yellow solid. LC-MS: m / z = 320.10 [M+H]⁺.

[0335] DIEA (417 μL, 304 mg, 2.348 mmol) was added to a DMF (1 mL) solution of A43-6 (250 mg, 0.78 mmol), A43-3 (307 mg, 0.78 mmol), and HATU (447 mg, 1.17 mmol). The mixture was stirred at room temperature for 1 h. LC-MS showed that the starting material was consumed and the target MS was detected. The mixture was purified by rapid chromatography (using a water-CH3CN system containing 0.1% TFA, eluting from 0% to 100% gradient) to give A43-7 (330 mg, 0.476 mmol, yield: 60.77%) as a yellow solid. LC-MS: m / z = 694.11 [M+H]⁺.

[0336] A solution of phenylsilane (47 mg, 0.432 mmol) in DCM (1 mL) was added to a MeOH (1 mL) solution of A43-7 (50 mg, 0.072 mmol) and Pd(PPh3)4 (17 mg, 0.014 mmol). The mixture was stirred at RT for 1 h. LC-MS showed that A43-7 was completely consumed and the target MS was detected. The mixture was purified by rapid chromatography (eluting from 0% to 100% using water / CH3CN containing 0.1% TFA as eluent) to give A43-8 (30 mg, 0.046 mmol, yield: 63.68%) as a yellow solid. LC-MS: m / z = 653.75 [M+H]⁺.

[0337] To a DMF (1 mL) solution of A43-8 (20 mg, 0.031 mmol), 19-2 (17 mg, 0.031 mmol), and HATU (18 mg, 0.046 mmol), DIEA (16 μL, 12 mg, 0.092 mmol) was added. The mixture was stirred at RT for 1 hour. LC-MS showed that the starting material was consumed and the target MS was detected. H2O (10 mL) was added to the mixture, and it was extracted with EA (5 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. A43-9 (90 mg, crude) was obtained as a yellow oil, which was used directly in the next reaction without purification. LC-MS: m / z = 1183.83 [M+H]⁺.

[0338] To a solution of A43-9 (80 mg, 0.068 mmol) in MeOH (0.5 mL), a solution of LiOH (28 mg, 0.676 mmol) in H₂O (0.5 mL) was added. The mixture was stirred at RT for 1 hour. LC-MS showed that A43-9 had been consumed and the target MS was detected. The mixture was purified by rapid chromatography (eluting from 0% to 100% using water / CH₃CN containing 0.1% TFA as eluent). A43-10 (15 mg, 0.014 mmol, yield: 21.27%) was given as a yellow solid. LC-MS: m / z = 1043.73 [M+H]⁺.

[0339] To a DMF (0.5 mL) solution of A43-10 (10 mg, 0.01 mmol), SM (1.7 mg, 0.01 mmol), and HATU (5.5 mg, 0.014 mmol), DIEA (5 μL, 3.7 mg, 0.029 mmol) was added. The mixture was stirred at RT for 1 hour. LCMS showed that the starting material was consumed and the target MS was detectable. The mixture was purified by rapid chromatography (eluting from 0% to 100% using water / CH3CN containing 0.1% TFA as eluent). A43 (3.1 mg, 0.003 mmol, purity 78.46%, yield: 27.75%) was obtained as a yellow solid.

[0340] LC-MS: m / z = 1166.21 [M+H]⁺.

[0341] 1 H NMR (400 MHz, MeOD) δ 8.41 (d, J= 5.7 Hz, 1H), 8.31 (d, J = 9.0Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 5.5 Hz, 1H), 7.69 (s, 1H), 7.30 – 7.14 (m, 5H), 6.75 (s, 2H), 5.63 (d, J = 16.2 Hz, 1H), 5.48 – 5.34 (m,4H), 4.54 (dd, J = 8.9, 6.0 Hz, 1H), 4.42 (d, J = 7.7 Hz, 1H), 4.36 (d, J =15.8 Hz, 1H), 4.23 (d, J = 15.9 Hz, 1H), 4.05 – 3.91 (m, 4H), 3.86 (d, J =16.7 Hz, 1H), 3.79 (d, J = 4.4 Hz, 1H), 3.75 – 3.71 (m, 2H), 3.65 – 3.57 (m,4H), 3.50 (p, J = 1.6 Hz, 1H), 3.44 – 3.39 (m, 2H), 3.15 (td, J = 3.7, 2.0Hz, 2H), 2.99 (dd, J = 13.9, 8.9 Hz, 1H), 2.20 (d, J = 7.7 Hz, 1H), 2.16 -2.11 (m, 2H), 2.08 – 1.93 (m, 3H), 1.05 (t, J = 7.4 Hz, 3H), 0.94 - 0.91 (m,1H).

[0342] The following compounds were synthesized according to the steps described in Example A1:

[0343] The following compounds were synthesized according to the steps described in Example A2: .

[0344] The following compounds were synthesized according to the steps described in Example A21:

[0345] The following compounds were synthesized according to the steps described in Example A34: .

[0346] The following compounds were synthesized according to the steps described in Example A38: .

[0347] Example B1: Preparation of antibody-drug conjugates (e.g., ADC-1).

[0348] Antibodies used in exemplary ADCs: The antibodies used in the ADC compounds of this embodiment were prepared using conventional methods, such as vector construction, eukaryotic cell transfection (e.g., HEK2943 cells (Life Technologies Cat. No. 11625019) transfection), purification, and expression. The prepared antibodies included trastuzumab light chain (SEQ. ID NO. 1), trastuzumab heavy chain (SEQ. ID NO. 2), pertuzumab light chain (SEQ. ID NO. 3), pertuzumab heavy chain (SEQ. ID NO. 4), B7H3 antibody light chain (SEQ. ID NO. 5), and B7H3 antibody heavy chain (SEQ. ID NO. 6).

[0349] General steps for coupling: At 37°C, a prepared tris(2-carboxyethyl)phosphine aqueous solution (10 mM, 0.082 mL, 0.82 µmol) was added to an antibody-buffered PBS solution (0.05 M PBS buffer, pH 6.5; 2.5 mL, 9.96 mg / mL, 0.168 µmol). The reaction solution was placed in a water bath and shaken at 37°C for 3 hours to terminate the reaction. The reaction solution was cooled to 25°C in a water bath and diluted to 5.0 mg / mL. 2.0 mL of this solution was used for the next reaction step.

[0350] The linker-camptothecin compound (2.1 mg, 2.02 µmol) was dissolved in 0.10 mL of DMSO, and then added to the above 2.0 mL solution. The reaction solution was placed in a water bath and shaken at 25 °C for 3 hours to terminate the reaction. The reaction solution was purified by desalting using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffer solution containing 0.001 M EDTA, pH=6.5) to obtain a PBS buffer solution of the exemplary product ADC, which was stored at 4 °C.

[0351] .

[0352] Drug loading analysis (UV method) of ADC was performed according to the method described in U.S. Patent Application Publication No. 2021 / 0353764 (i.e., paragraphs

[0702] to

[0718] ).

[0353] Drug loading analysis of ADCs (LC-MS method) was performed according to the method described in US Patent No. 11,572,414 (i.e., column 2, line 51 to column 3, line 15).

[0354] The aggregation level of ADCs was determined by size exclusion chromatography (SEC). All samples were filtered through a 0.22 μm filter membrane before HPLC-SEC analysis.

[0355] The HPLC method is operated as follows: Instrument: Thermo Ultimate 3000; Column: Waters XBridge BEH 200Å SEC 3.5 μm (7.8*300 mm); Mobile phase: PBS solution containing 15% isopropanol, pH 7.4; Flow rate: 0.5 mL / min, 30 min.

[0356] The following ADCs are synthesized according to the general steps described in Example B1: NA indicates that no measurement was performed.

[0357] Experiment 1: In vitro cytotoxicity test of camptothecin loading: The cytotoxicity of the small molecule fragment of this invention was evaluated using the human lung adenocarcinoma cell line A549. A549 cells were seeded at 2000 cells per well in 96-well plates; NCI-N87 cells at 3000 cells per well; SK-BR-3 cells at 3000 cells per well; and HARA cells at 3000 cells per well. After overnight incubation at 5% CO2 and 37°C, the respective dilutions were added. Three days later, cell viability was assessed using the Promega CellTiter-Glo chemiluminescence immunoassay kit according to the manufacturer's instructions. The results are shown in Table 1 below.

[0358] Table 1. Cytotoxicity of compound (D1) to A549 cells: NA indicates that no measurement was performed.

[0359] As shown in Table 1, in four types of tumor cell lines, the efficacy of compound (D1) was higher than that of the control compounds Dxd and ref-1. Therefore, the modification of the camptothecin nucleus in this invention can enhance anticancer efficacy.

[0360] Experiment 2: In vitro cytotoxicity assay of ADC: The cytotoxicity of the ADC of this invention was tested using cancer cell lines with different Her2 expression levels (including JIMT-1, NCI-N87, SK-BR-3, CAPAN-1, and CFPAC-1 cells). These cell lines were seeded at 1000-4000 cells per well in 96-well plates. After overnight incubation at 37°C with 5% CO2, various dilutions were added. Six days later, cell viability was assessed using the Promega Corp. CellTiter-Glo luminescent cell viability assay kit according to the manufacturer's instructions. The results are shown in Table 2 below.

[0361] Table 2. In vitro cytotoxicity assays of ADCs: ; NA indicates that no measurement was performed.

[0362] NCI-N87 and SK-BR-3 are both Her2-high expressing cancer cell lines, while CAPAN-1 and CFPAC-1 are previously reported Her2-low expressing cell lines. JIMT-1 has moderate Her2 expression but exhibits primary resistance to the anti-HER2 antibody trastuzumab. The ADC examples in this study all used the same anti-HER2 antibody trastuzumab, conjugated with the modified linker and novel payload of this invention. Compared to ADC-ref, all novel ADCs showed slightly better cytotoxicity in Her2-high expressing cancer cell lines, and surprisingly, significantly higher efficacy in Her2-low expressing cell lines and trastuzumab-resistant cell lines. This indicates that the selection of linker and payload in this invention plays a crucial role in enhancing ADC efficacy.

[0363] Experiment 3: In vitro liver microsomal stability test of the toxin:

[0364] Add 1.5 μL of the test compound spiking solution (0.5 μM, dissolved in DMSO), 1.9 μL of promethazine (10 mg / mL), and 18.75 μL of human liver microsomes (20 mg / mL) to preheated PBS solution (477.85 μL, pH 7.4). Incubate the spiking solution containing microsomes on ice for 15 minutes. Prepare a mixed working solution of 6 mM NADPH and 3 mM UDPGA by mixing 2 mL of 12 mM NADPH working solution (dissolved in PBS) with 2 mL of 6 mM UDPGA working solution (dissolved in PBS). Add 30 μL of 1.5 μM spiking solution containing 0.75 mg / mL microsomes to each test plate at different time points (0, 5, 15, 30, 45 minutes). Pre-incubate the remaining plates at 37°C for 5 minutes. At time point 0: Before adding 15 μL of UDPGA & NADPH stock solution, add 150 μL of ACN:MeOH (1:1) solution containing internal standard (IS) to the wells; at other time points: add 15 μL of UDPGA & NADPH stock solution to start the reaction and start timing. At 5, 15, 30, and 45 minutes, add 150 μL of ACN:MeOH (1:1) solution containing IS to the corresponding wells to terminate the reaction. After quenching the reaction, shake the plate for 10 minutes (600 rpm), then centrifuge at 6000 rpm for 15 minutes. Take 80 μL of supernatant from each well and transfer it to a 96-well sample plate containing 140 μL of pure water for LCMS analysis. The results are shown in Table 3 below.

[0365] The LCMS method parameters are as follows: Instrument: Waters ACQUITY UPLC I-Class PLUS & AB SCIEX Triple Quad 6500+; Column: Shim-pack GIST-HP C18-AQ (3 μm, 2.1*50 mm); Mobile phases: Phase A: H₂O containing 0.1% FA; Phase B: ACN containing 0.1% FA; Flow rate: 0.6 mL / min.

[0366] Table 3. In vitro liver microsomal stability test of the toxin: NA indicates that no measurement was performed.

[0367] As shown in Table 3, the compound of formula (D1) has a short half-life in liver microsomes, suggesting that its in vivo metabolism may be faster. Enhanced metabolism of free toxins is a favorable property for ADCs because it is expected to reduce systemic exposure to toxins after release from the ADC, thereby mitigating toxin-induced toxicity. On the other hand, the anticancer efficacy of ADCs is primarily driven by their delivery of toxins to the tumor site. This unique property of the compounds of this invention offers great potential for reducing non-target-related side effects caused by toxins released extratumorally while maintaining or enhancing the anticancer efficacy of ADCs.

[0368] Experiment 4: Rat Pharmacokinetic (PK) Study:

[0369] Male SD rats, weighing 180–200 g (Shanghai Bikaico Biotechnology Co., Ltd.), were used, with 3 rats per group. After intravenous administration of 0.5 mg / kg, blood samples were collected via the orbital vein at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours and transferred to heparinized tubes. Plasma was obtained by centrifugation at 10,000 rpm for 3 minutes. Samples of all compounds of formula (D1) were stored at -20°C until sent to Suzhou Chengyao Biotechnology Co., Ltd. for analysis. The results are shown in Table 4A below.

[0370] The LCMS method parameters are as follows: Instruments: Shimadzu LC-20ADXR or SIL-30ACMP or CTO-20AC & AB SCIEX Qtrap 5500; Column: ACQUITY UPLC® BEH C18 1.7 μm (2.1*50 mm); Mobile phase: Phase A: 10 mM ammonium acetate aqueous solution, Phase B: ACN; Flow rate: 0.5 mL / min.

[0371] Table 4A. Rat pharmacokinetic (PK) results: .

[0372] Male SD rats, 180–200 g (Shanghai Bikaico Biotechnology Co., Ltd.), 3 rats / group. Following intravenous injection (IV) of 10 mg / kg, blood samples were collected via the orbital vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h into heparin-containing tubes and centrifuged at 10,000 rpm for 3 min to obtain plasma. All (D1) compound samples were stored at -20℃ until sent to Suzhou Chengyao Biotechnology Co., Ltd. for analysis. The results are shown in Table 4B below.

[0373] The LCMS method has the following characteristics: Instruments: Shimadzu LC-20ADXR or SIL-30ACMP or CTO-20AC & AB SCIEX Qtrap5500; Column: ACQUITY UPLC® BEH C18 1.7 µm (2.1*50 mm); Mobile phase: A: 10mM ammonium acetate aqueous solution, B: CAN; Flow rate: 0.5 mL / min.

[0374] Table 4B. Rat PK Results:

[0375] As shown in Tables 4A and 4B, PK studies confirmed that compound (D1) exhibits higher clearance and lower exposure in plasma. This is significantly different from the known reference compound Dxd, which has a clearance rate 3-4 times lower. It is believed that faster clearance of free toxins can reduce systemic toxicity caused by toxins. This unique property holds great potential for conversion into safer ADCs, whose clinical application is also primarily limited by toxin-induced toxicity.

[0376] Experiment 5: Rat PK Study:

[0377] The NCI-N87 cell line (BeNa Culture Collection Center) was used to construct a CDX (cell line-derived xenograft) NCI-N87 xenograft mouse model. Each 4-6 week old female nude mouse (Balb / c nude mouse, Shanghai Southern Model Biotechnology Co., Ltd.) was subcutaneously injected with 200 μL of Matrigel (CORNING 3110003)-NCI-N87 cell suspension (Matrigel:PBS=1:1), containing 9.8 * 10-1 cells, into the right flank. 6 Each cell. Palpate the injection site up to three times a week until the tumor grows to an average size of 150 mm. 3 (Measured with a digital caliper). Animals were randomly divided into groups of three mice each. The antibody-drug conjugates ADC-5 and ADC-ref were administered via tail vein, respectively, at a dose of 10 mg / kg. Blood samples were collected via the orbital vein at 4 h and 24 h post-IV administration into heparinized tubes and centrifuged at 10,000 rpm for 3 minutes to obtain plasma. Lung and tumor tissue samples were collected simultaneously at 4 h and 24 h. Samples with effective payload concentrations were sent to Suzhou Chengyao Biotechnology Co., Ltd. for analysis.

[0378] The LCMS method has the following characteristics: Instruments: ACQUITY UPLC & Xevo TQ-XS; Column: ACQUITY UPLC® BEH C18 1.7 µm (2.1*50 mm); Mobile phase: A: 10mM ammonium acetate aqueous solution, B: ACN; Flow rate: 0.35 mL / min.

[0379] like Figure 9 and 10 As shown, the effective payload concentration of ADC-5 in plasma and lung tissue is significantly lower than that of ADC-ref; the effective payload concentrations of both ADCs in tumor tissue are much higher than in plasma, and the effective payload concentration of ADC-5 in tumor is comparable to that of ADC-ref, which ensures anticancer efficacy. Surprisingly, the tumor / plasma and tumor / lung selectivity of ADC-5 is approximately 3-4 times that of ADC-ref, further supporting the unique design of this invention: modification of the payload PK properties does not affect the ADC's delivery of the toxin to the tumor, but rather reduces the exposure of the free payload in plasma and lung. This is crucial because hematologic toxicity and interstitial lung disease are the two most common dose-limiting toxicities of ADCs in clinical practice, primarily caused by the payload as a toxin in a dose-dependent manner. The ADC of this invention can significantly reduce the exposure of the payload or toxin, providing a new solution for developing novel ADCs with both superior efficacy and safety.

[0380] Trial 6: In vivo efficacy study of ADCs

[0381] Capan-1 cells (Shanghai Enzyme Research Biotechnology Co., Ltd.) are a human pancreatic cancer cell line with low HER2 expression. They were resuspended in a mixture of physiological saline and Matrigel (CORNING 3102001) (Matrigel:PBS = 1:1), and 8 * 10⁸ cells were collected. 6 Capan-1 solid tumor model was constructed by subcutaneously injecting 10 cells into the right side of female nude mice (Balb / c nude mice, Shanghai Southern Model Biotechnology Co., Ltd.). The solid tumor was then transplanted into female nude mice for multiple passages. The tumor was dissected, rinsed with saline, and cut into 3*3 mm fragments. The solid tumor fragments were then subcutaneously injected into the right side of the female nude mice. The injection site was palpated up to 3 times per week until the tumor grew to an average size of 150 mm. 3 (Measured with a digital caliper). On day 0, animals were randomly divided into treatment groups, with 6 mice in each group. On days 0 and 11, antibody-drug conjugates ADC-5 and ADC-ref were administered via tail vein at a dose of 10 mg / kg, respectively. A saline-treated group served as the control group. Tumor growth inhibition rate (TGI) was calculated using the following formula: TGI (%) = [1 - (mean tumor volume in the treatment group on the evaluation day / mean tumor volume in the control group on the evaluation day)] * 100. Figure 1 and Figure 2 As shown, tumor growth was significantly inhibited after treatment with the ADC of this invention, and the tumor-suppressing effect was significantly better than that of the positive control ADC-ref. On day 53 after mice were inoculated with tumor cells, the average tumor volume in the solvent group (physiological saline) was 1195.9 mm. 3 The mean tumor volume in the ADC-5 treatment group was 141.0 mm. 3 The tumor growth inhibition rate was 88.2% compared to the solvent group; the mean tumor volume in the ADC-ref positive control group was 371.1 mm. 3 The tumor growth inhibition rate was 69.0% compared to the solvent group. At the end of the experiment, the tumor growth inhibition rate of ADC-5 was significantly better than that of the positive control. This surprising therapeutic effect of the ADC of this invention has special application value in clinical treatment, and is expected to reduce the frequency of administration, inhibit the development of drug resistance, improve clinical response rate, or improve overall survival. Despite the significant improvement in efficacy, the ADC of this invention did not cause a decrease in mouse body weight, which also demonstrates the good safety profile of the ADC of this invention.

[0382] Experiment 7: In vivo efficacy study of ADCs:

[0383] The NCI-N87 cell line (BeNa Culture Collection Center) was used to construct the CDX (cell line-derived xenograft) NCI-N87 xenograft mouse model. Each 4-6 week old female nude mouse (Balb / c nude mouse, Shanghai Southern Model Biotechnology Co., Ltd.) was subcutaneously injected with 200 μL of Matrigel (CORNING 3110003)-NCI-N87 cell suspension (Matrigel:PBS=1:1), containing 1*10-1 cells, into the right flank. 7 Each cell. Palpate the injection site up to 3 times a week until the tumor grows to an average size of 200 mm. 3 (Measured with a digital caliper). On day 0, the animals were randomly divided into treatment groups, with 6 mice in each group. On day 0, the ADC of the present invention was administered intravenously (iv) at a dose of 1 mg / kg; on day 11, the ADC of the present invention was administered intravenously (iv) at a dose of 2 mg / kg. A saline administration group was set up as a control group. Tumor size and mouse weight were measured and recorded twice a week. The tumor growth inhibition rate (TGI) was calculated using the following formula: TGI (%) = [1 - (mean tumor volume of the treatment group on the evaluation day / mean tumor volume of the control group on the evaluation day)] * 100.

[0384] like Figure 3 and Figure 4As shown, tumor growth was significantly inhibited after treatment with the ADC of this invention, and the tumor-suppressing effect was significantly better than that of the positive control ADC-ref. On day 33 after mice were inoculated with tumor cells, the average tumor volume in the solvent group (physiological saline) was 1856.0 mm. 3 The mean tumor volume in the ADC-4 treatment group was 416.2 mm. 3 The tumor growth inhibition rate was 77.6% compared to the solvent group; the mean tumor volume in the ADC-ref positive control group was 739.7 mm. 3 The tumor growth inhibition rate of ADC-4 was 60.1% compared to the solvent group. At the end of the experiment, the tumor growth inhibition rate of ADC-4 was significantly better than that of the positive control.

[0385] Experiment 8: In vivo efficacy study of ADCs:

[0386] The NCI-N87 cell line (BeNa Culture Collection Center) was used to construct a CDX (cell line-derived xenograft) NCI-N87 xenograft mouse model. Each 4-6 week old female nude mouse (Balb / c nude mouse, Shanghai Southern Model Biotechnology Co., Ltd.) was subcutaneously injected with 200 μL of Matrigel (CORNING 3110003)-NCI-N87 cell suspension (Matrigel:PBS=1:1), containing 9.8 * 10-1 cells, into the right flank. 7 Each cell. Palpate the injection site up to three times a week until the tumor grows to an average size of 150 mm. 3 (Measured with a digital caliper). On day 0, the animals were randomly divided into treatment groups, with 6 mice in each group. On day 0, the ADC of the present invention was administered intravenously (iv) at a dose of 1 mg / kg. A saline administration group was set up as a control group. Tumor size and mouse weight were measured and recorded twice a week. The tumor growth inhibition rate (TGI) was calculated according to the following formula: TGI (%) = [1 - (mean tumor volume of the treatment group on the evaluation day / mean tumor volume of the control group on the evaluation day)] * 100.

[0387] like Figure 5 and Figure 6 As shown, tumor growth was significantly inhibited after treatment with the ADC of this invention, and the tumor-suppressing effect was significantly better than that of the positive control ADC-ref. On day 33 after mice were inoculated with tumor cells, the average tumor volume in the solvent group (physiological saline) was 1137.4 mm. 3 The mean tumor volume in the ADC-5 treatment group was 97.0 mm. 3 The tumor growth inhibition rate in the ADC-8 treatment group was 91.5% compared to the solvent group; the mean tumor volume in the ADC-8 treatment group was 206.0 mm. 3The tumor growth inhibition rate was 82.0% compared to the solvent group; the mean tumor volume in the ADC-ref positive control group was 364.4 mm. 3 The tumor growth inhibition rate was 68.0% compared to the solvent group. At the end of the experiment, the tumor growth inhibition rates of ADC-5 and ADC-8 were significantly better than those of the positive control.

[0388] Experiment 9: In vivo efficacy study of ADCs:

[0389] The JIMT-1 cell line (BeNa Culture Collection Center) was used to construct the CDX (cell line-derived xenograft) JIMT-1 xenograft mouse model. Each 4-6 week old female nude mouse (Balb / c nude mouse, Hainan Model Biotechnology Co., Ltd.) was subcutaneously injected with 200 μL of Matrigel (CORNING 3102001)-JIMT-1 cell suspension (Matrigel:PBS=1:1), containing 6.3 * 10-1 cells, into the right flank. 6 Each cell. Palpate the injection site up to three times a week until the tumor grows to an average size of 150 mm. 3 (Measured with a digital caliper). On day 0, the animals were randomly divided into treatment groups, with 6 mice in each group. On day 0, the ADC of the present invention was administered intravenously (iv) at a dose of 10 mg / kg. A saline administration group was set up as a control group. Tumor size and mouse weight were measured and recorded twice a week. The tumor growth inhibition rate (TGI) was calculated according to the following formula: TGI (%) = [1 - (mean tumor volume of the treatment group on the evaluation day / mean tumor volume of the control group on the evaluation day)] * 100.

[0390] like Figure 7 and Figure 8 As shown, tumor growth was significantly inhibited after treatment with the ADC of this invention, and the tumor-suppressing effect was superior to that of the positive control ADC-ref. On day 31 after mice were inoculated with tumor cells, the average tumor volume in the solvent group (physiological saline) was 1054.9 mm. 3 The mean tumor volume in the ADC-5 treatment group was 312.4 mm. 3 The tumor growth inhibition rate was 70.4% compared to the solvent group; the mean tumor volume in the ADC-ref positive control group was 400.4 mm. 3 The tumor growth inhibition rate of ADC-5 was 62.0% compared to the solvent group. At the end of the experiment, the tumor growth inhibition rate of ADC-5 was better than that of the positive control.

[0391] Experiment 10: In vivo toxicity study of the payload:

[0392] Male SD rats, 180–200 g (Shanghai Bikaico Biotechnology Co., Ltd.), 4 rats per group. The effective load was administered intravenously (iv) at a dose of 2 mg / kg once daily for 4 consecutive days. A control group was established receiving physiological saline solution containing 5% (w / v) dimethyl sulfoxide and 20% (w / v) (2-hydroxypropyl)-β-cyclodextrin. Rats' body weight was measured and recorded daily.

[0393] like Figure 11 As shown, after administration of the effective load, a sustained decrease in body weight was observed. After drug withdrawal on day 4, the effects of compound (D1) gradually dissipated, and body weight recovered on day 6, significantly better than Dxd. However, ref-2 ( The toxicity caused by ref-2 was more severe, with no signs of recovery by day 6. This result also indicates that compound (D1) is much safer than ref-2, which is consistent with the unique PK properties of these new compounds, resulting in faster clearance.

[0394] Overall representative data demonstrate the surprising and excellent therapeutic potential of the compounds described herein, exhibiting unexpected advantages in potency, efficacy, and safety. Importantly, as shown in trials 1 through 10, the faster clearance of the free toxins described herein did not lead to a decrease in the efficacy of the ADCs constructed from them. The significant improvements in in vivo efficacy and pharmacokinetic properties of the ADCs presented herein offer significant benefits for human or mammalian treatment, including but not limited to higher clinical cure rates, reduced effective drug doses, and fewer potential adverse reactions.

[0395] Sequence List:

Claims

1. A ligand-drug conjugate having the following structural formula, or a pharmaceutically acceptable salt or solvate thereof, (LD) m , in: T represents the targeting ligand or binding ligand; L represents the connection unit; m is an integer or fraction selected from 1 to 12; D is a drug unit with formula D1: ； in: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a Selected from H or halogens; wherein the divalent group is independently selected from the group consisting of the following groups each time it appears: S-CH=N-, -O-CH=N-, -CH=CH-CH=CH-, -O(CH2)2-, -(CH2) p O(CH2) p -、-O-CH=CH-、 -(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; Each time p appears, it is independently selected from 1 or 2; R 1d Selected from H or halogen; R 2a and R 2b Each is independently selected from the group consisting of: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or R 2a With R 2b It combines with the carbon atom it is attached to to form C3-C6 cycloalkyl groups; Z is -R 3a -R 3b ; R 3b Selected from -OH, -SH and -NHR 3c ; R 3a Choose from the group consisting of the following groups: -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C0-C3 alkylene-C3-C 10 Cycloalkylene-C0-C3 alkylene-, -R 3g -C1-C6 alkylene-R 3g -C1-C6 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 arylene-C0-C3 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 Heteroaryl-C0-C3 alkylene-,-R 3g -C0-C3 alkylene-C3-C 10 Heterocyclic alkyl-C 0- C3 alkylene-, -N(C1-C8 alkyl)-C2-C8 alkylene-, and -NR 3d R 3e -R 3f -; R 3g It is either absent, or selected from the group consisting of the following groups: O, S, S(O), S(O). 2、 -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -NHC(=O)S-, -NHC(=S)NH-, and -NHS(O)2-; R 3d and R 3e It combines with the nitrogen atom to which it is attached to form an optionally substituted 4- to 9-membered ring containing 1 or 2 nitrogen atoms; R 3f The group is absent or selected from the following groups: -C(O)-N(C1-C3 alkyl)-C1-C8 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene(C1-C3 alkyl)-, -C1-C6 alkylene-, -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 Heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene-, and -C(O)-NH-C1-C8 alkylene-; R 3c Selected from H or C1-C6 alkyl groups; Wherein, D is covalently linked to L through any suitable linking site on D; optionally, the hydrogen atoms on the hydroxyl, thiol, primary or secondary amino groups of D are replaced with links to L, or the tertiary amino group of D is quaternized to form links to L. The condition is that when R 1a and R 1b Combine to form -O-CH=CH- and R 3a When choosing a group consisting of the following groups: -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C3-C 10 Cycloalkylene- and -R 3g -C1-C6 alkylene-R 3g When -C1-C6 alkylene-, R 3g Not -NHC(=O)-.

2. The ligand-drug conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a and R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b and R 1c When R combines to form a divalent group, 1a Selected from H or halogen; wherein, Each time a divalent group appears, it is independently selected from the group consisting of the following groups: -O(CH2)2-, -(CH2). p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、 -S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; R 3f It does not exist, or is selected from the group consisting of the following groups: -C1-C6 alkylene-, -C1-C6 alkylene (C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 Heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene-, and -C(O)-NH-C1-C8 alkylene-.

3. The ligand-drug conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a and R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b and R 1c When R combines to form a divalent group, 1a Selected from H or halogen; wherein, Each divalent group is independently selected from the group consisting of -S-CH=N-, -O-CH=N-, and -CH=CH-CH=CH-, and each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen.

4. The ligand-drug conjugate according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein -NR 3d R 3e -R 3f -Has the structure of Formula I, ； in: X is -C(R) 5b - or -N-; R 5a Does not exist, or R 5a and R 8 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl; or R 5a and R 5b Together with the atoms to which they are attached, they constitute a 3- to 6-membered cycloalkyl or a 4- to 8-membered heterocycloalkyl; wherein the 5- to 6-membered aryl, 5- to 6-membered heteroaryl, each "3- to 6-membered cycloalkyl" and each "4- to 8-membered heterocycloalkyl" are independently and optionally surrounded by 1 to 3 R 9 replace; R 4 R 5b R 6 R 7 and R 8 Independently selectable from H, halogen, hydroxyl, and C 1-8 Alkyl, C 3-6 The group consisting of cycloalkyl, aryl, and heteroaryl groups, wherein each C 1-8 Alkyl, C 3-6 Cycloalkyl, aryl, and heteroaryl groups are independently and optionally surrounded by 1 to 4 R groups. 9 Replace; or R 4 and R 5b Together with the atoms to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, provided that R 5a and R 5b Not forming a ring at the same time; or R 4 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 4 and R 6 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 7 and R 8 Together with the atoms to which they are attached, they form an oxo group, a 3- to 6-membered cycloalkyl group, or a 4- to 8-membered heterocycloalkyl group; wherein each 3- to 6-membered cycloalkyl group and each 4- to 8-membered heterocycloalkyl group is independently and optionally bonded by 1 to 4 R groups. 9 Replace; and R 4 R 5b R 6 R 7 and R 8 The remaining parts are independently selected from the group consisting of the following groups each time they appear: H, halogen, hydroxyl, C. 1-8 Alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, aryl, and heteroaryl groups are independently and optionally separated by one to four R groups. 9 replace; R 9 Each time it appears, it is independently selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, and heteroaryl group; or, when two R groups appear, they are selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, 9 When a group is attached to an adjacent carbon atom, it forms a fused C3-C6 cycloalkyl group together with the carbon atoms to which they are attached; or, when two R groups are attached to adjacent carbon atoms, they form a fused C3-C6 cycloalkyl group. 9 When groups are attached to the same carbon atom, they together form a spirocyclic C3-C6 cycloalkyl group; wherein each C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, heteroaryl group, fused C3-C6 cycloalkyl group, and spirocyclic C3-C6 cycloalkyl group is independently and optionally substituted by one to three groups selected from fluorine, hydroxyl, and C1-C3 alkyl groups; n 1 and n 2 Each integer is independently selected from 0, 1, 2, 3, and 4; provided that n is an integer. 1 + n 2 It can be 1, 2, 3 or 4.

5. The ligand-drug conjugate according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein -NR 3d R 3e -R 3f -Has a formula selected from the following: 。 6. The ligand-drug conjugate according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein -NR 3d R 3e -R 3f -Has a formula selected from the following: 。 7. The ligand-drug conjugate according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1a and R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; p is independently selected from the group consisting of 1 and 2 each time it appears.

8. The ligand-drug conjugate according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1c and R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; p is independently selected from the group consisting of 1 and 2 each time it appears.

9. The ligand-drug conjugate according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 3f For the choice of freedom - C3 - C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 The group consisting of cycloalkylene-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene-, and -C(O)-NH-C1-C8 alkylene-.

10. The ligand-drug conjugate according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 2a and R 2b Independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; optionally, D is obtained through R. 3b The O, S, or N atoms are covalently attached to L, where R 3b -OH, -SH or -NHR 3c The hydrogen atoms in the L atom are replaced by bonds connected to L.

11. The ligand-drug conjugate according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is -OH.

12. The ligand-drug conjugate according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from -C1-C6 alkylene-, -S-C1-C6 alkylene-, -S(O)2-C1-C6 alkylene-, and -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structural formula selected from the following: and .

13. The ligand-drug conjugate according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein D has D 1a D 1b D 1c D 1d D 1e D 1f D 1g D 1h D 1m D 1n D 1p or D 1q Structural formula: ； Where R 1e and R 1f Each time it appears, it is independently selected from H, halogens, and C1-C3 alkyl groups.

14. The ligand-drug conjugate according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein D has a structural formula selected from the group consisting of: 。 15. The ligand-drug conjugate according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein D has a structural formula selected from the group consisting of: 。 16. The ligand-drug conjugate according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a linking unit having the following structural formula: -L 1 -L 2 -L 3 -L 4 - Where L 1 For connecting subunits; L 2 It does not exist, or it is a separator; L 3 It is an amino acid unit; L 4 It does not exist, or it is a spacing element; and where L 1 Connect to T.

17. The ligand-drug conjugate of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 Selected from the following groups: ； Among them, Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5- to 6-arylene, and 5- to 6-heteroarylene; Y 1 Choose from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heterocycloalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, -NHC(O) CH2-(OCH2CH2) p 6 -OC1-C6 alkyl and cycloalkyl groups; p 6 Each occurrence is independently selected from integers between 3 and 15; and each of the above L... 1 The left side of the group is attached to T; L 2 Does not exist, or selected from -[NR] 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、 -NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、 -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、 -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 The group consisting of -C(O)-(C3-C6 cycloalkyl)-C(O)-; wherein R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 The following groups do not exist or can be selected: ； Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Choose freely from H, -CH2CH2S(O)2CH3, -CH2CH2N(CH 33 The group consisting of 2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

18. The ligand-drug conjugate according to claim 16 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 Selected from: ； Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5- to 6-arylene, and 5- to 6-heteroarylene; Y 1 Selected from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkylene and 5- to 10-membered heteroarylene; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of: C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, heteroalkylene, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroalkylene is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1 The left side of the group is attached to T; L 2 Does not exist, or selected from -[NR] 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、 -NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、 -NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 The group consisting of -C(O)-(C3-C6 cycloalkyl)-C(O)-; wherein, R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an independent integer selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 3 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 Not found, or selected from: ； Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

19. The ligand-drug conjugate of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 for ;W 1 for ;R 17 R 18 and R 19 Each time it appears, choose independently either H or -(CH2CH2O). p 7 The group consisting of -(C1-C6 alkyl), -SO3H, -PO(OH)2 and C1-C6 alkyl; R 20 Each occurrence is independently a C1-C6 alkylene group; p 7 W is an integer selected from 1 to 15; W is selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heterocycloalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally and independently further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1 The left side of the group is attached to T; L 2 Does not exist, or selected from -[NR] 10 -CH2C(O)] p 2 -、 -NR 10 (CH2CH2O) p 2 CH2CH2-、 -NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 The group consisting of -C(O)-(C3-C6 cycloalkyl)-C(O)-; wherein, R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1 On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L is an optionally substituted amino acid residue or an optionally substituted peptide residue consisting of 2 to 7 amino acids; wherein the L above 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 Not found, or selected from: Among them, R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Choose from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b ; Optionally, L is selected from the following structures: 。 20. The ligand-drug conjugate according to any one of claims 16 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein: L 2 Selected from -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 The group consisting of -C(O)-(C3-C6 cycloalkyl)-C(O)-; wherein R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent selection from an integer between 3 and 15; "5- to 6-arylagenal" each occurrence is an independent selection from... .

21. The ligand-drug conjugate according to any one of claims 16 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein: L 3 The residue is an amino acid residue or a peptide residue consisting of 2 to 7 amino acids; wherein the amino acid is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N); wherein the amino acid residue and peptide residue may optionally be further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2、-[N(CH3)-CH2-C(O)] g 1 -N(CH3)-CH2COOH, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 -NH-(CH2CH2O) g 1 -C1-C6 alkyl groups, -C(O)-(CH2CH2O) g 1 -(CH2) g -N[CH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]2, -NH-C[CH2OCH2CH2C(O)NHCH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]3; Optionally, the amino acid residues and peptide residues may be further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 ;in, g is an independent integer selected from 0 to 5 each time it appears; s is an integer selected from 0 to 3; Y 2 Y 3 and Y 4 Each time it appears, it is selected from groups composed of -CH2-, -NH-, -S-, and -O-; g 1 Each occurrence is an independent integer selected from 3 to 15; optionally, it is a peptide residue composed of one, two, or more phenylalanine and glycine; optionally, it is a peptide residue composed of four amino acids; optionally, it is a peptide residue composed of GGFG; wherein, the above L 3 The N-terminus of the group is connected to the L 1 or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b .

22. The ligand-drug conjugate according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following structures: 。 23. The ligand-drug conjugate according to any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following structures: 。 24. The ligand-drug conjugate according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate is selected from the following structural formulas: 。 25. The ligand-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 24, wherein T is a targeting antibody or a ligand binding antigen; wherein the antibody is selected from chimeric antibodies, humanized antibodies, and fully human antibodies; optionally, wherein T is a monoclonal antibody.

26. The ligand-drug conjugate according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein, T is selected from anti-Her2 (ErbB2) antibody, anti-EGFR antibody, anti-B7H3 antibody, anti-c-MET antibody, anti-Her3 (ErbB3) antibody, anti-Her4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MICI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenosynovin C antibody, anti-SLC44A4 antibody, anti-mesothelin antibody, and anti-ROR1 antibody, or their antigen-binding fragments.

27. The ligand-drug conjugate according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein, T is selected from trastuzumab, pertuzumab, nimotuzumab, enrototuzumab, imibetotuzumab, itotuzumab, pinatuzumab, bentuximab, gemtuzumab, bivaltuzumab, lovotuzumab, cBR96, and glentotuzumab, or an antigen-binding fragment.

28. The ligand-drug conjugate according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein T is trastuzumab.

29. The ligand-drug conjugate according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein, m is an integer or fraction selected from 2 to 8; alternatively, m is an integer or fraction selected from 3 to 8.

30. A compound having the formula LD, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: L represents the connection unit; D is a drug unit with formula D1: ； in: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a It is selected from H or halogens; the divalent group is independently selected each time it appears from -S-CH=N-, -O-CH=N-, -CH=CH-CH=CH-, -O(CH2)2-, -(CH2) p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; Each time p appears, it is independently selected from 1 or 2; R 1d Selected from H or halogen; R 2a and R 2b Independently selected from the group consisting of H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or R 2a and R 2b Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group; Z is -R 3a -R 3b ; R 3b Selected from -OH, -SH and -NHR 3c ; R 3a Choose Free-R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C0-C3 alkylene-C3-C 10 Cycloalkylene-C0-C3 alkylene-, -R 3g -C1-C6 alkylene-R 3g -C1-C6 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 arylene-C0-C3 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 Heteroaryl-C0-C3 alkylene-,-R 3g -C0-C3 alkylene-C3-C 10 Heterocyclic alkyl-C0-C3 alkylene-, -N(C1-C8 alkyl)-C2-C8 alkylene- and -NR 3d R 3e -R 3f -A group; R 3g It does not exist, or you can choose the group consisting of O, S, S(O), S(O)2, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -NHC(=O)S-, -NHC(=S)NH- and -NHS(O)2-; R 3d and R 3e Together with the nitrogen atom to which it is attached, it forms an optionally substituted 4- to 9-membered ring containing one or two nitrogen atoms; R 3f It does not exist, or can be selected from -C(O)-N(C1-C3 alkyl)-C1-C8 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene(C1-C3 alkyl)-, -C1-C6 alkylene-, -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-; R 3c Selected from H or C1-C6 alkyl groups; D is covalently linked to L through any suitable linking site; optionally, the hydrogen atom on the hydroxyl, mercapto, primary or secondary amine of D is replaced with a bond linked to L, or the tertiary amine of D is quaternized to form a bond linked to L. The prerequisite is that when R 1a With R 1b Combine to form -O-CH=CH-, and R 3a Selected from -R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C3-C 10 Cycloalkylene- and -R 3g -C1-C6 alkylene-R 3g When R is a group consisting of -C1-C6 alkylene-, 3g Not -NHC(=O)-.

31. The compound according to claim 30, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b When R¹ᶜ combines with R to form a divalent group, R 1a It is selected from H or halogens; the divalent group is independently selected from -O(CH2)2- or -(CH2) each time it appears. p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; R 3f It does not exist, or is selected from -C1-C6 alkylene-, -C1-C6 alkylene (C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

32. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a It is selected from H or halogen; wherein each divalent group is independently selected from the group consisting of -S-CH=N-, -O-CH=N- and -CH=CH-CH=CH-, and wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen.

33. The compound according to any one of claims 30 to 32, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein -NR 3d R 3e -R 3f -Has a structure of Formula I: ； in: X is -C(R) 5b - or -N-; R 5a Does not exist, or R 5a and R 8 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl; or R 5a and R 5b Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; wherein, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, each "3- to 6-membered cycloalkyl" and each "4- to 8-membered heterocycloalkyl" are independently and optionally surrounded by 1 to 3 R 9 replace; R 4 R 5b R 6 R 7 and R 8 Independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein each C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl is independently and optionally surrounded by 1 to 4 R 9 Replace; or R 4 With R 5b Together with the atoms to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, provided that R is present. 5a With R 5b Do not form a ring at the same time; or R 4 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 4 and R 6 Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups; or R 7 With R 8 Together with the atoms to which they are attached, they form an oxo group, a 3- to 6-membered cycloalkyl group, or a 4- to 8-membered heterocycloalkyl group; wherein each of the 3- to 6-membered cycloalkyl groups and the 4- to 8-membered heterocycloalkyl groups is independently and optionally surrounded by 1 to 4 R groups. 9 Replace; and R 4 R 5b R 6 R 7 and R 8 The remaining parts, each time appearing, are independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein the C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl are independently and optionally separated by 1 to 4 R. 9 replace; R 9 Each time it appears, it is independently selected from the group consisting of halogen, oxo group, hydroxyl group, cyano group, C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, and heteroaryl group; or two R groups. 9 When a group is attached to an adjacent carbon atom, it forms a fused C3-C6 cycloalkyl group together with the attached carbon atom; or two R groups... 9 When the group is attached to the same carbon atom, it forms a spirocyclic C3-C6 cycloalkyl group together with the carbon atom to which it is attached; wherein each C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, heteroaryl group, fused C3-C6 cycloalkyl group and spirocyclic C3-C6 cycloalkyl group is independently and optionally substituted by 1 to 3 substituents selected from fluorine, hydroxyl and C1-C3 alkyl groups; n 1 and n 2 Each is an independent integer selected from 0, 1, 2, 3, and 4; the prerequisite is n. 1 + n 2 It can be 1, 2, 3 or 4.

34. The compound according to any one of claims 30 to 33, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein -NR 3d R 3e -R 3f -Has a structure selected from the following: 。 35. The compound according to any one of claims 30 to 34, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein -NR 3d R 3e -R 3f -Has a structure selected from the following: 。 36. The compound according to any one of claims 30 to 35, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1a With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; Each time p appears, it is independently selected from the group consisting of 1 and 2.

37. The compound according to any one of claims 30 to 35, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1c With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- or -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-; wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; Each time p appears, it is independently selected from the group consisting of 1 and 2.

38. The compound according to any one of claims 30 to 37, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein R 3f Choose Free - C3 - C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 The group consisting of cycloalkylene-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

39. The compound according to any one of claims 30 to 38, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 2a and R 2b Independently selected from H, halogens, and C1-C3 alkyl groups; optionally, D is derived from R. 3b The O, S, or N atoms are covalently bonded to L; where R 3b -OH, -SH or -NHR 3c The hydrogen atoms on the L atom are replaced with bonds attached to the L atom.

40. The compound according to any one of claims 30 to 39, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 3b It is -OH.

41. The compound according to any one of claims 30 to 40, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 3a Selected from -C1-C6 alkylene-, -S-C1-C6 alkylene-, -S(O)2-C1-C6 alkylene- and -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structure selected from the following: and .

42. The compound according to any one of claims 30 to 41, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein D has D 1a D 1b D 1c D 1d D 1e D 1f D 1g D 1h D 1m D 1n D 1p or D 1q The structure shown: ； Where R 1e and R 1f Each time it appears, it is independently selected from H, halogens, and C1-C3 alkyl groups.

43. The compound according to any one of claims 30 to 42, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein D has a structural formula selected from: 。 44. The compound according to any one of claims 30 to 42, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein D has a structural formula selected from: 。 45. The compound according to any one of claims 30 to 44, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein L is a linking unit having the following structural formula: L 1a -L 2 -L 3 -L 4 - Where L 1a For connecting subunits; L 2 It either does not exist or is a separator; L 3 It is an amino acid unit; L 4 It either does not exist or is a spacer unit.

46. ​​The compound according to claim 45, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: L 1a Selected from: ； Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5-to-6-arylene, and 5-to-6-heteroarylene; Y 1 Choose from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, -NHC(O)CH2-(OCH2CH2). p 6 -OC1-C6 alkyl and cycloalkyl groups; p 6 Each occurrence is an independent integer selected from 3 to 15; and each of the above L... 1a The right side of the group is connected to L 2 or L 3 ; L 2 It does not exist, or is selected from the group consisting of the following groups: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、-NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence of L is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L is an optionally substituted amino acid residue or an optionally substituted peptide residue consisting of 2 to 7 amino acids; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 Not found, or selected from: ； Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

47. The compound according to claim 45, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: L 1a for ; where W 1 for ;where R 17 R 18 and R 19 Each time it appears, it is independently selected from H and -(CH2CH2O). p 7 -(C 1 -C 6 The group consisting of alkyl groups, -SO3H, -PO(OH)2, and C1-C6 alkyl groups; R 20 Each occurrence is independently a C1-C6 alkylene group; p 7 W is an integer selected from 1 to 15; W is selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, -aryl-(C1-C8 alkylene)-, heteroaryl, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heterocycloalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroaryl groups is optionally and independently further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1a The left side of the group is attached to T; L 2 Does not exist, or selected from -[NR] 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、 -NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-C(O)-、-O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 The group consisting of -C(O)-(C3-C6 cycloalkyl)-C(O)-; wherein R 10 Each time it appears, it is independently H, C1-C3 alkyl, or -(CH2CH2O). p 2 -C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L is an optionally substituted amino acid residue or an optionally substituted peptide residue consisting of 2 to 7 amino acids; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 It does not exist, or is selected from the group consisting of the following groups: ； Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b ; Optionally, L is selected from the following structures: 。 48. The compound according to claim 45 or 46, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: L 1a Selected from: ； Z 1 Each occurrence is selected from the group consisting of C1-C8 alkylene, C1-C8 alkenylene, C1-C8 ynynylene, 5-to-6-arylene, and 5-to-6-heteroarylene; Y 1 Choose from the group consisting of -O-, -S-, -CH2-, 4- to 8-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups; q 1 q 2 and q 3 Each is an independent integer selected from 1, 2, 3, and 4; W and W 1 Each occurrence is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, aryl, heteroalkylene, and straight-chain heteroalkylene, wherein the straight-chain heteroalkylene comprises 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, O, S, S(O), and S(O)2; and wherein each of the alkylene, alkenyl, ynylene, heteroalkylene, cycloalkylene, straight-chain heteroalkylene, aryl, and heteroalkylene is optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuteralkyl, alkoxy, and cycloalkyl; and wherein each of the above L 1a The right side of the group is connected to L 2 or L 3 ; L 2 Not present, or selected from the group consisting of: -[NR 10 -CH2C(O)] p 2 -、-NR 10 (CH2CH2O) p 2 CH2CH2-、 -NR 10 -(CH2) p 1 -C(O)-, -O-(CH2) p 1 -C(O)-, -S-(CH2) p 1 -C(O)-, -CH2-(CH2) p 1 -C(O)-、 -NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)- and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(C3-C6 cycloalkyl)-C(O)-; where R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence of L is an independent integer selected from 3 to 15; where each of the above L... 2 The left side of the group is connected to L 1a On the right side, and each L 2 The right side of the group is connected to L 3 ; L 3 The L can be an optional substituted amino acid residue or a peptide residue consisting of 2 to 7 amino acids that can be optionally substituted; wherein the L above 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b ; L 4 Not found or selected from: ； Where R 14 and R 15 Each occurrence is independently selected from the group consisting of H, halogens, and C1-C3 alkyl groups; R 11 R 12 and R 13 Each time it appears, it is independently H or C1-C3 alkyl; R 16 Selected from the group consisting of H, -CH2CH2S(O)2CH3, -CH2CH2N(CH3)2 and C1-C3 alkyl groups; wherein each of the above L 4 The left side of the group is connected to L 3 The C-end, and each L 4 The right side of the group is connected to R 3b .

49. The compound according to any one of claims 45 to 48, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: Where L 2 Selected from -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -C(O)-、-NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -O-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -S-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, -CH2-(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 -C(O)-(CH2) p 4 -O-(CH2) p 5 -C(O)-, and -NR 10 -(CH2) p 1 -(5- to 6-methylheteroaryl)-(CH2CH2O) p 2 -(CH2) p 3 -NR 10 The group consisting of -C(O)-(C3-C6 cycloalkyl)-C(O)-; wherein R 10 Each occurrence is independently of H or C1-C3 alkyl; p 1 p 3 p 4 and p 5 Each occurrence is an integer independently selected from 0, 1, 2, 3, and 4; p 2 Each occurrence is an independent selection from integers between 3 and 15: "5- to 6-arylamininyl" each occurrence is an independent selection from... .

50. The compound according to any one of claims 45 to 49, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein L 3 The residue is an amino acid residue or a peptide residue consisting of 2 to 7 amino acids; wherein the amino acid is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N); wherein the amino acid residue and peptide residue are optionally further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2、-[N(CH3)-CH2-C(O)] g 1 -N(CH3)-CH2COOH, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 -NH-(CH2CH2O) g 1 -C1-C6 alkyl, -C(O)-(CH2CH2O) g 1 -(CH2) g -N[CH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]2, -NH-C[CH2OCH2CH2C(O)NHCH2CH(OH)CH(OH)CH(OH)CH(OH)CH2(OH)]3; Optionally, the amino acid residues and peptide residues may be further substituted by one or more substituents selected from: halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, alkoxy, cycloalkyl, -[N(CH3)-CH2-C(O)] g 1 -NH2, -C(O)-CH2-[N(CH3)-C(O)-CH2] g 1 -NH-C(O)-CH3、 ;in, g is an independent integer selected from 0 to 5 each time it appears; s is an integer selected from 0 to 3; Y 2 Y 3 and Y 4 Each time it appears, select the group consisting of -CH2-, -NH-, -S-, and -O-; g 1 Each occurrence is an independent integer selected from 3 to 15; optionally, it is a peptide residue composed of one, two, or more phenylalanine and glycine; optionally, it is a peptide residue composed of four amino acids; optionally, it is a peptide residue composed of GGFG; wherein the above L 3 The N-terminus of the group is connected to the L 1a or L 2 On the right side, and L 3 The C-terminus of the group is connected to the L 4 or R 3b .

51. The compound according to any one of claims 30 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein L is selected from the following structures: 。 52. The ligand-drug conjugate according to any one of claims 30 to 50, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following structures: 。 53. The compound according to any one of claims 30 to 52, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein the compound is selected from the following structural formulas: 。 54. A compound having formula D1: ； Or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a It is selected from H or halogens; wherein, each time the divalent group appears, it is independently selected from -S-CH=N-, -O-CH=N-, -CH=CH-CH=CH-, -O(CH2)2-, -(CH2). p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; Each time p appears, it is independently selected from 1 or 2; R 1d Selected from H or halogen; R 2a and R 2b Independently selected from the group consisting of H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or R 2a and R 2b They combine with the carbon atoms they are attached to to form C3-C6 cycloalkyl groups; Z is -R 3a -R 3b ; R 3b Selected from -OH, -SH and -NHR 3c ; R 3a Choose Free-R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C0-C3 alkylene-C3-C 10 Cycloalkylene-C0-C3 alkylene-, -R 3g -C1-C6 alkylene-R 3g -C1-C6 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 arylene-C0-C3 alkylene-, -R 3g -C0-C3 alkylene-C5-C 12 Hybrid aryl-C0-C 33 Alkylene-, -R 3g -C0-C3 alkylene-C3-C 10 Heterocyclic alkyl-C0-C3 alkylene-, -N(C1-C8 alkyl)-C2-C8 alkylene- and -NR 3d R 3e -R 3f -A group; R 3g It does not exist, or you can choose the group consisting of O, S, S(O), S(O)2, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -NHC(=O)S-, -NHC(=S)NH- and -NHS(O)2-; R 3d and R 3e They combine with the nitrogen atoms to which they are attached to form optional 4- to 9-membered rings containing one or two nitrogen atoms; R 3f It does not exist, or is selected from -C(O)-N(C1-C3 alkyl)-C1-C8 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene(C1-C3 alkyl)-, -C1-C6 alkylene-, -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-; R 3c Selected from H or C1-C6 alkyl groups; The prerequisite is that when R 1a With R 1b Combine to form -O-CH=CH-, and R 3a Choose Free-R 3g -C1-C6 alkylene-, -R 3g -C1-C6 alkylene(C3-C 10 cycloalkyl)-, -R 3g -C3-C 10 When the group consists of cycloalkylene- and -R³ᵍ-C1-C6 alkylene-R³ᵍ-C1-C6 alkylene-, R 3g Not -NHC(=O)-.

55. The compound according to claim 54, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a It is selected from H or halogens; wherein, each time the divalent group appears, it is independently selected from -O(CH2)2- or -(CH2). p O(CH2) p -、-O-CH=CH-、-(CH2) p NH(CH2) p -、-S(CH2)2-、-(CH2) p S(CH2) p -、-S-CH=CH-、-(CH2) p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl group or a halogen; R 3f It does not exist, or is selected from -C1-C6 alkylene-, -C1-C6 alkylene (C3-C 10 cycloalkyl)-, -C3-C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 Cycloalkylene-,-NH-C(O)-C3-C 10 The group consisting of heterocyclic alkyl-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

56. The compound according to claim 54, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1b With R 1a or R 1c Combine to form a divalent group; when R 1a With R 1b When R combines to form a divalent group, 1c Selected from H or halogen; when R 1b With R 1c When R combines to form a divalent group, 1a It is selected from H or halogen; wherein each divalent group is independently selected from the group consisting of -S-CH=N-, -O-CH=N- and -CH=CH-CH=CH-; and each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen.

57. The compound according to any one of claims 54 to 56, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein -NR 3d R 3e -R 3f -Has a structure of Formula I: ； in: X is -C(R) 5b - or -N-; R 5a Does not exist, or R 5a With R 8 Together with the atoms they are attached to, they form 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl; or R 5a With R 5b Together with the atoms to which they are attached, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; wherein, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, each "3- to 6-membered cycloalkyl" and each "4- to 8-membered heterocycloalkyl" are independently and optionally surrounded by 1 to 3 R 9 replace; R 4 R 5b R 6 R 7 and R 8 Independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein the C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl are each optionally independently separated by 1 to 4 R. 9 Replace; or R 4 and R 5b Together with the atoms they are attached to, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl, provided that R 5a and R 5b Do not form a ring at the same time; or R 4 and R 7 Together with the atoms they are attached to, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; or R 6 and R 7 Together with the atoms they are attached to, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; or R 4 and R 6 Together with the atoms they are attached to, they form 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl; or R 7 and R 8 Together with the atoms they are attached to, they form oxo, 3- to 6-membered cycloalkyl, or 4- to 8-membered heterocycloalkyl; wherein each 3- to 6-membered cycloalkyl and 4- to 8-membered heterocycloalkyl is independently and optionally bonded by 1 to 4 R atoms. 9 Replace; and R 4 R 5b R 6 R 7 and R 8 The remaining groups, each time they appear, are independently selected from the group consisting of H, halogen, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, wherein the C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl groups are independently and optionally influenced by 1 to 4 R groups. 9 replace; R 9 Each time it appears, it is independently selected from the group consisting of halogen, oxo, hydroxyl, cyano, C1-C8 alkyl, C3-C6 cycloalkyl, C1-C8 alkoxy, aryl, and heteroaryl; or two Rs. 9 When a group is attached to an adjacent carbon atom, it forms a fused C3-C6 cycloalkyl group together with the carbon atom to which it is attached; or two R groups... 9 When groups are attached to the same carbon atom, they together with the carbon atom to which they are attached form a spirocyclic C3-C6 cycloalkyl group; wherein each C1-C8 alkyl group, C3-C6 cycloalkyl group, C1-C8 alkoxy group, aryl group, heteroaryl group, fused C3-C6 cycloalkyl group, and spirocyclic C3-C6 cycloalkyl group is independently and optionally substituted by one to three substituents selected from fluorine, hydroxyl, and C1-C3 alkyl groups; n 1 and n 2 Each is an independent integer selected from 0, 1, 2, 3, and 4; provided that n 1 + n 2 It can be 1, 2, 3 or 4.

58. The compound according to any one of claims 54 to 57, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein -NR 3d R 3e -R 3f -Has a structural formula selected from the following: 。 59. The compound according to any one of claims 54 to 58, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein -NR 3d R 3e -R 3f -Has a structural formula selected from the following: 。 60. The compound according to any one of claims 54 to 59, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1a With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- and -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2- and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; Each time p appears, it is independently selected from the group consisting of 1 and 2.

61. The compound according to any one of claims 54 to 59, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 1c With R 1b They combine to form a divalent group, which is selected from -S-CH=CH- and -(CH2). p S(=O)(CH2) p -, -OC(=O)-CH2-O-, -OC(=O)-CH2-NH-, -OC(=O)-CH2-S-, -OC(=O)-CH2-CH2-, -(CH2) p S(=O)2(CH2) p The group consisting of -, -CH2C(=O)OCH2-, and -OC(=O)-CH2-, wherein each divalent group is optionally substituted by at least one C1-C6 alkyl or halogen; Each time p appears, it is independently selected from the group consisting of 1 and 2.

62. The compound according to any one of claims 54 to 61, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein: R 3f Choose Free - C3 - C 10 Cycloalkylene-, -NH-C(O)-C1-C6 alkylene-, -N(C1-C3 alkyl)-C(O)-C1-C6 alkylene-, -NH-C(O)-C3-C 10 The group consisting of cycloalkylene-, -NH-C(O)-O-C1-C6 alkylene-, -NH-C(O)-NH-C1-C6 alkylene-, -C(O)-C1-C8 alkylene-, -C(O)O-C1-C8 alkylene- and -C(O)-NH-C1-C8 alkylene-.

63. The compound according to any one of claims 54 to 62, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein R 2a and R 2b It is independently selected from H, halogens and C1-C3 alkyl groups.

64. The compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein R 3b It is -OH.

65. The compound according to any one of claims 54 to 64, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein R 3a Selected from -C1-C6 alkylene-, -S-C1-C6 alkylene-, -S(O)2-C1-C6 alkylene- and -NR 3d R 3e -R 3f -; where -NR 3d R 3e -R 3f -Has a structural formula selected from the following: and .

66. The compound according to any one of claims 54 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein the compound has a D 1a D 1b D 1c D 1d D 1e D 1f D 1g D 1h D 1m D 1n D 1p or D 1q The structure shown: ； Where R 1e and R 1f Each time it appears, it is independently selected from H, halogens, and C1-C3 alkyl groups.

67. The compound according to any one of claims 54 to 66, or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein the compound comprises: 。 68. A pharmaceutical composition comprising a therapeutically effective amount of a ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 29, and a pharmaceutically acceptable carrier, diluent or excipient.

69. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 54 to 67 or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.

70. A method of treating a tumor in a subject in need, comprising administering to the subject a ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 29; or a pharmaceutical composition according to claim 68.

71. A method of treating a tumor in a subject in need, comprising administering to the subject a compound according to any one of claims 54 to 67 or a pharmaceutically acceptable salt, solvate, tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof; or a pharmaceutical composition according to claim 69.

72. The method according to claim 70 or 71, wherein the tumor is cancer.

73. The method of claim 72, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, or relapsed anaplastic large cell lymphoma).

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