Linker, ligand-drug conjugate, and pharmaceutical use

Abstract

Disclosed in the present invention are a new linker compound, a ligand-drug conjugate, a pharmaceutical composition containing the compound or the conjugate, and a corresponding pharmaceutical use.

Description

Linkers, ligand-drug conjugates and their pharmaceutical uses Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to camptothecin derivatives, linkers, ligand-drug conjugates, and their pharmaceutical uses in the treatment or prevention of proliferative diseases. Background Technology

[0002] Camptothecin is a water-insoluble cytotoxic alkaloid. Camptothecin and its analogues are known potential anticancer agents and have been shown to have in vivo and in vitro therapeutic activity.

[0003] Camptothecin and its analogues are known inhibitors of DNA topoisomerase I. Its analogue eczema is also an inhibitor of DNA topoisomerase I and has shown strong anticancer activity.

[0004] Ecinotecan, a small molecule compound with antitumor activity, is a camptothecin derivative known to exhibit antitumor effects by inhibiting DNA topoisomerase I. Developed by Daiichi Sankyo, it was initially used as a monotherapy in Phase III clinical trials, primarily for bone cancer, prostate cancer, breast cancer, and pancreatic cancer. Unlike irinotecan, which is currently used clinically, ecilenotecan does not require enzyme activation. Furthermore, compared to SN-38, the pharmacodynamic component of irinotecan, and topotecan, which is also used clinically, ecilenotecan exhibits stronger inhibitory activity against topoisomerase I and stronger cell-damaging activity against various cancer cells in vitro. Ecinotecan has not yet been successfully marketed as a monotherapy, presumably due to its high cell activity, resulting in a narrow therapeutic window.

[0005] Ligand-drug conjugates (ADCs) are a novel type of targeted therapy. One class of ADCs typically consists of three parts: an antibody or antibody-like ligand, a small molecule drug, and a linker (also called a conjugate) that couples the ligand and drug. ADCs utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and effectively release them, achieving therapeutic goals. In 2000, Pfizer's ADC drug Mylotarg was first launched in the United States, bringing this promising and challenging field of ADCs into the public eye. In recent years, the pharmaceutical market has witnessed a new wave of ADC research and development; as of the application date, 13 ADC drugs have been launched globally.

[0006] DS-8201 (trade name: Enhertu), an antibody-drug conjugate jointly developed and commercialized by Daiichi Sankyo and AstraZeneca, was launched in December 2019. This drug combines eczema with glycolic acid to form an amide derivative, which is then linked to form an ADC. As a new generation of antibody-drug conjugates, Enhertu has shown the potential to become a blockbuster drug.

[0007] It is essential and urgent to explore and discover camptothecin derivatives with superior antitumor activity, improve the safety and efficacy of small molecule antitumor compounds in ADC drug applications, and optimize linkers to obtain antitumor drugs with excellent efficacy. Summary of the Invention

[0008] The first aspect of this invention provides a ligand-drug conjugate of Formula III or a pharmaceutically acceptable salt thereof.

[0009] Where Ab is the ligand, L is the linker, and D is the drug moiety;

[0010] n is any integer or decimal from 1 to 15; preferably, n is any integer or decimal from 1 to 13; preferably, n is any integer or decimal from 3 to 10.

[0011] The connector is -L 1 -L 2 -L 3 -L 4 -L 5 -; where L 1 The end is connected to the ligand, L 5 The end is connected to the drug portion;

[0012] L 2 Selected from single bonds, alkyne groups, alkenyl groups, and -NR groups. 1L Combinations of one, two, three, or more of -, -O-, -C(O)-, alkylene, and heteroalkylene, wherein the ynylene, alkenylene, alkylene, and heteroalkylene are optionally represented by one or more R 1L replace;

[0013] L 3 for

[0014] Where r1 is selected from integers between 0 and 20;

[0015] r2 is selected from 0, 1, and 2;

[0016] * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites;

[0017] L 4 It is a peptide residue containing 2 to 7 amino acid residues, wherein the amino acid is optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl;

[0018] L 5 Selected from single key, * L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -C(=O)-* G 、* L4 -NR 2L (CR 3L R 4L ) t -* G 、* L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -Z1-C(=O)-* G and* L4 -NR 2L -Ar 2 -(CR 3L R 4L ) t -Z1-C(=O)-* G ;* L4 Indicates with L 4 The connection site, * G Indicates the connection site with G;

[0019] Wherein, t is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; Z1 is independently selected as a single bond, O, S, or NH each time it appears; Ar 2 Each occurrence is independently an arylene or heteroarylene, the heteroarylene containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the arylene or heteroarylene is optionally surrounded by one or more atoms selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Substitution of alkyl group 2;

[0020] R 1L R 2L and R 5L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C1-6 Alkoxy, deuterated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH;

[0021] R 3L and R 4L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-6 alkylene-OH and R 2H ;

[0022] R 1H and R 2H Each occurrence is independently -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w Z2 is selected from single bonds, O, and NR. 7L and NR 7L C(O), W1 is selected from CH2CH2O and C(O)CH2N(R) 8L j1 and j2 are each independently selected from integers from 0 to 6 each time they appear, j3 is each independently selected from 0 or 1 each time it appears, and r3 is each independently selected from integers from 1 to 30 each time it appears.

[0023] R w Selected from hydrogen, hydroxyl, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -NR7R 8L -C 1-6 Alkylene-NR7R 8L and -C(O)-NR7R 8L ;

[0024] R 6L R 7L and R 8L Each time it appears, it is independently selected from hydrogen and C. 1-6 alkyl;

[0025] Ar 1 and Ar 3Each of the following groups is independently selected from 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl, wherein each of the 3-10-membered heterocyclic and 5-10-membered heteroaryl groups independently comprises one, two, or three heteroatoms independently selected from N, O, S, and P, wherein the 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl groups are optionally substituted by one or more substituents selected from oxo, hydroxy, cyano, amino, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, and cycloalkyl groups;

[0026] In the formula, when r2 is 0, R 3L and R 4L At least one of them is R 2H R 2H -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w And j3 is not 0, and r3 is not 0;

[0027] L 1 Selected from Among them, L p’ Selected from single bonds, 6-10 arylene groups, and 5-8 heteroarylene groups, wherein the 5-8 heteroarylene group comprises one, two, or three heteroatoms each independently selected from N, O, and S, wherein the 6-10 arylene group and the 5-8 heteroarylene group are optionally separated by one or more R atoms. 5L replace;* L2 Indicates with L 2 The connection site, Indicates the connection site.

[0028] In one of the implementations, wherein,

[0029] Each occurrence of t is independently 0, 1, or 2; and / or

[0030] L p’ Selected from single-bonded, phenyl, fluorinated phenyl and pyridyl groups; and / or

[0031] Each occurrence of Z1 is independently a single bond, O, or S; preferably a single bond or O; more preferably O; and / or

[0032] Z2 is selected from single bonds, O, NH, N(C) 1-3 Alkyl), NHC(O) and N(C) 1-3 Alkyl)C(O), preferably, Z2 is selected from single bond, O, NH and NHC(O); and / or

[0033] W1 is selected from CH2CH2O and C(O)CH2N(C 1-3 Alkyl); preferably, W1 is CH2CH2O or C(O)CH2N(CH3); and / or

[0034] j1 and j2 are each independently selected from 0, 1, 2, 3, 4, and 5 each time they appear; preferably, j1 and j2 are 0, 1, or 2; and / or

[0035] Each occurrence of r3 is an independent integer selected from 6-30, preferably from 8-24, more preferably 8, 12, or 24; and / or

[0036] R w C 1-6 Alkyl or -C(O)-C 1-6 Alkyl group, preferably C 1-3 Alkyl or -C(O)-C 1-3 Alkyl groups, more preferably -CH3 or -C(O)CH3; and / or

[0037] R 1H and R 2H Each time it appears, it is selected independently. Among them, R 7L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups, j1, each time appearing independently selected from 0, 1, 2, 3, 4, 5, and 6; j2, each time appearing independently selected from 0, 1, 2, 3, 4, 5, and 6; preferably, R 1H and R 2H Each time it appears, it is selected independently. In this context, j1 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears.

[0038] Preferably, R 1H and R 2H Each time it appears, it is selected independently. and / or

[0039] Ar 1 and Ar 3 Each of these groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 Substituents of cycloalkyl groups;

[0040] Preferably, Ar 1 and Ar 3 Each of the following groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, and C. 1-6 Alkyl substituents;

[0041] Preferably, Ar 1 and Ar 3 Each time it appears, it is selected independently. Preferably, Ar 1 and Ar 3 Each time it appears, it is independent.

[0042] In one of the implementations, wherein,

[0043] The drug fraction D is camptothecin or a derivative thereof; preferably, the drug fraction D has the structure shown in formula (II-1) or (II-2):

[0044] R1, R3, R4, R5, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Alkoxy group; preferably, R1, R3 and R5 are hydrogen;

[0045] R2 and R6 are each independently selected from C(R1)2 and NR1; preferably, R2 and R6 are each independently C(R1)2; preferably, R2 and R6 are each independently CH2.

[0046] n1 and n2 are each independently selected from 1, 2, 3, 4, 5 and 6; preferably, n1 and n2 are each independently 1, 2 or 3; preferably, n1 and n2 are each independently 1, 2 or 3.

[0047] R4 and R8 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, preferably, R4 and R8 are each independently selected from hydrogen, fluorine and methyl; preferably, R4 is methyl and R8 is fluorine;

[0048] Preferably, the drug portion D is:

[0049] and / or

[0050] L 1 Selected from and / or

[0051] L p’ Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein the phenylene and the 5-8-membered heteroaryl group are each independently optionally separated by one or more R groups. 5L replace;

[0052] Preferably, L p’ Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, and wherein the phenylene and 5-8-membered heteroaryl groups are each independently selected by 1, 2, 3, 4, 5, or 6 R atoms. 5L replace;

[0053] Preferably, L p’ Selected from single bonds, phenylene, and pyridylene; wherein each of the phenylene and pyridylene groups is independently optionally surrounded by 1, 2, 3, or 4 R groups. 5L Replace; and / or

[0054] R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 cycloalkyl;

[0055] Preferably, R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl and -OC 1-3 alkyl;

[0056] Preferably, R 5L Each occurrence is independently selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3, preferably R. 5L For F;

[0057] Preferably, L p’The group is selected from single bonds, phenylene, and pyridinyl groups; wherein the phenylene and pyridinyl groups are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3;

[0058] Preferably, L p’ Selected from single bonds, in,* Lj Indicates with L j The connection site, * L2 Indicates with L 2 Connection sites; and / or

[0059] L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 Alkylene and C 1-6 One, two, or three or more of the heteroalkyl groups, wherein the C 1-6 Alkylene and C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. 1L replace;

[0060] Preferably, L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 A combination of one or more alkylene groups, wherein the C 1-6 Alkylene is optionally surrounded by one or more R 1L replace;

[0061] Preferably, L 2 Selected from single bond, -O-, * LL1 -NR 1L -C(O)-* L3 、* L1 -C 1-6 Alkylene-C(O)-NR 1L -* L3 、* L1 -C 1-6 Alkylene-OC(O)-NR 1L -* L3 and* L1 -C 1-6 Alkylene-NR 1L -C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; among which, * L1 Indicates with L 1 The connection site, * L3 Indicates with L 3Connection sites;

[0062] Preferably, L 2 Selected from single bond, -O-, * L1 -NH-C(O)-* L3 、* L1 -C 1-6 Alkylene-C(O)-NH-* L3 、* L1 -C 1-6 Alkylene-OC(O)-NH-* L3 and* L1 -C 1-6 Alkylene-NH-C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; and / or

[0063] R 1L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH;

[0064] Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -C. 1-6 Alkylene-NH2;

[0065] Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -methylene-NH2;

[0066] Preferably, L 2 Selected from single bond, -O-, * L1 -NH-C(O)-* L3 , and / or

[0067] L 3 for Among them, Ar 1 R 1H R 6L As defined in claim 1 or 2;

[0068] r1 is selected from 0, 1, 2, 3, 4, or 5; r2 is 0 or 1; where, * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites;

[0069] Preferably, L 3 Selected from * L2 -(CH2CH2O) r1 -CH2-Ar 1 -CH2-C(O)-* L4 ,

[0070] Preferably, R 1H Each time it appears, it is selected independently. Wherein, j1 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; preferably, j1 is independently 0, 2 or 4 each time it appears; preferably, j2 is independently 0, 1 or 2 each time it appears.

[0071] Preferably, R 1H Each time it appears, it is independent.

[0072] Preferably, L 3 Selected from and / or

[0073] L 4 It is a peptide containing 2, 3, 4, 5 or 6 amino acids, wherein the amino acids are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl.

[0074] Preferably, L 4 A peptide containing 2, 3, 4, 5, or 6 amino acids, wherein said amino acids are optionally converted by one or more groups selected from halogen, hydroxyl, cyano, amino, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 Substituents of cycloalkyl groups;

[0075] Preferably, L 4 A peptide containing 2, 3, 4, 5 or 6 amino acid residues selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid and aspartic acid.

[0076] Preferably, L 4 It is a dipeptide, tripeptide or tetrapeptide composed of amino acid residues selected from alanine, phenylalanine, glycine, lysine and citrulline.

[0077] Preferably, L 4 The peptide is selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine, glycine-glycine-phenylalanine-glycine, valine-citrulline and valine-alanine.

[0078] The amino acid is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, and cycloalkyl groups, preferably, optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, and C6 groups. 1-6 Alkyl substituents;

[0079] Preferably, L 4 Selected from in,* L3 Indicates with L 3 The connection site, * L5 Indicates with L 5 The connection site.

[0080] In one implementation, t is independently 0, 1, or 2 each time it occurs; and / or

[0081] Each occurrence of Z1 is independently a single bond, O, or S; preferably a single bond or O; more preferably O; and / or

[0082] Ar 2 Each occurrence is independently a phenylene group, which is optionally oxidized by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2 is substituted; preferably, Ar 2 Each time it appears independently and / or

[0083] R 1L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups; preferably selected from hydrogen and C. 1-3 Alkyl groups, preferably hydrogen; and / or

[0084] R 3L and R 4L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl and R 2H;wherein, j1 is independently selected from 0, 1, 2, 3, and 4 each time it appears, preferably 1; r3 is selected from integers from 1 to 30; and / or

[0085] L 5 -D is selected from

[0086] R 2H Selected from In this case, j1 is independently 0, 1, or 2 each time it appears;

[0087] Preferably, L5-D is selected from Each time r3 appears, it is independently selected from an integer between 8 and 24, preferably 8, 12, or 24.

[0088] In one embodiment, the connector L is selected from:

[0089] Among them, n17 is selected from 8, 12, and 24 each time; Indicates the connection site.

[0090] In one embodiment, the ligand-drug conjugate is selected from the following structures:

[0091] Wherein, n is an integer or decimal from 1 to 10; preferably, n is an integer or decimal from 3 to 8; Ab is a ligand.

[0092] The first aspect of the present invention provides a linker compound of formula I or a pharmaceutically acceptable salt thereof, L j -L p -L 2 -L 3 -L 4 -L 5 -G (Formula I);

[0093] In the formula,

[0094] G is a leaving group;

[0095] L j for Among them, XS For single bonds or N(C) 1-6 alkyl);

[0096] Each time R appears, it is an independent thiol reactive group;

[0097] L p Selected from single bonds, 6-10 arylene groups, and 5-8 heteroarylene groups, wherein the 5-8 heteroarylene group comprises one, two, or three heteroatoms each independently selected from N, O, and S, wherein the 6-10 arylene group and the 5-8 heteroarylene group are optionally separated by one or more R atoms. 5L replace;

[0098] L 2 Selected from single bonds, alkyne groups, alkenyl groups, and -NR groups. 1L Combinations of one, two, three, or more of -, -O-, -C(O)-, alkylene, and heteroalkylene, wherein the ynylene, alkenylene, alkylene, and heteroalkylene are optionally represented by one or more R 1L replace;

[0099] L 3 for

[0100] Where r1 is selected from integers between 0 and 20;

[0101] r2 is selected from 0, 1, and 2;

[0102] * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites;

[0103] L 4 It is a peptide residue containing 2 to 7 amino acid residues, wherein the amino acid is optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl;

[0104] L 5 Selected from single key, * L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -C(=O)-* G 、* L4 -NR 2L (CR 3L R 4L ) t -*G 、* L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -Z1-C(=O)-* G and* L4 -NR 2L -Ar 2 -(CR 3L R 4L ) t -Z1-C(=O)-* G ;* L4 Indicates with L 4 The connection site, * G Indicates the connection site with G;

[0105] Wherein, t is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; Z1 is independently selected as a single bond, O, S, or NH each time it appears; Ar 2 Each occurrence is independently an arylene or heteroarylene, the heteroarylene containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the arylene or heteroarylene is optionally surrounded by one or more atoms selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Substitution of alkyl group 2;

[0106] R 1L R 2L and R 5L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH;

[0107] R 3L and R 4L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-6 alkylene-OH and R 2H ;

[0108] R 1H and R 2H Each occurrence is independently -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w Z2 is selected from single bonds, O, and NR. 7L and NR 7L C(O), W1 is selected from CH2CH2O and C(O)CH2N(R) 8L j1 and j2 are each independently selected from integers from 0 to 6 each time they appear, j3 is each independently selected from 0 or 1 each time it appears, and r3 is each independently selected from integers from 1 to 30 each time it appears.

[0109] R w Selected from hydrogen, hydroxyl, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -NR7R 8L -C 1-6 Alkylene-NR7R 8L and -C(O)-NR7R 8L ;

[0110] R 6L R 7L and R 8L Each time it appears, it is independently selected from hydrogen and C. 1-6 alkyl;

[0111] Ar 1 and Ar 3 Each of the following groups is independently selected from 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl, wherein each of the 3-10-membered heterocyclic and 5-10-membered heteroaryl groups independently comprises one, two, or three heteroatoms independently selected from N, O, S, and P, wherein the 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl groups are optionally substituted by one or more substituents selected from oxo, hydroxy, cyano, amino, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, and cycloalkyl groups;

[0112] In the formula, when r2 is 0, R 3L and R 4L At least one of them is R 2H R 2H -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2-Z2-(W1) r3 -R w And j3 is not 0, and r3 is not 0.

[0113] In one of the implementations, wherein,

[0114] Z2 is selected from single bonds, O, NH, N(C) 1-3 Alkyl), NHC(O) and N(C) 1-3 Alkyl)C(O), preferably, Z2 is selected from single bond, O, NH and NHC(O); and / or

[0115] W1 is selected from CH2CH2O and C(O)CH2N(C 1-3 Alkyl); preferably CH2CH2O or C(O)CH2N(CH3); and / or

[0116] j1 and j2 are each independently selected from 0, 1, 2, 3, 4, and 5 each time they appear, preferably 0, 1, or 2; and / or

[0117] Each occurrence of r3 is an independent integer selected from 6-30, preferably from 8-24, more preferably 8, 12, or 24; and / or

[0118] R w C 1-6 Alkyl or -C(O)-C 1-6 Alkyl group, preferably C 1-3 Alkyl or -C(O)-C 1-3 Alkyl groups, more preferably -CH3 or -C(O)CH3; and / or

[0119] R 1H and R 2H Each time it appears, it is selected independently. Among them, R 7L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups, j1 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears;

[0120] Preferably, R 1H and R 2H Each time it appears, it is selected independently. In this context, j1 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears.

[0121] Preferably, R 1H and R 2HEach time it appears, it is selected independently.

[0122] In one of the implementations, wherein,

[0123] Ar 1 and Ar 3 Each of these groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 Substituents of cycloalkyl groups;

[0124] Preferably, Ar 1 and Ar 3 Each of the following groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, and C. 1-6 Alkyl substituents;

[0125] Preferably, Ar 1 and Ar 3 Each time it appears, it is selected independently. Preferably, Ar 1 and Ar 3 Each time it appears, it is independent.

[0126] In one of the implementations, X S It is a single bond or N(CH3); each time R appears, it is an independently reactive mercapto group;

[0127] Preferably, each occurrence of R is independently selected from halogens and -S-Ar. 4 More preferably, each occurrence of R is independently selected from F, Cl, Br, I, and -S-Ar;

[0128] Ar 4 Selected from phenyl, C 1-6 Alkylphenyl-, C 1-6 Alkoxyphenyl-, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl, C 1-6 Alkylphenyl-, C 1-6 alkoxyphenyl-, 2-pyridyl, 2-pyrimidinyl, and 1-methylimidazol-2-yl are optionally surrounded by 1, 2, 3, or 4 R groups. a Substitution; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl The phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, and 1-methylimidazol-2-yl are optionally surrounded by 1, 2, or 3 R groups. a replace;

[0129] W2 is selected from amino, -NR a -C 1-6 Alkyl, -NR a -C 1-6 Alkoxy, -NR a -C 1-6 Alkylene-NR b R c -NR a -C 1-6 Alkylene-C 1-6 Alkoxy and 5 to 8-membered heterocyclic alkyl groups, wherein the 5 to 8-membered heterocyclic alkyl groups contain 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms, wherein the S atom may optionally be substituted by 1 or 2 oxo groups;

[0130] R a Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH;

[0131] R b R c Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0132] Preferably, W2 is selected from amino, -NR a -C 1-6 alkyl,

[0133] Preferably, R is independently selected from halogens each time it appears. More preferably, R is selected independently each time it appears, choosing chlorine, bromine,

[0134] Preferably, L j Selected from More preferably, L j Selected from

[0135] In one implementation, L p Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein the phenylene and the 5-8-membered heteroaryl group are each independently optionally separated by one or more R groups. 5L replace;

[0136] Preferably, L p Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein the phenylene and the 5-8-membered heteroaryl group are each independently optionally separated by 1, 2, 3, 4, 5, or 6 R atoms. 5L replace;

[0137] Preferably, L p Selected from single bonds, phenylene, and pyridylene; wherein each of the phenylene and pyridylene groups is independently optionally surrounded by 1, 2, 3, or 4 R groups. 5L Replace; and / or

[0138] R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 cycloalkyl;

[0139] Preferably, R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl and -OC 1-3 alkyl;

[0140] Preferably, R 5L Each occurrence is independently selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3, preferably R. 5L For F;

[0141] Preferably, L p The group is selected from single bonds, phenylene, and pyridinyl groups; wherein the phenylene and pyridinyl groups are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3;

[0142] Preferably, L p Selected from single bonds, in,* Lj Indicates with L j The connection site, * L2 Indicates with L 2 The connection site.

[0143] In one implementation, L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1- 6-alkylene and C 1-6 One, two, or three or more of the heteroalkyl groups, wherein the C 1-6 Alkylene and C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. 1L replace;

[0144] Preferably, L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 A combination of one or more alkylene groups, wherein the C 1-6 Alkylene is optionally surrounded by one or more R 1L replace;

[0145] Preferably, L 2 Selected from single bond, -O-, * Lp -NR 1L -C(O)-* L3 、* Lp -C 1-6 Alkylene-C(O)-NR 1L -* L3 、* Lp -C 1-6 Alkylene-OC(O)-NR 1L -* L3 and* Lp -C 1-6 Alkylene-NR 1L -C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; among which, * Lp Indicates with L p The connection site, *L3 Indicates with L 3 Connection sites;

[0146] Preferably, L 2 Selected from single bond, -O-, * Lp -NH-C(O)-* L3 、* Lp -C 1-6 Alkylene-C(O)-NH-* L3 、* Lp -C 1-6 Alkylene-OC(O)-NH-* L3 and* Lp -C 1-6 Alkylene-NH-C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; and / or

[0147] R 1L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH;

[0148] Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -C. 1-6 Alkylene-NH2;

[0149] Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -methylene-NH2;

[0150] Preferably, L 2 Selected from single bond, -O-, * Lp -NH-C(O)-* L3 ,

[0151] In one implementation, L 3 for Among them, Ar 1 R 1H R 6L As defined in any of the preceding items;

[0152] r1 is selected from 0, 1, 2, 3, 4, or 5; r2 is 0 or 1; where, * L2 Indicates with L 2 The connection site, * L4 Indicates with L4 Connection sites;

[0153] Preferably, L 3 Selected from * L2 -(CH2CH2O) r1 -CH2-Ar 1 -CH2-C(O)-* L4 ,

[0154] Preferably, R 1H Each time it appears, it is selected independently. Wherein, j1 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; preferably, j1 is independently 0, 2 or 4 each time it appears; preferably, j2 is independently 0, 1 or 2 each time it appears.

[0155] Preferably, R 1H Each time it appears, it is independent.

[0156] Preferably, L 3 Selected from

[0157] In one implementation, L 4 It is a peptide containing 2, 3, 4, 5 or 6 amino acids, wherein the amino acids are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl.

[0158] Preferably, L 4 A peptide containing 2, 3, 4, 5, or 6 amino acids, wherein said amino acids are optionally converted by one or more groups selected from halogen, hydroxyl, cyano, amino, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 Substituents of cycloalkyl groups;

[0159] Preferably, L 4 A peptide containing 2, 3, 4, 5 or 6 amino acid residues selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid and aspartic acid.

[0160] Preferably, L 4It is a dipeptide, tripeptide or tetrapeptide composed of amino acid residues selected from alanine, phenylalanine, glycine, lysine and citrulline.

[0161] Preferably, L 4 The peptide is selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine, glycine-glycine-phenylalanine-glycine, valine-citrulline and valine-alanine.

[0162] The amino acid is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, and cycloalkyl groups, preferably, optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, and C6 groups. 1-6 Alkyl substituents;

[0163] Preferably, L 4 Selected from in,* L3 Indicates with L 3 The connection site, * L5 Indicates with L 5 The connection site.

[0164] In one implementation, t is independently 0, 1, or 2 each time it occurs; and / or

[0165] Each occurrence of Z1 is independently a single bond, O, or S; preferably a single bond or O; more preferably O; and / or

[0166] Ar 2 Each occurrence is independently a phenylene group, which is optionally oxidized by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2 is substituted; preferably, Ar 2 Each time it appears independently and / or

[0167] R 1L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups; preferably selected from hydrogen and C. 1-3 Alkyl groups, preferably hydrogen; and / or

[0168] R 3L and R 4L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl and R2H ; where j1 is selected independently from 0, 1, 2, 3 and 4 each time it appears, preferably 1; r3 is selected from integers from 1 to 30;

[0169] Preferably, L5-G is selected from

[0170] Preferably, R 2H Selected from In this case, j1 is independently 0, 1, or 2 each time it appears;

[0171] Preferably, L5-G is selected from Each time r3 appears, it is independently selected from an integer between 8 and 24, preferably 8, 12, or 24.

[0172] In one embodiment, G is selected from halogen, hydroxyl, -Ots, -O-(4-nitrophenyl) and -ONO2.

[0173] In one embodiment, the compound is selected from:

[0174] Wherein, r3 is independently selected from an integer from 1 to 30 each time it appears, preferably from an integer from 6 to 30, more preferably from an integer from 8 to 24, and even more preferably from 8, 12, or 24; preferably, the compound is selected from:

[0175] A third aspect of the present invention provides a compound as shown in Formula II or a pharmaceutically acceptable salt thereof, L j -L p -L 2 -L 3 -L 4 -L 5 -D (Formula II);

[0176] In the formula, L j L p L 2 L 3 L 4 L 5 As defined in any of the preceding items;

[0177] Wherein, D is a drug; preferably, the drug D is a drug for treating cancer, preferably, the drug D is camptothecin or a derivative thereof; preferably, the drug D has the structure shown in formula (II-1) or (II-2):

[0178] R1, R3, R4, R5, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Alkyl group; R2 and R6 are each independently selected from C(R1)2 and NR1; preferably C(R1)2; preferably CH2;

[0179] n1 and n2 are each independently selected from 1, 2, 3, 4, 5 and 6; preferably 1, 2 or 3;

[0180] Preferably, R1, R3, and R5 are hydrogen; and / or

[0181] R4 and R8 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, preferably, R4 and R8 are each independently selected from hydrogen, fluorine and methyl; preferably, R4 is methyl and R8 is fluorine;

[0182] Preferably, the drug portion D is:

[0183] In one embodiment, the compound is selected from:

[0184] A fourth aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof, selected from...

[0185] The fifth aspect of this invention provides a ligand-drug conjugate with the structure shown in Formula 3-1 or a pharmaceutically acceptable salt thereof.

[0186] Where Abs is the ligand, Ls is the linker, and Ds is the drug moiety;

[0187] ns is any integer or decimal from 1 to 15; preferably, ns is any integer or decimal from 1 to 13; preferably, ns is any integer or decimal from 3 to 10.

[0188] The drug component Ds can be any of the following structures.

[0189] Indicates the connection site.

[0190] The sixth aspect of this invention provides a ligand-drug conjugate with the structure shown in Formula 3-2 or a pharmaceutically acceptable salt thereof.

[0191] Where Abs is the ligand, Ls is the linker, and Ds is the drug moiety;

[0192] ns is any integer or decimal from 1 to 15; preferably, ns is any integer or decimal from 1 to 13; preferably, ns is any integer or decimal from 3 to 10.

[0193] The connecting portion Ls is a connector L as defined in any of the preceding items; or the Ls includes -L 1s -;

[0194] L 1s Selected from -(succinimide-3-yl-N)-, -(succinimide-3-yl-N)-Ws-C(=O)-, The left side connects to the ligand portion;

[0195] Among them, Ws is selected from C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Ws is C 1-8 Alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 The heteroalkylene group comprises 1 to 3 heteroatoms independently selected from N, O, or S, wherein the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups. Preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, C groups, and S groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 The cycloalkyl group is substituted with one or more substituents; more preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally selected from halogens, -OH, -CN, and C. 1-3 Alkyl and -OC 1-3 The alkyl substituents are substituted, preferably, the alkylene, cycloalkylene and heteroalkylene are unsubstituted or optionally substituted with substituents selected from Cl, Br, F, -OH, -CN, methyl and -OCH3;

[0196] Xs is selected from single bond, C 1-10 Alkylene, C 1-10alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Xs is selected from single bond, C 1-8 Alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 Heteroalkyl;

[0197] The drug component Ds can be any of the following structures.

[0198] Indicates the connection site.

[0199] In one implementation, the connection portion Ls is -L 1s -L 2s -L 3s -L 4s -;

[0200] L 1s Selected from -(succinimide-3-yl-N)-, -(succinimide-3-yl-N)-Ws-C(=O)-, Preferably, L 1s Selected from

[0201] Among them, Ws is selected from C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Ws is C 1-8 Alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 The heteroalkylene group comprises 1 to 3 heteroatoms independently selected from N, O, or S, wherein the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups. Preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, C groups, and S groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C5-8 The cycloalkyl group is substituted with one or more substituents; more preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally selected from halogens, -OH, -CN, and C. 1-3 Alkyl and -OC 1-3 The alkyl substituents are substituted, preferably, the alkylene, cycloalkylene and heteroalkylene are unsubstituted or optionally substituted with substituents selected from Cl, Br, F, -OH, -CN, methyl and -OCH3;

[0202] Xs is selected from single bond, C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Xs is selected from single bond, C 1-8 Alkylene, C 1- 8-alkylene-cycloalkylene or C 1-8 Heteroalkyl;

[0203] Preferably, L 1s Selected from Preferably, L 1s Selected from

[0204] L 2s Selected from -(CH2CH2O) rs CH2CH2C(=O)-、-(CH2CH2O) rs C(=O)-、-NR 1Ls (CH2CH2O) rs C(=O)-、-(CH2CH2O) rs CH2C(=O)-、-NR 1Ls (CH2CH2O) rs CH2CH2C(=O)-、-NR 1Ls (CH2CH2O) rs CH2C(=O)-、-NR 1Ls CH2-Ar 1s -(CH2CH2O) rs CH2CH2NR 1Ls C(=O)CH2OCH2C(=O)-、-NR 1Ls (CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) r sCH2CH2C(=O)-、-S-(CH2) rs C(=O)-、-O-(CH2CH2O)rs CH2-Ar 1s -(CH2CH2O) rs CH2CH2C(=O)-、-O-(CH2CH2O) rs CH2-Ar 1s -CH2C(=O)-、-CH(CH2NH2)NR 1Ls C(=O)-(CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) rs CH2CH2C(=O)-、 Or a single key, where rs is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and n17s is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 each time it appears; js is independently selected from 0, 1, 2, 3, 4, 5, 6 each time it appears; preferably rs is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; preferably, L 2s Selected from Where rs is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and n17s is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 each time it appears; js is independently selected from 0, 1, 2, 3, 4, 5, 6 each time it appears; preferably, rs is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; preferably, L 2s Selected from -NR 1Ls (CH2CH2O) rs CH2CH2C(=O)-、-O-(CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) rs CH2CH2C(=O)-、-O-(CH2CH2O) rs CH2-Ar 1s -CH2C(=O)-; rs is an integer of 1, 2, 3, 4, or 5; preferably, L 2s Selected from Ar 1sSelected from 6-10 aryl groups, 5-10 heteroaryl groups containing 1-3 heteroatoms independently selected from N, O, P, and S, 3-10 cycloalkyl groups, or 3-10 heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, P, and S; preferably, Ar 1s Selected from Preferably, Ar 1s Selected from L 3s A peptide consisting of 2 to 7 amino acid residues, preferably L 3s A peptide consisting of 2, 3, 4, 5, or 6 amino acid residues, wherein the amino acids are unsubstituted or optionally further substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups, preferably, optionally further substituted by substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, C groups, and cycloalkyl groups. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 The cycloalkyl group is substituted by one or more substituents;

[0205] L 4s Selected from -NR 2Ls (CR 3L R 4L ) ts -Z-(CR 3Ls R 4Ls ) ts -C(=O)-、-NR 2Ls (CR 3Ls R 4Ls ) ts -、-NR 2Ls (CR 3Ls R 4Ls ) ts -Zs-(CR 3Ls R 4L ) ts -Zs-C(=O)-、 -NR 2s -Ar 2s -(CR 3Ls R 4Ls ) ts -Zs-C(=O)-、-NR 2s -Ar 2s -(CR 3Ls R 4Ls ) ts -Zs-C(=O)-NR 2s -(CR 3Ls R4Ls ) ts -NR 2s -、-NR 2s -(CR 3Ls R 4Ls ) ts -NR 2s - or single bond, where ts is an integer of 0, 1, 2, 3, 4, 5, or 6 each time it appears; Zs is a single bond, O, S, or -NH- each time it appears; Ar 2s It is an arylene or heteroarylene, preferably selected from 6-membered arylene or 5-8-membered heteroarylene, wherein the heteroarylene contains 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S; the arylene or heteroarylene is unsubstituted or optionally selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), and -N(C) 1-6 Alkyl)2 is substituted; preferably, L 4s Selected from -NR 2Ls (CR 3Ls R 4Ls ) ts -、-NR 2Ls -Ar 2s -(CR 3Ls R 4Ls ) ts -ZC(=O)-;-NR 2Ls -Ar 2s -(CR 3Ls R 4Ls ) ts -Zs-C(=O)-NR 2Ls -(CR 3Ls R 4sL ) ts -NR 2Ls -C(=O)-、-NR 2Ls -(CR 3Ls R 4Ls ) ts -NR 2Ls -C (=O)- or single key, where ts is an independent integer of 1, 2, or 3 each time it appears; Zs is an independent integer of 0 each time it appears; Ar 2s The arylene group is unsubstituted or optionally selected from H, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Alkyl group substitution; preferably, L 4sSelected from single bonds, -NH-CH2-, -NH-phenylene-CH2-O-CO-, -NH-phenylene-CH2-O-CO-N(CH3)-CH2-CH2-N(CH3)-CO-, -N(CH3)-CH2-CH2-N(CH3)-CO-;

[0206] R 1Ls and R 2Ls Whether the elements are the same or different, and each occurrence is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and -C 1-6 alkylene-OH;

[0207] R 3Ls and R 4Ls Whether the elements are the same or different, and each occurrence is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and -C 1-6 alkylene-OH; and

[0208] L 1s The end is connected to the ligand, L 4s The end is connected to the drug portion.

[0209] In one of the implementations, L 3s It is a peptide residue composed of 2-6 amino acids selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid, and aspartic acid; preferably, it is a dipeptide, tripeptide, or tetrapeptide residue composed of alanine, phenylalanine, glycine, lysine, and citrulline; preferably, L 3s The peptide residues are selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine-glycine, valine-citrulline, and valine-alanine.

[0210] The peptide residues are either unsubstituted or optionally further substituted with one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups, preferably, optionally further substituted with substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, and C groups. 1-6 Alkyl substituent substitution. In one embodiment, the linking moiety Ls is selected from:

[0211] Preferably,

[0212] in Indicates the connection site.

[0213] In one embodiment, the ligand-drug conjugate is selected from the following structures:

[0214] Preferably:

[0215] Wherein, ns is an integer or decimal from 1 to 10; preferably, ns is an integer or decimal from 3 to 8;

[0216] Abs is a ligand.

[0217] In one implementation, L js -L 2s -L 3s –L 4s -Ds(Equation 5-1);

[0218] Where -L 2s -、-L 3s -、-L 4s - and -Ds are as defined in any of the preceding items;

[0219] L js Selected from

[0220] And Ws, Xs as defined in any one of claims 22-26, preferably, L js Selected from

[0221] In one of the implementation schemes,

[0222] Preferably,

[0223] In one embodiment, the Ab or Abs is an antibody or its antigen-binding fragment or polypeptide, wherein the antibody is selected from chimeric antibodies, humanized antibodies and fully human antibodies.

[0224] Preferably, the antibody or its antigen-binding fragment is selected from anti-TROP-2 antibody, anti-HER2 antibody, anti-NECTIN4 antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis antibody, etc. The antibody, or anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody, or an antigen-binding fragment thereof; preferably, the antibody or antigen-binding fragment thereof is selected from anti-B7-H3 antibody or an antigen-binding fragment thereof; preferably, the amino acid sequence pair of the anti-B7-H3 antibody is selected from SEQ ID NO:1 and SEQ ID NO:2, and SEQ ID NO:3 and SEQ ID NO:4.

[0225] A seventh aspect of the invention provides a ligand-drug conjugate, wherein the compound described above is used as the small molecule toxin portion of the drug.

[0226] The eighth aspect of the present invention provides a ligand-drug conjugate comprising a covalently linked antibody or antigen-binding fragment thereof and a linker-small molecule toxin moiety, wherein a compound described in any of the preceding claims is used as the linker-drug moiety in the drug.

[0227] A ninth aspect of the present invention provides a pharmaceutical composition comprising an effective amount of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof or a ligand-drug conjugate according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0228] The tenth aspect of this invention provides the use of any of the compounds described in any of the preceding claims or pharmaceutically acceptable salts thereof, or ligand-drug conjugates described in any of the preceding claims or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in the preceding claims in the preparation of a medicament for treating or preventing tumors.

[0229] The eleventh aspect of the present invention provides a method for preventing or treating tumors, comprising administering to a subject in need an effective amount of any of the compounds described in any of the preceding statements or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate described in any of the preceding statements or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the preceding statements.

[0230] The twelfth aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof described in any of the preceding claims, or a ligand-drug conjugate or a pharmaceutically acceptable salt thereof described in any of the preceding claims, or a pharmaceutical composition thereof described in the preceding claims, for the prevention or treatment of tumors.

[0231] The thirteenth aspect of the present invention provides the use of the compound described above or a salt thereof, characterized in that it is used as a toxin in an antibody-drug conjugate to prepare the antibody-drug conjugate.

[0232] The eighth aspect of the present invention provides the use of the compounds described in any of the preceding descriptions for preparing ligand-drug conjugates, the ligand-drug conjugates comprising a covalently linked antibody or antigen-binding fragment thereof and a linker-drug moiety, wherein the linker-drug moiety is a compound described in any of the preceding descriptions. Detailed Implementation

[0233] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0234] Terms and Definitions

[0235] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art.

[0236] Some compounds of the present invention may exist in a free form or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereomers and enantiomers), tautomers, solvates, polymorphs, and isotopic compounds, which, when administered to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

[0237] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid and base of a particular compound without any adverse biological effects. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, which are salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as malic acid, fumaric acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, acrylic acid, mandelic acid, etc.; or (2) base addition salts, which are salts formed with alkali metals such as lithium, sodium, potassium, etc.; salts formed with alkaline earth metals such as calcium, magnesium, etc.; and salts formed with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucosamine, triethanolamine, dehydrorosinamine, etc. Other pharmaceutically acceptable salts are known to those skilled in the art.

[0238] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted in vivo into the desired compound. Therefore, the term "administration" in the treatment methods provided by this invention includes administering the compounds disclosed in this invention, or, although not explicitly disclosed, being converted in vivo into the compounds disclosed in this invention to treat the various diseases. Conventional methods for selecting and preparing suitable drug prodrug derivatives have been described in books such as *Design of Prodrugs* (H. Bundgaard, Elsevier, 1985).

[0239] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0240] The compounds of this invention do not have a precisely defined stereostructure at any particular position. This invention includes all stereoisomers of the compounds and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in this invention. In the synthesis of such compounds, or in the use of racemic or epimerization methods known to those skilled in the art, the resulting products may be mixtures of stereoisomers.

[0241] When tautomers of the compounds of this invention are present, unless otherwise stated, this invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0242] The invention encompasses any possible solvates and polymorphs when the compounds of the invention and their pharmaceutically acceptable salts are present in solvate or polymorphic form. There are no particular limitations on the type of solvent forming the solvate, provided that the solvent is pharmacologically acceptable. For example, solvents such as water, ethanol, propanol, and acetone may be used.

[0243] This invention also includes all pharmaceutically acceptable isotopic compounds identical to those of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2H), tritium (3H)); isotopes of carbon (e.g., 13C and 14C); isotopes of chlorine (e.g., 37Cl); isotopes of iodine (e.g., 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 17O and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 34S).

[0244] The term "ligand" is a macromolecular compound that recognizes and binds to antigens or receptors associated with target cells. The role of the ligand is to deliver the drug to the target cell population that has bound to it. In embodiments of this invention, the ligand is denoted as Ab. The ligand can form a linker bond with a linker unit via heteroatoms on the ligand, preferably an antibody or its antigen-binding fragment or polypeptide. The antibody is selected from chimeric antibodies, humanized antibodies, fully human antibodies, or murine antibodies; preferably, it is a monoclonal antibody.

[0245] The term "drug" refers to a cytotoxic drug, denoted as D or Ds, which is a chemical molecule that can strongly disrupt the normal growth of tumor cells.

[0246] The terms "connector unit," "connector fragment," "connector unit," "connector part," or "connector" refer to a chemical structural fragment or bond that is connected to a ligand at one end and to a drug at the other end. It can connect to other connectors before being connected to the drug.

[0247] The maleimide ring in the double-conjugated bridging ADC can be either open-ring or closed-ring, and the linker portion in the corresponding coupling compound... It will become When referring to closed-loop forms, open-loop forms are also included, and vice versa.

[0248] The term "ligand-drug conjugate" refers to a ligand linked to a biologically active drug via a stable linker unit. In this disclosure, "ligand-drug conjugate" is preferably an antibody-drug conjugate (ADC), which refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a stable linker unit.

[0249] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0250] The term "antibody" refers to immunoglobulin, a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and sequence of the constant region of the heavy chain of immunoglobulins differ, thus their antigenicity also differs. Based on this, immunoglobulins can be divided into five classes, or isotypes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε chains, respectively. Within the same class of Ig, differences in the amino acid composition of the hinge region and the number and position of disulfide bonds in the heavy chain can further divide them into different subclasses; for example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. The light chains are classified as κ or λ chains based on differences in the constant region. Each of the five classes of Ig can have either a κ chain or a λ chain. The antibodies described in this disclosure are preferably specific antibodies against cell surface antigens on target cells. Non-limiting examples include the following antibodies: anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-NECTIN4 antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, and anti-Lewis antibody. The antibody or its antigen-binding fragment is an anti-VEGFR antibody, an anti-GPNMB antibody, an anti-Integrin antibody, an anti-PSMA antibody, an anti-Tenascin-C antibody, an anti-SLC44A4 antibody, an anti-Mesothelin antibody, or an antigen-binding fragment thereof; more preferably, the antibody or its antigen-binding fragment is an anti-B7-H3 antibody, an anti-NECTIN4 antibody, an anti-HER2 (ErbB2) antibody, or an antigen-binding fragment thereof.

[0251] The antibodies of the present invention include murine antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies, with humanized antibodies and fully human antibodies being preferred.

[0252] In this invention, the term "mouse antibody" refers to an antibody prepared using mice based on knowledge and skills in the art. Preparation involves injecting the test subject with a specific antigen, followed by isolating a hybridoma expressing an antibody with the desired sequence or functional characteristics.

[0253] The term "chimeric antibody" refers to an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody. It can reduce the immune response induced by murine antibodies. To create a chimeric antibody, a hybridoma that secretes murine-specific monoclonal antibodies must first be established. Then, the variable region gene is cloned from the murine hybridoma cells. Next, the constant region gene of the human antibody is cloned as needed. The murine variable region gene and the human constant region gene are then linked to form a chimeric gene, which is inserted into an expression vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic system.

[0254] The term "humanized antibody," also known as a CDR-grafted antibody, refers to an antibody produced by grafting a mouse CDR sequence into the variable region framework of a human antibody, i.e., into a framework sequence of a different type of human germline antibody. This can overcome the heterologous response induced by chimeric antibodies carrying a large amount of mouse protein components.

[0255] The term "fully human antibody," also known as "fully human monoclonal antibody," refers to an antibody whose variable and constant regions are both human-derived, thus eliminating immunogenicity and toxic side effects.

[0256] The term “antigen-binding fragment” refers to one or more fragments of an antibody that maintain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used for antigen-binding function. Examples of binding fragments included in “antigen-binding fragments” include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by disulfide bridges on hinge regions; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VH and VL domains of a single arm of the antibody; (v) single-domain or dAb fragments (Ward et al., (1989) Nature 341: 544-546) consisting of a VH domain; and (vi) separate complementarity-determining regions (CDRs) or (vii) combinations of two or more separate CDRs optionally connected by synthetic linkers. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked by synthetic linkers using recombinant methods, thereby enabling the production of a single protein chain in which the VL and VH regions pair to form a monovalent molecule (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). Such single-chain antibodies are also intended to be included in the term "antigen-binding fragment" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and fragments are screened for functionality in the same manner as for intact antibodies. Antigen-binding moieties can be generated by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.

[0257] Fab is an antibody fragment with a molecular weight of approximately 50,000 and antigen-binding activity obtained by treating IgG antibody molecules with the protease papain (which cleaves the amino acid residue at position 224 of the H chain). Approximately half of the N-terminal side of the H chain and the entire L chain are linked together by disulfide bonds.

[0258] F(ab')2 is an antibody fragment with a molecular weight of approximately 100,000, possessing antigen-binding activity, and containing two Fab regions connected at the hinge position, obtained by digesting the portion below the two disulfide bonds in the hinge region of IgG with the enzyme pepsin.

[0259] Fab' is an antibody fragment with a molecular weight of approximately 50,000 and antigen-binding activity obtained by cleaving the disulfide bonds in the hinge region of the aforementioned F(ab')2.

[0260] In addition, the Fab' can be produced by inserting DNA encoding the Fab' fragment of an antibody into a prokaryotic or eukaryotic expression vector and then introducing the vector into a prokaryote or eukaryote to express the Fab'.

[0261] The terms “single-chain antibody,” “single-chain Fv,” or “scFv” refer to molecules containing a variable domain (or region; VH) of the antibody heavy chain and a variable domain (or region; VL) of the antibody light chain linked by a linker. Such scFv molecules may have a general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeating GGGGS amino acid sequences or variants thereof, for example, using variants with 1–4 repeats (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444–6448). Other connectors that may be used in this disclosure are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56 and Roovers et al. (2001), Cancer Immunol.

[0262] The term "CDR" refers to one of the six hypervariable regions within the variable domain of an antibody that primarily facilitate antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat EA et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242. As used herein, the Kabat definition of CDR 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.

[0263] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, most preferably an alkyl group containing 1 to 6 carbon atoms, and even more preferably an alkyl group containing 1 to 3 carbon atoms. The term "C" 1-6 "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). For example, "C1-6 "alkyl" can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, etc.

[0264] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0265] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, sulfur, or sulfur groups (e.g., S(O)₂), and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 ring atoms are heteroatoms; more preferably, the cycloalkyl ring comprises 3 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0266] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, with phenyl being more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.

[0267] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring.

[0268] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogen groups.

[0269] The term "deuterated alkyl" refers to an alkyl group that has been replaced by one or more deuterium atoms.

[0270] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0271] The term "drug fraction" or the code "D" refers to any compound that has the desired biological activity and reactive functional groups for the preparation of the conjugates described in this invention.

[0272] The term "cytotoxic drugs" refers to a class of drugs that can effectively kill tumor cells and inhibit their proliferation. These include topoisomerase I (TOP1) inhibitors, tubulin polymerization inhibitors, topoisomerase II (TOP2) inhibitors, dihydrofolate reductase inhibitors, thymidine synthase inhibitors, purine nucleoside synthase inhibitors, nucleotide reductase inhibitors, DNA polymerase inhibitors, RNA polymerase II inhibitors, and other compounds that can inhibit cell proliferation. Topoisomerase I (TOP1) inhibitors include, but are not limited to, camptothecin derivatives such as SN-38, Dxd, and Dx-8951; tubulin polymerization inhibitors such as eryribulin, MMAE, MMAF, and maytansine; and topoisomerase II inhibitors such as doxorubicin (structure shown below):

[0273] The term "camptothecin derivatives" refers to pyrrolquinoline alkaloid derivatives, such as:

[0274] wait.

[0275] The terms “substitution” and “substituted” refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0276] If a substituent is described as “optionally…substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. If a substituent is described as “independently selected” or “each independently is,” then each substituent is selected independently of the others. Thus, each substituent may be the same as or different from another (other) substituent. For example, a substituent or substitution position or different substituents or substitution positions may have R groups (e.g., but not limited to R) that may have the same or different symbols. 1L R 2L R 3L When choosing R2 and R3, each R is selected independently; they can be the same or different. The same applies to the selection of numerical values ​​such as d, g, m, and n.

[0277] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0278] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0279] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0280] In this invention, "pharmaceuticalally acceptable carrier" refers to a diluent, excipient, formulation, or mediator administered co-administered with the active ingredient, and which, to the extent of reasonable medical judgment, is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat one or more symptoms of a target disease or condition.

[0281] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0282] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of the condition or illness to which the term is applied, or one or more symptoms of the condition or illness, or to prevent the condition or illness, or one or more symptoms of the condition or illness.

[0283] Example

[0284] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, all chemical raw materials and reagents used in the following examples are commercially available products. The abbreviations appearing in this document and their meanings are as follows:

[0285] Table 1. Abbreviations and their meanings

[0286] Cell name and origin

[0287] Unless otherwise stated, the cell lines or cell strains used in the embodiments of this invention can be obtained commercially.

[0288] SK-BR-3 cell line was purchased from Nanjing Berry Genomics Co., Ltd.

[0289] The NCI-N87 cell line was purchased from Nanjing Berry Genomics Co., Ltd.

[0290] T47D cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0291] MDA-MB-453 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0292] A375 cell line, purchased from ATCC;

[0293] The NCI-H1703 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0294] Example 1:

[0295] Synthesis route:

[0296] Synthesis of intermediates 1-2:

[0297] Compound 1-1 (10.0 g, 32.54 mmol) was dissolved in methanol (100 mL), and sodium borohydride (862 mg, 22.79 mmol) was added in portions. The reaction was then maintained at room temperature for 2 h, and the reaction was monitored by LCMS to ensure completion. The reaction solution was concentrated under reduced pressure to obtain a white solid, which was dissolved in 20 mL of water until clear. The pH of the system was adjusted to 4 by slowly adding 1 N hydrochloric acid solution, resulting in the precipitation of a large amount of white solid. The filter cake was collected and dried to obtain compound 1-2 (8.5 g, 84%). LCMS (ESI): m / z found [M+H] + =310.0.

[0298] Synthesis of intermediates 1-3:

[0299] Compound 2 (8.5 g, 27.49 mmol) was dissolved in acetic acid (200 mL), and sodium periodate (8.3 g, 39.03 mmol) was dissolved in water (35 mL). The sodium periodate aqueous solution was added to the acetic acid solution of compounds 1-2, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure to remove a large amount of acetic acid. 200 mL of ethyl acetate and a suitable amount of water were added for extraction and separation. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compounds 1-3 (7.86 g, 93%). LCMS (ESI): m / z found [M+H] + =308.0.

[0300] Synthesis of intermediates 1-4:

[0301] Zinc powder (11.58 g, 176.71 mmol) was dissolved in tetrahydrofuran (50 mL). After purging with nitrogen three times, trimethylchlorosilane (5.96 mL, 46.09 mmol) was added. The mixture was heated to 70 °C and refluxed for 15 min. Heating was then removed, and tert-butyl bromoacetate (25.76 mL, 176.71 mmol) was slowly added dropwise. The mixture was refluxed again for 15 min, and then a tetrahydrofuran solution (200 mL) of compounds 1-3 (7.86 g, 25.61 mmol) was added. After the addition was complete, the mixture was refluxed for 4 h, and the reaction was monitored by LCMS to ensure complete reaction. The reaction solution was diluted with 400 mL of dichloromethane, washed three times with an appropriate amount of water, and the extract was separated. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by dry normal-phase column chromatography to obtain compounds 1-4 (9.3 g, 90%). LCMS (ESI): m / z found [M+H] + =396.0.

[0302] Synthesis of intermediate 1:

[0303] Compounds 1-4 (9.3 g, 23.72 mmol) were dissolved in trifluoroacetic acid (100 mL) and reacted at room temperature for 8 h. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure to remove a large amount of trifluoroacetic acid, and dissolved in an appropriate amount of methanol until clear. The solution was purified by reversed-phase column chromatography to obtain compound 1 (3.52 g, 54%). Compound 1 was separated by SGC (supercritical fluid chromatography) to obtain single-configuration compounds 1a and 1b. LC-MS (ESI): m / z found [M+H] + =278.0.

[0304] Example 2a:

[0305] Synthesis route:

[0306] Synthesis of intermediate 2-2:

[0307] Compound 2-1 (1 g, 10.446 mmol) was dissolved in DCM (10 mL) at room temperature, and benzylamine (2.8 g, 20.365 mmol) was added. The mixture was left to react overnight at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure, dissolved in a small amount of methanol, and purified by reversed-phase column chromatography to give an orange solid product (400 mg, 30%). LC-MS (ESI): m / z found [M+H] + =273.

[0308] Synthesis of intermediates 2-3:

[0309] Compound 2-2 (400 mg, 1.471 mmol) was dissolved in EtOH / EA (25 mL) at room temperature, palladium on carbon was added, and the mixture was purged with hydrogen overnight. The filtrate was collected and concentrated to give a brown solid product (180 mg, 87%). LC-MS (ESI): m / z found [M+H] + =183.

[0310] Synthesis of intermediates 2-4:

[0311] Compounds 2-3 (180 mg, 0.989 mmol) were dissolved in THF / H₂O (10 mL) at room temperature, and Fmoc-Cl (254 mg, 0.989 mmol) and K₂CO₃ (273 mg, 1.988 mmol) were added. The mixture was stirred in an ice bath for 30 min. The reaction was monitored by LC-MS until complete. The reaction solution was diluted with a small amount of ethyl acetate, and then washed with an appropriate amount of water. The extract was separated and purified by normal column chromatography to give a brown solid product (140 mg, 35%). LC-MS (ESI): m / z found [M+H] + =405.2.

[0312] Synthesis of intermediates 2-5:

[0313] Compound 2-4 (140 mg, 0.346 mmol) was dissolved in toluene (10 mL) at room temperature, and compound 1-a (91 mg, 0.346 mmol) and TSOH (45 mg, 0.156 mmol) were added. The mixture was stirred at 110 °C for 2 h. The filter cake was collected by filtration to give a black solid product (89 mg, 40%). LC-MS (ESI): m / z found [M+H] + =646. Synthesis of compound 2a:

[0314] Compound 2-5 (50 mg, 0.077 mmol) was dissolved in DMF (2 mL) at room temperature, and piperidine (16 mg, 0.232 mmol) was added. The reaction was carried out at room temperature for 2 h. After the reaction was complete, the mixture was purified by HPLC to give a yellow solid compound 2a (10 mg, 30%). LC-MS (ESI): m / z found [M+H] + =424.

[0315] Example 3:

[0316] Synthesis route:

[0317] Synthesis of intermediate 3-2:

[0318] Under ice bath conditions, 3-1 (5 g, 0.0305 mol) was added to TFA (100 mL), followed by three portions of NaNO2 (6.3 g, 0.091 mol). The mixture was stirred at room temperature for 2.5 h. The reaction mixture was monitored by TLC until complete. The reaction solution was quenched with 100 mL of water, extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed three times with saturated sodium bicarbonate aqueous solution, collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in DCM and purified by dry forward column chromatography to give a pale yellow solid compound (3.29 g, 51.73%). LC-MS (ESI): m / z found [M+H] + =210.0.

[0319] Synthesis of intermediate 3-3:

[0320] Compound 3-2 (3.29 g, 0.0157 mol) was dissolved in EtOH (40 mL) at room temperature, and Pd / C (0.84 g, 0.0078 mol) was added. The reaction was carried out at room temperature for 6 h under hydrogen catalysis, and the reaction was monitored by TLC until the reactants were fully reacted. The reaction solution was filtered through diatomaceous earth, and the Pb / C filter cake was slurried with methanol and filtered twice. The filtrates were combined and dried under reduced pressure to give a yellow solid compound (1.43 g, 50.7%). LC-MS (ESI): m / z found [M+H] + =180.15.

[0321] Synthesis of intermediates 3-4:

[0322] Compound 3-3 (1.43 g, 0.008 mol) was added to DCM (25 mL) under ice bath conditions. Acetyl chloride (1.13 mL, 0.016 mol) and DIEA (2.08 mL, 0.012 mol) were slowly added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until the starting material was completely reacted. Methanol (3 mL) was added to the system and stirred for 10 min. The reaction solution was dried under reduced pressure. The crude product was dissolved in DCM and purified by dry forward column chromatography to obtain a yellow solid compound (1.48 g, 83.85%). LC-MS (ESI): m / z found [M+H] + =222.2.

[0323] Synthesis of intermediates 3-5:

[0324] Compounds 3-4 (1.38 g, 0.006 mol) were added to glacial acetic acid (20 mL) under ice bath conditions. Hydrobromic acid (0.72 mL, 0.012 mol) and liquid bromine (0.38 mL, 0.0072 mol) were then slowly added, purging with nitrogen three times. The mixture was stirred at room temperature for 12 h. LC-MS was used to monitor the reaction until complete. The reaction was quenched with water, stirred for 10 min, filtered, and the filter cake was washed with water. The filter cake was collected, dried under reduced pressure, dissolved in a small amount of DCM, and purified by dry forward column chromatography to obtain a pale yellow solid compound (1.65 g, 88.14%). LC-MS (ESI): m / z found [M+H] + =300.15. Synthesis of intermediates 3-6:

[0325] Compound 3-5 (1.55 g, 0.005 mol) was added to EtOH (15 mL), followed by 12 N hydrochloric acid (4.5 mL). The mixture was heated to 80 °C and reacted for 6 h. LC-MS was used to monitor the reaction progress. The reaction solution was cooled to room temperature, and water (60 mL) and saturated NaHCO3 aqueous solution (60 mL) were added to adjust the pH to neutral. The mixture was extracted twice with DCM, and the organic phase was collected, washed once with water, washed once with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, dried under reduced pressure, dissolved in a small amount of DCM, and purified by dry forward column chromatography (petroleum ether: ethyl acetate = 80:20) to give a yellow solid compound (950 mg, 86.13%). LC-MS (ESI): m / z found [M+H] + =214.15.

[0326] Synthesis of intermediates 3-8:

[0327] At room temperature, compound 3-6 (850 mg, 0.004 mol) was dissolved in toluene (3 mL), followed by the sequential addition of compound 3-7 (1.05 g, 0.004 mol) and PPTS (100 mg, 0.0004 mol). After three nitrogen purgings, the mixture was heated to 110 °C and reacted overnight. LC-MS monitoring showed that the starting material reacted completely. The system was cooled to room temperature, and ethanol (3 mL) was added and stirred for 5 min. The mixture was then filtered, and the filter cake was washed with ethanol and collected and dried under reduced pressure to obtain a dark green solid compound (892.3 mg, 50.87%). LC-MS (ESI): m / z found [M+H]. + =441.30. Synthesis of intermediates 3-9:

[0328] Compound 3-8 (892.3 mg, 0.002 mol) was dissolved in DMSO (9 mL) at room temperature, and NaN3 (131.59 mg, 0.002 mmol) was added. The reaction was allowed to proceed for 3 h at room temperature. LC-MS was used to monitor the reaction until complete. Water (10 mL) was added to the reaction solution, and the mixture was stirred for 10 min. The mixture was then filtered, the filter cake was washed with water, and the filter cake was collected and lyophilized to obtain a gray solid compound (1.45 g, 100%). LC-MS (ESI): m / z found [M+H] + =448.25.

[0329] Synthesis of intermediate 3-10:

[0330] Compound 3-9 (1.35 g, 0.003 mol) was dissolved in EtOH (15 mL) at room temperature, and P(OEt)3 (3.11 mL, 0.018 mmol) was added. The mixture was heated to 50 °C and reacted for 12 h. LC-MS was used to monitor the reaction of the starting material until complete. The reaction solution was cooled to room temperature, and 18 mL of hydrogen chloride-ethyl acetate solution was added. The mixture was then heated to 60 °C and reacted for 12 h. LC-MS (5-100, 3 min) was used to monitor the reaction of the intermediate state until complete. The reaction solution was cooled, filtered, and the filter cake was washed with ethanol. The filter cake was collected and dried under reduced pressure to give a brown solid compound (1.384 g, 100%). LC-MS (ESI): m / z found [M+H] + =422.2.

[0331] Synthesis of intermediate 3-11:

[0332] Compound 3-10 (1.38 g, 0.0033 mol) was dissolved in pyridine (15 mL) under ice bath conditions, and TESOTf (7.05 mL, 0.032 mmol) was added. The reaction was allowed to proceed overnight at room temperature. LC-MS was used to monitor the reaction until completion. Fmoc-Cl (1.69 g, 0.0065 mol) was added, and the reaction was continued for 4 h. TLC was used to detect the completion of the intermediate reaction. The reaction solution was dried under reduced pressure, and the crude product was dissolved twice with methanol. The solution was then dissolved in DCM, washed three times with water, and the aqueous phase was extracted three times with DCM. The combined organic phases were washed once with saturated NaCl aqueous solution, dried and concentrated with anhydrous Na2SO4, and purified by dry normal-phase column chromatography to give a brown solid compound (823.3 mg, 41%). LC-MS (ESI): m / z found [M+H] + =758.0.

[0333] Synthesis of intermediate 3-12:

[0334] Compound 3-11 (823.3 mg, 1.083 mmol) was dissolved in toluene (18 mL) at room temperature. Lawson's reagent (1.3115 g, 3.25 mmol) was added, and the mixture was purged with nitrogen three times. The temperature was raised to 110 °C and reacted for 4 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, dissolved in a small amount of DCM, and purified by normal-phase column chromatography to obtain an orange-yellow solid compound (529.9 mg, 63.19%). LC-MS (ESI): m / z found [M+H] + =774.0.

[0335] Synthesis of intermediate 3-13:

[0336] Compound 3-12 (529.9 mg, 0.648 mmol) was dissolved in DMF (2.5 mL) at room temperature, and morpholine (1 mL) was added. The reaction was carried out at room temperature for 4 h. The reaction mixture was monitored by TLC until the starting material was completely reacted. 25 mL of morpholine was added to the reaction mixture, and the mixture was extracted four times with DCM. The combined organic phases were washed once with saturated ammonium chloride aqueous solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by normal-phase column chromatography to give a yellow solid compound (228.8 mg, 60.57%). LC-MS (ESI): m / z found [M+H] + =552.0.

[0337] Synthesis of compound 3:

[0338] Compound 3-13 (228.8 mg, 0.414 mmol) was dissolved in dry DCM (2 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by reversed-phase column chromatography to give a yellow solid compound 3 (191 mg, 100%). LC-MS (ESI): m / z found [M+H] + =438.6.

[0339] Example 4:

[0340] Synthesis route:

[0341] Synthesis of compound 4:

[0342] Compound 3 (20 mg, 1.0 eq) was dissolved in DMF at room temperature, followed by the addition of 4-1 (16 mg, 1.0 eq), HOBt (7 mg, 1.1 eq), and DIPEA (24 μL). The reaction was carried out at room temperature for 1.5 h. LC-MS (ESI): m / z found [M+H] +=640.0. The reaction solution was purified by pre-HPLC (0.05% TFA, in an acidic system, compound 4-2 was directly deprotected to give compound 4), and concentrated under reduced pressure to give a yellow solid compound 4 (3.29 mg, 16%). LCMS (ESI): m / z found [M+H] + =526.0.

[0343] Example 5:

[0344] Synthesis route:

[0345] Synthesis of intermediate 5-2:

[0346] Dissolve 5-1 (1 g, 0.0053 mol) in sulfuric acid in an ice bath. Add potassium nitrate (543.2 mg, 0.0053 mol) slowly in portions. After the addition is complete, heat to room temperature and react overnight. Monitor the reaction of the starting material by TLC until complete. Cool the system to 0°C, slowly add water, extract with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate, purify by normal-phase column chromatography, and concentrate under reduced pressure to give a pale yellow solid compound (250 mg, 20.3%). Synthesis of intermediate 5-3:

[0347] A solution of 5-2 (50 mg, 0.216 mmol) in ethyl acetate (1 mL) was added to a refluxed solution of ferrous sulfate (276.2 mg, 1.181 mmol) in water (2 mL). Ammonia solution (1 mL) was added dropwise, and the mixture was refluxed for 5 min. LC-MS showed product formation, and TLC showed complete reaction of the starting material. The system was cooled, filtered, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, concentrated, purified by normal phase, and concentrated under reduced pressure to give a pale yellow solid compound (30 mg, 68.9%). LC-MS (ESI): m / z found [M+H] + =202.

[0348] Synthesis of intermediate 5-4:

[0349] Compound 5-3 (166 mg, 0.825 mmol) and compound 3-7 (217.2 mg, 0.825 mmol) were dissolved in toluene, and then acetic acid (0.2 mL) was added. The mixture was heated to reflux and stirred for 15 min, followed by the addition of p-toluenesulfonic acid (20 mg). The reaction was continued overnight with stirring. LC-MS was used to monitor the reaction until complete. The mixture was cooled, filtered, and the solid was washed with ethanol. The filter cake was dried to give a yellow solid compound (270 mg, 76.3%). LC-MS (ESI): m / z found [M+H] + =429.

[0350] Synthesis of intermediate 5-5:

[0351] 5-4 (50 mg, 0.116 mmol) was dissolved in methanol (0.5 mL) and water (0.5 mL). Sulfuric acid (0.5 mL, 10.0 V) was added under ice bath conditions, followed by ferrous sulfate heptahydrate (37.6 mg, 0.14 mmol) and hydrogen peroxide (0.25 mL, 5 V). The reaction was carried out at room temperature for 4 h, and the reaction was monitored by LC-MS to ensure complete reaction. The system was cooled, and water was added under ice bath conditions. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with sodium thiosulfate, and purified by adding anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography to give a white solid compound (20.7 mg, 38.6%). LC-MS (ESI): m / z found [M+H] + =458.8.

[0352] Synthesis of intermediates 5-6:

[0353] 5-5 (100 mg, 0.218 mmol) was dissolved in dry pyridine (1 mL), and TESOTf (576 mg, 2.18 mmol) was added under ice bath conditions. The reaction was carried out overnight at room temperature, and the reaction was monitored by LC-MS to ensure complete reaction. The system was concentrated under reduced pressure, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, anhydrous sodium sulfate was added, and the mixture was filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography to give a white solid (90 mg, 60.1%). LC-MS (ESI): m / z found [M+H] + =686.8.

[0354] Synthesis of intermediates 5-7:

[0355] Dissolve 5-6 (90 mg, 0.131 mmol) in toluene (1 mL), add Lawson's reagent (132.48 mg, 0.327 mmol), and react at 110 °C for 4 h. Monitor the reaction of the starting material by TLC until complete. After concentration under reduced pressure, purify by normal-phase column chromatography to give a red oily compound (70 mg, 76.0%).

[0356] Synthesis of compound 5:

[0357] Compound 5-7 (140 mg, 0.199 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored for completeness by LC-MS. The system was then concentrated under reduced pressure, dissolved in a small amount of DMF, and the resulting yellow solid compound 5 (2 mg, 2.1%) was prepared by Prep-HPLC. LC-MS (ESI): m / z found [M+H] + =474.6. 1H NMR(400MHz,DMSO-d6)δ8.19(s,2H),7.82(s,1H),6.70(s,1H),6.01–5.89(m,2H),5.69(s,2H),5 .52(d,J=16.0Hz,1H),5.29(d,J=4.0Hz,2H),1.90(dt,J=8.9,6.6Hz,2H),0.87(t,J=8.0Hz,3H).

[0358] Example 6:

[0359] Synthesis route:

[0360] Synthesis of intermediate 6-1:

[0361] Compound 5-5 (230 mg, 0.502 mmol) was dissolved in DCM (10 mL) at room temperature, and SOCl2 (230 μL in 2 mL DCM) was added dropwise. The reaction was carried out at room temperature for 1 h. The reaction of the starting material was monitored by TLC and LC-MS to ensure complete reaction. The product was diluted with DCM and toluene and concentrated to obtain 230 mg, 96%. LC-MS (ESI): m / z found [M+H] + =476.6.

[0362] Synthesis of intermediate 6-2:

[0363] Compound 6-1 (230 mg, 0.482 mmol) was dissolved in DMSO (3 mL) at room temperature. NaN3 (34 mg, 0.482 mmol) was added, and the mixture was reacted at room temperature for 2 h. LC-MS was used to monitor the reaction until complete. The reaction solution was slurried with water, filtered, and the resulting solid was diluted with methanol and concentrated to obtain a yellow solid product (220 mg, 98%). LC-MS (ESI): m / z found [M+H] + =483.6.

[0364] Synthesis of intermediate 6-3:

[0365] Compound 6-2 (220 mg, 0.455 mmol) was dissolved in ethanol (3 mL) at room temperature. Triethyl phosphite (132 mg, 1.137 mmol) was added, and the mixture was reacted at 50 °C for 2 h. After the reaction was complete as monitored by LC-MS, the mixture was cooled to room temperature, and ethyl hydrochloride solution (3 mL) was added. The reaction was then carried out at 60 °C for 16 h. The reaction solution was concentrated and purified by normal column chromatography to obtain a yellow solid product (105 mg, 50%). LC-MS (ESI): m / z found [M+H] + =457.8. Synthesis of intermediate 6-4:

[0366] Compound 6-3 (100 mg, 0.218 mmol) was dissolved in pyridine (2 mL) at room temperature. TESOTf (575 mg, 2.18 mmol) was added, and the mixture was reacted at room temperature for 4 h. After intermediate formation was monitored by LC-MS, Fmoc-Cl (113 mg, 0.437 mmol) was added, and the mixture was reacted at room temperature for 20 h. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated and purified by normal column chromatography to obtain a yellow solid product (70 mg, 40%). LC-MS (ESI): m / z found [M+H] + =794.5.

[0367] Synthesis of intermediate 6-5:

[0368] Compound 6-4 (70 mg, 89 μmol) was dissolved in toluene (2 mL) at room temperature. Lawson's reagent (89 mg, 220 μmol) was added, followed by nitrogen purging and reaction at 110 °C for 4 h. The reaction mixture was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated and purified by normal column chromatography to obtain a yellow solid product (60 mg, 84%). LC-MS (ESI): m / z found [M+H] + =810.6.

[0369] Synthesis of intermediate 6-6:

[0370] Compound 6-5 (60 mg, 0.074 mmol) was dissolved in DMF (1 mL) at room temperature. Morpholine (0.5 mL) was added, and the mixture was reacted at room temperature for 0.5 h. LC-MS was used to monitor the reaction until complete. The reaction solution was extracted with ethyl acetate and brine. The organic phase was purified by forward chromatography and concentrated to give a yellow solid compound (41.3 mg, 95%). LC-MS (ESI): m / z found [M+H] + =588.35.

[0371] Synthesis of compound 6:

[0372] Compound 6-6 (41.3 mg, 0.070 mmol) was dissolved in DCM (1 mL) at room temperature. TFA (20 μL) was added, and the mixture was reacted at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was filtered, purified by reverse column chromatography, concentrated, and lyophilized to give a yellow solid, compound 6 (14 mg, 42%). LC-MS (ESI): m / z found [M+H] + =474.2. 1H NMR (400MHz, DMSO-d6) δ8.54(s,2H),8.28(s,1H),7.84(s,1H),6.74(s,1H),5.94(d,J=16.7Hz,1H), 5.88(s,2H),5.56(d,J=16.7Hz,1H),4.77(s,2H),1.24(d,J=3.0Hz,3H),0.86(q,J=6.7,6.2Hz,3H).

[0373] Example 7:

[0374] Synthesis route:

[0375] Synthesis of intermediate 7-2:

[0376] 7-1 (100 mg, 0.657 mmol) was dissolved in DMF, and deuterated dichloromethane (286 mg, 3.28 mmol) and potassium carbonate (272 mg, 1.97 mmol) were added. The mixture was heated to 90 °C and reacted overnight. The reaction solution was cooled, water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed twice with water and once with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by normal-phase column chromatography, and concentrated under reduced pressure to give a white solid compound (48 mg, 43.9%). LC-MS (ESI): m / z found [M+H] + =167.2.

[0377] Synthesis of intermediate 7-3:

[0378] 7-2 (50 mg, 0.3 mmol) was dissolved in glacial acetic acid (1 mL), followed by the addition of nitric acid (1 mL). The mixture was then heated to 40°C and reacted for 2 h. LC-MS was used to monitor the reaction until complete. The system was cooled, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, purified by normal-phase column chromatography, and concentrated under reduced pressure to give a white solid compound (33 mg, 51.9%). LC-MS (ESI): m / z found [M+H] + =212.4. Synthesis of intermediate 7-4:

[0379] 7-3 (1.0244 g, 4.851 mmol) was dissolved in acetic acid (10 mL), and acetic anhydride (1.089 g, 10.67 mmol) and Fe (4.074 g, 72.76 mmol) were added. The mixture was reacted overnight at room temperature. The reaction mixture was monitored by TLC until complete. The reaction solution was filtered, and the filter cake was washed twice with DCM. The filtrate was purified by normal-phase column chromatography to obtain the product (0.903 g, 83.72%). LC-MS (ESI): m / z found [M+H]+ =223.9.

[0380] Synthesis of intermediate 7-5:

[0381] Dissolve 7-4 (50 mg, 0.224 mmol) in acetic acid (1 mL). Add a solution of hydrobromic acid in acetic acid (109.8 mg, 0.118 mmol) dropwise under ice bath conditions, followed by the addition of bromine (42.95 mg, 0.269 mmol). React at room temperature for 4 h until the solution becomes clear. Monitor the reaction of the starting material by LC-MS until complete. Add water to the system under ice bath conditions. Extract three times with ethyl acetate. Combine the organic phases, wash twice with sodium thiosulfate, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by normal-phase column chromatography to give a white solid compound (23 mg, 34%). LC-MS (ESI): m / z found [M+H] + =303.2

[0382] Synthesis of intermediate 7-6:

[0383] 7-5 (140 mg, 0.463 mmol) was dissolved in ethanol (1.5 mL), and concentrated hydrochloric acid (0.5 mL) was added under ice bath conditions. The reaction was carried out at 60 °C for 3 h, and LC-MS analysis showed that the reaction proceeded completely. The system was concentrated under reduced pressure, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography to give a yellow solid compound (90 mg, 90.2%). LC-MS (ESI): m / z found [M+H] + =216.1.

[0384] Synthesis of intermediate 7-7:

[0385] Dissolve 7-6 (115 mg, 0.535 mmol) in toluene (1 mL) and acetic acid (1 mL), add PPTS (13.44 mg, 0.052 mmol) and 3-7 (141 mg, 0.535 mmol), and react at 110 °C overnight. LC-MS was used to monitor the reaction until complete. The system was concentrated under reduced pressure and dissolved in a small amount of DCM / MeOH. An appropriate amount of diethyl ether was added, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was dried to obtain a brown solid compound (160 mg, 67.3%). LC-MS (ESI): m / z found [M+H]. + =444.9.

[0386] Synthesis of intermediates 7-8:

[0387] 7-7 (160 mg, 0.359 mmol) was dissolved in DMSO (1.5 mL), and sodium azide (23.41 mg, 0.359 mmol) was added. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by LC-MS to ensure completion. After cooling the system, water (15 mL) was added, resulting in the precipitation of a large amount of solid. The mixture was filtered, the filter cake was washed twice with water, and dried to obtain a brown solid compound (100 mg, 61.58%). LC-MS (ESI): m / z found [M+H] + =449.8. Synthesis of intermediates 7-9:

[0388] Dissolve 7-8 (100 mg, 0.221 mmol) in ethanol (1 mL), add triethyl phosphite (92.01 mg, 0.554 mmol), and react at 50 °C for 4 h. LC-MS was used to monitor the reaction until complete. After cooling, add 2 mL of ethyl acetate solution of hydrogen chloride, and continue the reaction at 60 °C overnight. LC-MS was used to monitor the reaction until complete. The system was then directly filtered, and the filter cake was washed twice with ethanol and dried to obtain a brown solid compound (25 mg, 26.5%). LC-MS (ESI): m / z found [M+H] + =424.8.

[0389] Synthesis of intermediates 7-10:

[0390] Dissolve 7-9 (25 mg, 0.058 mmol) in dry pyridine (1 mL), add TESOTf (155.29 mg, 0.58 mmol), and react overnight at room temperature. LCMS was used to monitor the reaction until complete. After cooling the system, Fmoc-Cl (30 mg, 0.117 mmol) was added, and the reaction was continued at room temperature for 2 hours. LCMS was used to monitor the reaction until complete. The system was then concentrated under reduced pressure and subjected to normal-phase column chromatography to obtain a white oily product (12.0 mg, 26.7%). LC-MS (ESI): m / z found [M+H] + =760.2.

[0391] Synthesis of intermediate 7-11:

[0392] 7-10 (68.0 mg, 0.09 mmol) was dissolved in toluene (1 mL), Lawson's reagent (90.48 mg, 0.22 mmol) was added, and the mixture was heated to 110 °C for 4 h. TLC analysis showed the reaction was complete. After cooling, the system was concentrated under reduced pressure and purified by normal-phase column chromatography to obtain a yellow solid (51.0 mg, 73.3%). LC-MS (ESI): m / z found [M+H] + =776.2.

[0393] Synthesis of intermediate 7-12:

[0394] 7-11 (51.0 mg, 0.07 mmol) was dissolved in DMF (1 mL), and morpholine (0.5 mL) was added. The reaction was carried out at room temperature for 4 h, and the reaction was confirmed to be complete by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed twice with water, and then once with brine. Anhydrous sodium sulfate was added, and the mixture was dried. The product was purified by normal-phase column chromatography to give a yellow solid compound (11.0 mg, 30.2%). LC-MS (ESI): m / z found [M+H] + =554.2

[0395] Synthesis of compound 7:

[0396] 7-12 (11.0 mg, 0.02 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The mixture was reacted overnight at room temperature, and the reaction was confirmed to be complete by LC-MS. The system was concentrated under reduced pressure, dissolved in a small amount of DMF, and the resulting yellow solid compound 7 (0.14 mg, 1.6%) was prepared by Prep-HPLC. LC-MS (ESI): m / z found [M+H] + =440.2.

[0397] Example 8a:

[0398] Synthesis route:

[0399] Synthesis of compound 8a:

[0400] Compound 8-1 (5 mg, 0.0303 mmol) was dissolved in DMF (3 mL), and compound 1-a (8 mg, 0.0303 mmol) and trimethylchlorosilane (14 μL, 0.109 mmol) were added. The mixture was heated to 100 °C and reacted for 2 h. The reaction was monitored by LC-MS to ensure complete reaction. The mixture was purified by pre-HPLC and lyophilized to give compound 8a (3.97 mg, 30%). LC-MS (ESI): m / z found [M+H] + =407.0.

[0401] Example 9a:

[0402] Synthesis route:

[0403] Synthesis of intermediate 9-2:

[0404] 9-1 (5 g, 24.87 mmol) was dissolved in acetic acid (15 mL), and nitric acid (5 mL) was slowly added under ice bath conditions. The mixture was then heated to room temperature and reacted for 2 h. The reaction was monitored by LC-MS to ensure complete reaction. A large amount of solid precipitated from the reaction solution; the dried filter cake was collected to give a yellow solid compound (5.48 g, 93%). LC-MS (ESI): m / z found [M+H] + =247.0.

[0405] Synthesis of intermediate 9-3:

[0406] 9-2 (5 g, 20.32 mmol) was dissolved in N,N-dimethylformamide (50 mL), and 3-butyn-1-ol (2.3 mL, 30.49 mmol), cuprous iodide (77 mg, 0.41 mmol), palladium dichloride (143 mg, 0.20 mmol), and triethylamine (14 mL, 101.62 mmol) were added. The mixture was heated to 50 °C and reacted for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, and an equal volume of 1% ammonia solution was added. After stirring for 30 min, a large amount of solid precipitated. The filter cake was collected, slurried with water, washed three times, filtered again, and dried to obtain the compound (4.148 g, 80%). LC-MS (ESI): m / z found [M+H] + =236.0.

[0407] Synthesis of intermediate 9-4:

[0408] 9-3 (148 mg, 0.629 mmol) was dissolved in ethanol (9 mL) and water (1 mL). Tin powder (299 mg, 2.517 mmol), sodium sulfide pentahydrate (32 mg, 0.189 mmol), and hydrochloric acid (195 μL, 6.293 mmol) were added. The mixture was purged with nitrogen three times and heated to 78 °C for 4 h. The reaction was monitored by LC-MS until complete. The tin powder was removed by hot diatomaceous earth filtration, and the filtrate was collected and concentrated under reduced pressure. The tin powder was dissolved in an appropriate amount of ethyl acetate, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was filtered twice, and the filtrate was collected. The organic phase was extracted and collected by separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound (100 mg, 71%). LC-MS (ESI): m / z found [M+H] + =224.0.

[0409] Synthesis of compound 9a

[0410] Compound 9-4 (10 mg, 0.045 mmol) was dissolved in toluene (3 mL), and compound 1-a (12 mg, 0.045 mmol) and pyridine 4-methylbenzenesulfonic acid (5.6 mg, 0.022 mmol) were added. The mixture was heated to 110 °C and reacted for 2 h. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was concentrated under reduced pressure to remove toluene. A small amount of N,N-dimethylformamide was added to dissolve the solution, and the mixture was purified by pre-HPLC to obtain compound 9a (2.61 mg, 12%). LC-MS (ESI): m / z found [M+H] + =465.0.

[0411] Example 10a:

[0412] Synthesis route:

[0413] Synthesis of intermediate 10-2:

[0414] Boron trichloride (56.7 mL, 56.68 mmol) was dissolved in dichloromethane (200 mL) under ice-water bath conditions. Compound 10⁻¹ (10 g, 70.85 mmol), chloroacetonitrile (5.4 mL, 85.02 mmol), and aluminum trichloride (12.3 g, 92.11 mmol) were added sequentially. The mixture was stirred at 0 °C for 10 min, then heated to room temperature and reacted at room temperature for 10 min. The temperature was then raised again to 40 °C and maintained overnight. TLC monitoring showed the reaction was complete. The reaction solution was cooled in an ice-water bath, and 30 mL of water was added and stirred for 10 min in an ice bath. 2N hydrochloric acid solution was added and the mixture was stirred for 1 h. The solution was diluted with dichloromethane, washed three times with water, and the combined organic phases were dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by normal-phase column chromatography to obtain the compound (3.2 g, 24%). LC-MS (ESI): m / z found [M+H] + =218.00.

[0415] Synthesis of intermediate 10-3:

[0416] Compound 10-2 (50 mg, 0.230 mmol) was dissolved in toluene (10 mL), and compound 1-a (64 mg, 0.230 mmol) and pyridine 4-methylbenzenesulfonic acid (29 mg, 0.115 mmol) were added. The mixture was heated to 110 °C and reacted for 2 h. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was concentrated under reduced pressure to remove toluene. A small amount of N,N-dimethylformamide was added to dissolve the solution, and the mixture was purified by pre-HPLC to obtain compound (31 mg, 29%). LC-MS (ESI): m / z found [M+H] + =459.0.

[0417] Synthesis of compound 10a:

[0418] Compound 10⁻³ (10 mg, 0.022 mmol) was dissolved in ethanol (5 mL), and hexamethylenetetramine (6.2 mg, 0.044 mmol) was added. The mixture was heated to 80 °C and reacted for 4 h. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure and dissolved in a small amount of N,N-dimethylformamide. The solution was purified by pre-HPLC to obtain compound 10a (0.3 mg, 3%). LC-MS (ESI): m / z found [M+H] + =440.0.

[0419] Example 11a:

[0420] Synthesis route:

[0421] Synthesis of intermediate 11-1:

[0422] 9-2 (550 mg, 2.236 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 4-pentyn-1-ol (312 μL, 3.353 mmol), cuprous iodide (8.5 mg, 0.045 mmol), palladium dichloride (16 mg, 0.022 mmol), and triethylamine (1.5 mL, 11.178 mmol) were added. The mixture was heated to 50 °C and reacted for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, and an equal volume of 1% ammonia solution was added. The mixture was stirred for 30 min, and a large amount of solid precipitated. The filter cake was collected, slurried with water, washed three times, filtered again, and dried to obtain the compound (370 g, 66%). LC-MS (ESI): m / z found [M+H] + =250.0.

[0423] Synthesis of intermediate 11-2:

[0424] 11-1 (370 mg, 1.485 mmol) was dissolved in ethanol (9 mL) and water (1 mL). Tin powder (705 mg, 5.939 mmol), sodium sulfide pentahydrate (75 mg, 0.445 mmol), and hydrochloric acid (475 μL, 14.846 mmol) were added. The mixture was purged with nitrogen three times and heated to 78 °C for 4 h. The reaction was monitored by LC-MS until complete. The tin powder was removed by diatomaceous earth filtration while hot, and the filtrate was collected and concentrated under reduced pressure. The tin powder was dissolved in an appropriate amount of ethyl acetate, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was filtered twice, and the filtrate was collected. The organic phase was extracted and collected by separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound (180 mg, 51%). LC-MS (ESI): m / z found [M+H] + =238.0.

[0425] Synthesis of compound 11a:

[0426] Compound 11-3 (10 mg, 0.042 mmol) was dissolved in toluene (3 mL), and compound 1-a (12 mg, 0.042 mmol) and pyridine 4-methylbenzenesulfonic acid (5.3 mg, 0.021 mmol) were added. The mixture was heated to 110 °C and reacted for 2 h. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was concentrated under reduced pressure to remove toluene. A small amount of N,N-dimethylformamide was added to dissolve the solution, and the mixture was purified by pre-HPLC to obtain compound 11a (0.74 mg, 4%). LC-MS (ESI): m / z found [M+H] + =479.0.

[0427] Example 12a:

[0428] Synthesis route:

[0429] Synthesis of compound 12:

[0430] Glycolic acid (0.95 mg, 0.0125 mmol) was dissolved in N,N-dimethylformamide (3 mL) under ice bath conditions. HATU (5.2 mg, 0.0137 mmol) was added, and the reaction was allowed to proceed for 15 min. Then, compound 9 and N,N-diisopropylethylamine (3.9 μL, 0.0228 mmol) were added, and the mixture was heated to room temperature for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was purified by pre-HPLC to obtain compound 12 (1.3 mg, 23%). LC-MS (ESI): m / z found [M+H] + =498.0.

[0431] Example 13a:

[0432] Synthesis route:

[0433] Synthesis of intermediate 13-2:

[0434] Under ice bath conditions, BCl3 (6 mL, 0.0064 mmol) was dissolved in DCE (20 mL). After 10 min on ice, 3-fluoro-4-methylaniline (1 g, 0.008 mmol), 5-bromopentanilonitrile (1.5 mg, 0.0096 mmol), and AlCl3 (1.39 g, 0.01 mmol) were added sequentially. The reaction was continued under ice bath conditions for another 10 min, then the temperature was raised to 80 °C and maintained overnight. LC-MS was used to monitor the reaction progress. The reaction solution was cooled and placed in an ice bath. Water (10 mL) was slowly added to quench the reaction, followed by 2N hydrochloric acid solution (3 mL). The mixture was stirred for 3 h, filtered, and the filtrate was separated into layers. The aqueous phase was extracted twice with DCM, and the organic phase was collected, dried over anhydrous sodium sulfate, and purified by normal-phase column chromatography to obtain a yellow oily solid (906 mg, 39%). LC-MS (ESI): m / z found [M+H] + =289.02.

[0435] Synthesis of intermediate 13-3:

[0436] At room temperature, 13-2 (100 mg, 0.345 mmol) was dissolved in toluene (2.5 mL), followed by the sequential addition of compound 1-a (96.2 mg, 0.345 mmol), TsOH·H₂O (6.59 mg, 0.0345 mmol), and glacial acetic acid (2 mL). The mixture was heated to 110 °C and reacted for 6 h. LC-MS monitoring showed that the starting material reacted completely. The reaction solution was cooled to room temperature and concentrated under reduced pressure, then purified by normal column chromatography to obtain a brown solid compound (25.3 mg, 13.77%). LC-MS (ESI): m / z found [M+H] + =530.2.

[0437] Synthesis of compound 13a:

[0438] At room temperature, 13-3 (25.3 mg, 0.048 mmol) was added to 2 mL of 10% H₂SO₄ aqueous solution, and the mixture was heated to 110 °C and reacted for 5 h. LC-MS monitoring showed that the reaction proceeded completely. The reaction solution was filtered, and the pure white solid compound 13a (5.81 mg, 26.06%) was obtained by pre-HPLC. LC-MS (ESI): m / z found [M+H] + =467.0.

[0439] Example 14a:

[0440] Synthesis route:

[0441] Synthesis of compound 14a:

[0442] Glycolic acid (0.45 mg, 0.0047 mmol) was dissolved in DMF (1 mL) under ice bath conditions. HATU (2.68 mg, 0.0056 mmol) was added, and the mixture was reacted under ice bath conditions for 20 min. Then, DIEA (2.06 μL, 0.0094 mmol) and compound 2 (2.5 mg, 0.0047 mmol) were added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored for completeness by LC-MS. The reaction solution was filtered and purified by pre-HPLC to obtain a white solid compound 14a (1.21 mg, 35.19%). LC-MS (ESI): m / z found [M+H] + =482.0.

[0443] Example 15a:

[0444] Synthesis route:

[0445] Synthesis of intermediate 15-2:

[0446] Compound 15-1 (10 g, 79.91 mmol) was dissolved in DCE (100 mL) under ice-water bath conditions. Boron trichloride (96 mL, 63.93 mmol) and 4-chlorobutyronitrile (9.9 mL, 95.89 mmol) were added sequentially. The mixture was stirred at 0 °C for 10 min, then heated to room temperature and reacted at room temperature for 10 min. The temperature was then raised to 80 °C and refluxed for 3 h. The mixture was cooled to room temperature, and 200 mL of 2N HCl aqueous solution was added. The mixture was then heated to 80 °C and refluxed for 30 min. The reaction was cooled to room temperature, and TLC monitoring showed complete reaction. The mixture was diluted with dichloromethane, washed three times with water, and the combined organic phases were dried over anhydrous NaSO4 and concentrated under reduced pressure. The resulting product was purified by normal-phase column chromatography to obtain the compound (4.45 g, 24.2%). LC-MS (ESI): m / z found [M+H] + =230.00.

[0447] Synthesis of intermediate 15-3:

[0448] Compound 15-2 (40 mg, 0.174 mmol) was dissolved in toluene (2 mL), followed by compound 1-a (48 mg, 0.174 mmol), p-toluenesulfonic acid monohydrate (3.4 mg, 0.017 mmol), and acetic acid (2 mL). The mixture was heated to 110 °C and reacted for 6 h. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was concentrated under reduced pressure and purified by normal column chromatography to give compound 15-3 (20 mg, 16.3%). LC-MS (ESI): m / z found [M+H] + =471.0.

[0449] Synthesis of compound 15a:

[0450] Compound 15-3 (20 mg, 0.022 mmol) was dissolved in 10% H₂SO₄ solution, heated to 110 °C, and reacted overnight. The reaction was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure, dissolved in a small amount of N,N-dimethylformamide, and purified by pre-HPLC (5-50% ACN in H₂O, 0.1% HCOOH) to give compound 15a (0.9 mg, 4.7%). MS (ESI): m / z found [M+H] + =453.0.

[0451] Example 16a:

[0452] Synthesis route:

[0453] Synthesis of intermediate 16-2:

[0454] 16-1 (1 g, 5.58 mmol) was dissolved in DCM (10 mL). The reaction solution was cooled to 0 °C, and DIEA (1.38 mL, 8.37 mmol) and acetyl chloride (569 mg, 7.26 mmol) were added. The reaction solution was heated to room temperature and stirred for 1.5 h. LC-MS monitoring showed no residue of the starting material, indicating the reaction was complete. The reaction solution was concentrated under reduced pressure to give the compound (2.2 g, 100%). LC-MS (ESI): m / z found [M+H] + =222.1.

[0455] Synthesis of intermediate 16-3:

[0456] 16-2 (2.2 g, 9.91 mmol) was dissolved in acetic acid (12 mL), and a solution of hydrogen bromide in acetic acid (3.65 g, 14.86 mmol, 33% purity) was added. Liquid bromine (1.89 g, 11.89 mmol) was then slowly added dropwise. The reaction mixture was allowed to react at room temperature for 1 h, and the reaction was monitored by LC-MS until complete. The reaction mixture was then poured into ice water and stirred for 10 min. The filter cake was collected and washed twice with water. The mixture was then slurried with water, washed three times, filtered, and the filter cake was dried to obtain the compound (1.83 g, 61.4%). LC-MS (ESI): m / z found [M+H] + =300.0.

[0457] Synthesis of intermediate 16-4:

[0458] 16-3 (500 mg, 1.67 mmol) was dissolved in ultra-dry ethanol (2.5 mL), and concentrated hydrochloric acid (2.5 mL) was added. The reaction mixture was heated to 60 °C and reacted for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction mixture was cooled to room temperature, and ice water and saturated sodium bicarbonate aqueous solution were added sequentially. DCM extraction was performed, and the organic phase was washed three times with water and dried over anhydrous sodium sulfate. The compound (136 mg, 37.9%) was purified by normal column chromatography. LC-MS (ESI): m / z found [M+H] + =214.0.

[0459] Synthesis of intermediate 16-5:

[0460] Compound 16-4 (30 mg, 0.14 mmol) was dissolved in toluene (35 mL), and compound 1-a (38.8 mg, 0.14 mmol) and p-toluenesulfonic acid (13.3 mg, 0.07 mmol) were added. The mixture was refluxed using a water separator for 1 h. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was filtered, and the filter cake was dried to obtain the compound (31 mg, 48.7%). LC-MS (ESI): m / z found [M+H] + =455.0.

[0461] Synthesis of compound 16a:

[0462] Compound 16-5 (10 mg, 0.022 mmol) was dissolved in ethanol (5 mL), and hexamethylenetetramine (9.3 mg, 0.066 mmol) was added. The mixture was heated to 80 °C and reacted overnight. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure, dissolved in a small amount of N,N-dimethylformamide, and purified by pre-HPLC (5-50% ACN in H₂O, 0.1% HCOOH) to give compound 16a (0.82 mg, 8.35%). LC-MS (ESI): m / z found [M+H] + =435.0.

[0463] Example 17:

[0464] Synthesis route:

[0465] Synthesis of intermediate 17-2:

[0466] Boron trichloride (32 mL, 31.96 mmol) was dissolved in DCM (80 mL) under ice-water bath conditions. 3-fluoro-4-methylaniline (5 g, 39.95 mmol), chloroacetonitrile (3.53 g, 46.95 mmol), and aluminum trichloride (6.9 g, 51.94 mmol) were added sequentially. The mixture was stirred at 0 °C for 10 min, then heated to room temperature and reacted at room temperature for 10 min. The temperature was then raised again to 40 °C and maintained overnight. TLC monitoring showed the reaction was complete. The reaction solution was cooled in an ice-water bath, and 30 mL of water was added and stirred for 10 min in an ice bath. 2N hydrochloric acid solution was added and the reaction was stirred for 1 h. The solution was diluted with dichloromethane, washed three times with water, and the combined organic phases were dried over anhydrous NaSO4 and concentrated before column chromatography to obtain the compound (2.15 g, 27%). LC-MS (ESI): m / z found [M+H] + =202.0.

[0467] Synthesis of intermediate 17-3:

[0468] Compound 17-2 (500 mg, 2.487 mmol) was dissolved in 5 mL of toluene at room temperature. Compound 3-7 (624 mg, 2.369 mmol) and pyridine 4-methylbenzenesulfonic acid (30 mg, 0.118 mmol) were added. After purging with nitrogen three times, the mixture was heated to 110 °C and reacted overnight. LC-MS monitoring showed that the reaction proceeded completely. The reaction solution was concentrated under reduced pressure, dissolved in a small amount of DMF, and separated by reversed-phase column chromatography to give the compound (467 mg, 46% yield). LC-MS (ESI): m / z found [M+H] + =429.0.

[0469] Synthesis of intermediate 17-3:

[0470] Compound 17-3 (200 mg, 0.466 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-hydroxyphthalimide (76 mg, 0.466 mmol) and triethylamine (71 μL, 0.513 mmol) were added. The mixture was heated to 70 L and reacted for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was purified by C18 reversed-phase column chromatography to give the compound (90 mg, 35%). LC-MS (ESI): m / z found [M+H] + =556.0.

[0471] Synthesis of compound 17:

[0472] Compound 17-3 (40 mg, 0.072 mmol) was dissolved in dichloromethane (5 mL), and hydrazine hydrate (4.3 mg, 0.086 mmol) was added. The reaction was maintained at room temperature for 4 h. The reaction was monitored by LC-MS until completion. The reaction solution was purified by pre-HPLC to obtain compound 17 (90 mg, 35%). LC-MS (ESI): m / z found [M+H] + =426.0.

[0473] Example 18:

[0474] Synthesis route:

[0475] Synthesis of intermediate 18-2:

[0476] 2,6-Difluorobenzaldehyde (100 mg, 0.704 mmol) and hydroxylamine hydrochloride (59 mg, 0.845 mmol) were dissolved in a mixed solvent of ethanol (4 mL) and water (2 mL) at room temperature. Sodium hydroxide (34 mg, 0.845 mmol) was added, and the mixture was stirred overnight. The reaction was monitored by LC-MS until complete. Dilute hydrochloric acid was added to adjust the pH to 5-6, followed by dilution with ethyl acetate. The mixture was washed three times with water, and the combined organic phases were dried over anhydrous NaSO4 and concentrated under reduced pressure to obtain the compound (100 mg, 90.41%). LC-MS (ESI): m / z found [M+H] + =158.0.

[0477] Synthesis of intermediate 18-3:

[0478] Compound 18-2 (100 mg, 0.636 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature, and N-chlorosuccinimide (85 mg, 0.636 mmol) was added. The mixture was slowly heated to 50 °C and reacted for 2 h. LC-MS monitoring showed that the reaction proceeds were completely reacted. The reaction solution was diluted with ethyl acetate, washed three times with water, and the combined organic phases were dried over anhydrous NaSO4 and concentrated under reduced pressure to give the compound (108 mg, 88.64%). LC-MS (ESI): m / z found [M+H] + =192.0.

[0479] Synthesis of compound 18:

[0480] Compound 18-4 (10 mg, 0.0235 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 17-3 (6.8 mg, 0.035 mmol) and N,N-diisopropylethylamine (11 μL, 0.060 mmol) were added. The mixture was reacted at room temperature for 2 h, and the reaction was monitored by LC-MS until complete. The reaction solution was purified by pre-HPLC to obtain compound 18 (1.5 mg, 10.99%). LC-MS (ESI): m / z found [M+H] + =581.0.

[0481] Example 19a:

[0482] Synthesis route:

[0483] Synthesis of compound 19a:

[0484] Glycolic acid (2 mg, 0.023 mmol) was dissolved in DMF, and HATU (14.99 mg, 0.039 mmol) was added. The mixture was reacted in an ice bath for 15 min, followed by the addition of compound 16 (13.76 mg, 0.032 mmol) and DIEA (13.72 μL, 0.079 mmol). The mixture was heated to room temperature and reacted for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was filtered and purified by pre-HPLC to obtain compound 19a (0.42 mg, 3.24%). LC-MS (ESI): m / z found [M+H] + =493.5.

[0485] Example 20:

[0486] Synthesis route:

[0487] Synthesis of intermediate 20-2:

[0488] 20-1 (1 g, 4.67 mmol) was dissolved in dioxane (20 mL). Potassium phosphate (1.98 g, 9.35 mmol) and dimethylphosphine oxide (0.547 g, 7.01 mmol) were added, followed by Pd2(dba)3 (0.428 g, 0.47 mmol) and Xantphos (0.541 g, 0.93 mmol). After the addition was complete, the reaction mixture was purged with nitrogen and heated to 110 °C with stirring for 2 h. LC-MS monitoring showed no residue of the starting material, indicating the reaction was complete. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, and extracted with water and ethyl acetate. The organic phases were combined, concentrated to dryness under reduced pressure, and purified by normal column chromatography to give compound 20-2 (0.204 g, 20.7%). LC-MS (ESI): m / z found [M+H] + =211.2.

[0489] Synthesis of compound 20:

[0490] Compound 20-2 (10 mg, 0.047 mmol) was dissolved in toluene (5 mL), and compound 3-7 (12.5 mg, 0.047 mmol) and PPTS (0.3 mg, 0.00023 mmol) were added. The mixture was refluxed using a water separator for 1 h. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was filtered, the filter cake was dried, and purified by pre-HPLC to obtain compound 20 (6.93 mg, 33.4%). LC-MS (ESI): m / z found [M+H] + =438.4.

[0491] Example 21a:

[0492] Synthesis route:

[0493] Synthesis of compound 21a:

[0494] Compound 20-2 (20 mg, 0.095 mmol) was dissolved in toluene (3 mL). Compound 1-a (26.3 mg, 0.095 mmol) and p-toluenesulfonic acid monohydrate (9 mg, 0.0048 mmol) were added, followed by the addition of acetic acid (3 mL). The mixture was refluxed for 1 h using a water separator. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was filtered, and the filter cake was dried and purified by pre-HPLC to obtain compound 21a (4.42 mg, 10.32%). LC-MS (ESI): m / z found [M+H] + =452.4.

[0495] Example 22a:

[0496] Synthesis route:

[0497] Synthesis of intermediate 22-2:

[0498] 22-1 (1 g, 4.03 mmol) was dissolved in toluene (20 mL). Cesium carbonate (4.2 g, 8.06 mmol) and tert-butyl carbamate (0.567 g, 4.84 mmol) were added, followed by Pd2(dba)3 (0.185 g, 0.2 mmol) and X-phos (0.385 g, 0.81 mmol). After the addition was complete, the reaction mixture was purged with nitrogen and heated to 90 °C with stirring overnight. LC-MS monitoring showed no residue of the starting material, indicating the reaction was complete. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, and extracted with water and ethyl acetate. The organic phases were combined, concentrated to dryness under reduced pressure, and purified by normal column chromatography to obtain compound 22-2 (0.927 g, 80.6%). LC-MS (ESI): m / z found [M+H] + =284.2.

[0499] Synthesis of intermediate 22-3:

[0500] Compound 22-2 (0.927 g, 3.25 mmol) was dissolved in a mixture of ethanol (20 mL) and water (5 mL). Ammonium chloride powder (0.282 g, 5.27 mmol) was added, followed by iron powder (0.727 g, 13.01 mmol). Nitrogen gas was introduced, and the reaction mixture was heated to 80 °C and reacted overnight. LC-MS monitoring confirmed complete reaction. No reactants remained. The iron powder was filtered off, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate and water. The combined organic phases were purified by normal column chromatography to obtain compound 22-3 (0.385 g, 46.5%). LC-MS (ESI): m / z found [M+H] + =254.3.

[0501] Synthesis of compound 22a:

[0502] Compound 22-3 (25 mg, 0.98 mmol) was dissolved in toluene (3 mL). Compound 1-a (27.2 mg, 0.98 mmol) and p-toluenesulfonic acid monohydrate (9.3 mg, 0.049 mmol) were added, followed by the addition of acetic acid (3 mL). The mixture was refluxed for 1 h using a water separator. The reaction was monitored by LC-MS until complete. After cooling, the reaction solution was filtered, and the filter cake was dried and purified by pre-HPLC to obtain compound 22a (2.37 mg, 6.1%). LC-MS (ESI): m / z found [M+H] + =395.4.

[0503] Example 23:

[0504] Synthesis route:

[0505] Synthesis of intermediate 23-2:

[0506] At room temperature, tert-butyl hydroxymethylcarbamate (300 mg, 2.038 mmol) was added to isopropanol (5 mL), followed by methyl bromoacetate (231.55 μL, 2.45 mmol) and DIPEA (426.06 μL, 2.45 mmol). The mixture was purged with nitrogen three times and heated to 85 °C overnight. TLC analysis confirmed complete reaction of the starting material. The reaction solution was dried under reduced pressure. The crude product was dissolved in ethyl acetate, and the organic phase was washed three times with saturated brine. The collected organic phase was dried over anhydrous sodium sulfate and purified by dry normal-phase column chromatography. The purified product was concentrated under reduced pressure to give a colorless oily solid compound 23-2 (256.3 mg, 57.3%). LC-MS (ESI): m / z found [M+H] + =220.2.

[0507] Synthesis of intermediate 23-3:

[0508] At room temperature, 23-2 (256.3 mg, 1.17 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of a sodium hydroxide (93.52 mg, 2.34 mmol) aqueous solution (1 mL). The reaction was allowed to proceed for 4 h at room temperature. TLC analysis confirmed the reaction was complete. The pH was adjusted to approximately 4-5 with 1 M HCl aqueous solution. Ethyl acetate was added to dilute the reaction solution. The organic phase was washed twice with water and twice with saturated brine. The collected organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily solid compound 23-3 (75 mg, 31.26%). LC-MS (ESI): m / z found [M+H] + =206.0.

[0509] Synthesis of intermediate 23-4:

[0510] Under ice-water bath conditions, 23-2 (60 mg, 0.292 mmol) was added to DMF (2.5 mL), followed by HATU (133.4 mg, 0.351 mmol). After stirring in an ice-water bath for 10 min, 18-4 (124.4 mg, 0.292 mmol) and DIEA (101.9 μL, 0.584 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. LC-MS was used to confirm the completeness of the reaction. The reaction solution was filtered, and the filtrate was purified manually by pre-HPLC to obtain a yellow solid compound 23-4 (139.6 mg, 77.9%). LC-MS (ESI): m / z found [M+H]+ =613.2.

[0511] Synthesis of compound 23:

[0512] Compound 3 (60 mg, 0.098 mmol) was added to DCM (2 mL) at room temperature, followed by 1 mL of hydrogen chloride-ethyl acetate solution. The mixture was stirred at room temperature for 30 min. LC-MS analysis confirmed the reaction was complete. The reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by reverse-phase column chromatography to obtain a yellow solid, compound 23 (19.4 mg, 38.64%). LC-MS (ESI): m / z found [M+H] + =513.2.

[0513] Example 24:

[0514] Synthesis route:

[0515] Synthesis of intermediate 24-1:

[0516] Compounds 9-4 (33.4 mg, 0.1498 mmol) and 3-7 (23.66 mg, 0.08986 mmol) were dissolved in NMP (0.3 mL) at room temperature, followed by the addition of p-toluenesulfonic acid (23.21 mg, 0.1348 mmol). The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 2 h. The reaction was monitored by LC-MS until complete. The mixture was purified by reversed-phase column chromatography, concentrated under reduced pressure, and lyophilized to give a yellowish-brown solid (21.8 mg, 32.3%). LC-MS (ESI): m / z found [M+H] + =451.0.

[0517] Synthesis of intermediate 24-2:

[0518] DMAP (1.36 mg, 0.011 mmol) was added to a pyridine solution of compound 24-1 (50 mg, 0.111 mmol) and acetic anhydride (57 mg, 0.556 mmol). The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The solution was concentrated under reduced pressure, extracted with DCM (20 mL x 2) and water (40 mL), dried, and concentrated to give a yellow solid product (61 mg, 100%). LC-MS (ESI): m / z found [M+H] + =535.0.

[0519] Synthesis of intermediate 24-3:

[0520] Lawson's reagent (67.5 mg, 0.169 mmol) was added to a solution of compound 24-2 (30 mg, 0.056 mmol) in 3 mL of 1,4-dioxane, and the mixture was stirred at 90 °C for 12 h. The reaction was complete as monitored by LC-MS. The mixture was concentrated under reduced pressure, extracted with EA (20 mL x 2) and water (40 mL), dried, and concentrated to give a yellow solid product (15 mg, 54.5%). LC-MS (ESI): m / z found [M+H] + =551.0.

[0521] Synthesis of compound 24:

[0522] Compound 24-3 (31 mg, 0.056 mmol) was dissolved in HCl (1.6 mL) and stirred at 90 °C for 40 min. The reaction was confirmed to be complete by LC-MS. The reaction solution was filtered, concentrated, and purified by HPLC to give a yellow solid product (8 mg, 34.3%). LC-MS (ESI): m / z found [M+H] + =467.0.

[0523] Example 25:

[0524] Synthesis route:

[0525] Synthesis of intermediate 25-2:

[0526] Compound 25-1 (1.0 g, 2.55 mmol) was dissolved in dry pyridine (10.0 mL), and TES-OTF (6.72 g, 25.48 mmol) was added. The mixture was reacted overnight at room temperature. LC-MS analysis showed that the reaction was complete. The system was concentrated under reduced pressure and purified by normal-phase column chromatography to give a white oily compound (1.3 g, 82.19%). LC-MS (ESI): m / z found [M+H] + =621.2.

[0527] Synthesis of intermediate 25-3:

[0528] Compound 25-2 (1.3 g, 2.09 mmol) was dissolved in toluene (13.0 mL), Lawson's reagent (2.11 g, 5.23 mmol) was added, and the mixture was heated to 110 °C for 4 h. TLC analysis showed that the reaction proceeded completely. After cooling, the mixture was concentrated under reduced pressure and purified by normal-phase column chromatography to obtain a yellow solid compound (500 mg, 37.4%). LC-MS (ESI): m / z found [M+H] + =638.2.

[0529] Synthesis of compound 25:

[0530] Compound 25-3 (500 mg, 0.78 mmol) was dissolved in DCM (5 mL), and TFA (5 mL) was added. The mixture was reacted overnight at room temperature, and the reaction was confirmed to be complete by LC-MS. The system was concentrated under reduced pressure, dissolved in a small amount of DMF, and purified by reversed-phase column chromatography to obtain a yellow solid compound 25 (210 mg, 65.5%). LC-MS (ESI): m / z found [M+H] + =409.2

[0531] Example 26:

[0532] Except for replacing the corresponding reaction raw materials, Example 26 was synthesized according to the synthesis method of Example 14a, and Examples 2b to 22b were synthesized according to the synthesis methods of Examples 2a to 22a. The structures and LC-MS information of Examples 2b to 22b are shown in Table 1.

[0533] Table 1. Structures and LC-MS of Examples 26a and 2b-22b

[0534] Example 27:

[0535] Synthesis route:

[0536] Synthesis of compound 27:

[0537] At room temperature, 27-1 (16 mg, 0.011 mmol) and HATU (5.1 mg, 0.013 mmol) were dissolved in DMF (2 mL), and compound 2a (10 mg, 0.011 mmol) and DIEA (3.8 μL, 0.022 mmol) were added. The product was purified by HPLC to obtain a yellow solid, 27-1 (2.02 mg, 30%). LC-MS (ESI): m / z found [M / 2+H] + =948.32.

[0538] Example 28:

[0539] Synthesis route:

[0540] Synthesis of compound 28:

[0541] Compound 27-1 (17 mg, 0.0114 mmol) and HATU (5.2 mg, 0.0137 mmol) were dissolved in DMF (3 mL) under ice bath conditions and reacted for 15 min. Then, compound 3a (5 mg, 0.0114 mmol) and DIPEA (3.9 μL) were added, followed by slow heating to room temperature and stirring for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was purified by pre-HPLC and lyophilized to give a yellow solid, compound 28 (7.01 mg, 32%). LC-MS (ESI): m / z found [M / 2+H] + =955.2.

[0542] Example 29:

[0543] Synthesis route:

[0544] Synthesis of intermediate 29-2:

[0545] 29-1 (500 mg, 1.61 mmol) was dissolved in DCM (35 mL), and (PNP)₂CO (1.96 g, 6.44 mmol) and DIEA (208 mg, 1.61 mmol) were added. The mixture was reacted at room temperature for 16 h. TLC showed that the reaction proceeded substantially to completion. After concentration under reduced pressure, the mixture was purified by normal-phase column chromatography and concentrated under reduced pressure to give a yellow solid compound (550 mg, 63.7%).

[0546] Synthesis of intermediate 29-3:

[0547] 29-2 (61.2 mg, 0.114 mmol) was dissolved in DMF (2 mL), HOBt (17 mg, 0.126 mmol) was added, and the mixture was stirred for 30 min. Then, DIEA (30 mg, 0.228 mmol) and compound 3a (50 mg, 0.114 mmol) were added, and the mixture was reacted at room temperature for 2 h. The mixture was purified by reversed-phase column chromatography, concentrated under reduced pressure, and lyophilized to give a yellow solid compound (76 mg, 79%). LC-MS (ESI): m / z found [M+H] + =835.4.

[0548] Synthesis of intermediate 29-4:

[0549] 29-3 (76 mg, 0.091 mmol) was dissolved in DMF (3 mL), and piperidine (78 mg, 0.91 mmol) was added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The compound was purified by pre-HPLC and lyophilized to give a yellow solid compound (20 mg, 30%). LC-MS (ESI): m / z found [M+H] + =612.35.

[0550] Synthesis of compound 29:

[0551] 29-5 (11 mg, 8.17 μmol) was dissolved in DMF (1 mL), and HATU (5 mg, 9.8 μmol) was added. The mixture was reacted at room temperature for 2 h, followed by the sequential addition of DIEA (1 mg, 8.17 μmol) and 294 (3.73 mg, 8.17 μmol), and the reactions were continued at room temperature for 6 h. The reaction was monitored for completeness by LC-MS. Pre-HPLC was performed, and the mixture was lyophilized to give a yellow solid compound 29 (2.01 mg, 12.6%). LC-MS (ESI): m / z found [M / 2+H] + =970.85.

[0552] Except for replacing the corresponding reaction raw materials, Example 30 was synthesized according to the synthesis method of Example 29. The structure and LC-MS information are shown in Table 1.

[0553] Table 2. Structure and LC-MS of Example 30

[0554] Example 31:

[0555] Synthesis route:

[0556] Synthesis of intermediate 31-2:

[0557] Compound 31-1 (200 mg, 0.112 mmol) was dissolved in DCM (5 mL) at room temperature, and TFA (2 mL) was added. The reaction was carried out at room temperature for 2 h. After dilution with water, one drop of the free product DIEA was added, followed by extraction with EA, concentration under reduced pressure, and purification by reversed-phase column chromatography to obtain a yellow solid compound (140 mg, 86%). LC-MS (ESI): m / z found [M+H] + =469.20.

[0558] Synthesis of intermediate 31-3:

[0559] At room temperature, Boc-L-Val (50 mg, 0.088 mmol) and HATU (136 mg, 0.112 mmol) were dissolved in DMF (1.5 mL), followed by the addition of compound 31-2 (50 mg, 0.088 mmol) and DIEA (116 mg, 0.120 mmol). The reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The compound was purified by reversed-phase column chromatography and concentrated under reduced pressure to obtain the compound (150 mg, 71%). LC-MS (ESI): m / z found [M+H] + =668.2.

[0560] Synthesis of intermediate 31-4:

[0561] At room temperature, 31-3 (75 mg, 0.112 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction was allowed to proceed for 2 h at room temperature. The reaction was monitored by LC-MS until complete, and the solid was purified by reversed-phase column chromatography to obtain a yellow solid (60 mg, 86%). LC-MS (ESI): m / z found [M+H] + =568.20.

[0562] Synthesis of intermediate 31-5:

[0563] At room temperature, Azido-dPEG 4-acid (28 mg, 0.088 mmol) was dissolved in DMF (1.5 mL), followed by the sequential addition of HATU (55 mg, 0.112 mmol), 31-4 (55 mg, 0.088 mmol), and DIEA (25 mg, 0.120 mmol). The reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The product was purified by reversed-phase column chromatography and lyophilized to obtain the target product (37 mg, 56%). LC-MS (ESI): m / z found [M+H] + =840.30.

[0564] Synthesis of compound 31:

[0565] At room temperature, 31-6 (16 mg, 0.088 mmol) was dissolved in DMSO (1.5 mL), followed by the addition of ascorbic acid (8.5 mg, 0.112 mmol), anhydrous copper sulfate (6 mg), and 31-5 (55 mg, 0.088 mmol). The mixture was reacted at room temperature for 2 h. LC-MS monitoring showed that the reaction was essentially complete. The mixture was purified by pre-HPLC and lyophilized to give a yellow solid compound 31 (2.3 mg). LC-MS (ESI): m / z found [M / 2+H] + =818.70.

[0566] Example 32:

[0567] Synthesis route:

[0568] Synthesis of compound 32:

[0569] Compound 10a (5 mg, 0.0114 mmol) was dissolved in N,N-dimethylaniline (3 mL) under ice bath conditions, followed by the addition of N,N-diisopropylethylamine (2 μL, 0.0114 mmol). After reacting for 15 min, compound 31-1 (16 mg, 0.0114 mmol) and N,N-diisopropylethylamine (2 μL, 0.0114 mmol) were added, followed by incubation at room temperature for 2 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was purified by pre-HPLC to obtain compound 32 (4.84 mg, 25%). LC-MS (ESI): m / z found [M+H] + =1721.0.

[0570] Example 33:

[0571] Example 33:

[0572] Synthesis route:

[0573] Synthesis of intermediate 33-2:

[0574] Compound 33-1 (1 g, 0.0063 mmol) was dissolved in methanol (60 mL) at room temperature. MeSNa (884 mg, 0.0126 mmol) and K₂CO₃ (1.74 g, 0.0126 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. LCMS (5-100, 3 min) was used to determine if the reaction was complete. The reaction solution was dried under reduced pressure. The crude product was dissolved in water, and the aqueous phase was washed three times with ethyl acetate. The collected aqueous phase was placed in an ice bath, and 2N hydrochloric acid was slowly added repeatedly until a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with pure water. The filter cake was collected and lyophilized to give a white solid, compound 33-2 (707 mg, 65.93%). LCMS (ESI): m / z found [M+H] + =171.0.

[0575] Synthesis of intermediate 33-3:

[0576] Compound 33-2 (300 mg, 1.765 mmol) was dissolved in 10 mL of DCM under ice bath conditions. HOSU (245 mg, 2.118 mmol) and EDCI (406 mg, 2.118 mmol) were added sequentially. After stirring in an ice bath for 2 h, amino-hexaethylene glycol-carboxylic acid (624 mg, 1.765 mmol) and TEA (245 μL, 1.176 mmol) were added, and the reaction was allowed to proceed at room temperature for 2 h. LC-MS analysis confirmed complete reaction of the starting material. The reaction solution was dried under reduced pressure, dissolved in a small amount of methanol, purified by reverse column chromatography, and lyophilized to obtain a pale yellow oily solid, compound 33-3 (285.9 mg, 32.04%). LC-MS (ESI): m / z found [M+H] + =506.2.

[0577] Synthesis of intermediate 33-4:

[0578] Compound 33-3 (285.9 mg, 0.565 mmol) was dissolved in 10 mL of DCM under ice bath conditions. M-chloroperoxybenzoic acid (243.96 g, 1.414 mmol) was added, and the mixture was in an ice bath for 10 min, then the reaction was carried out at room temperature for 3 h. LC-MS (100-1000, 4 min) was used to determine if the reaction was complete. The reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by reverse-phase column chromatography and lyophilized to give compound 33-4 (173 mg, 56.9%) as a pale yellow oily solid. LC-MS (ESI): m / z found [M+H] + =538.4.

[0579] Synthesis of intermediate 33-6:

[0580] Compound 33-4 (50 mg, 0.093 mmol) was dissolved in DMF (2.5 mL) under ice bath conditions. HATU (40.32 mg, 0.106 mmol) was added, and the mixture was reacted under ice bath conditions for 10 min. Then, DIEA (30.78 μL, 0.176 mmol) and compound 33-5 (31.3 mg, 0.093 mmol) were added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored for completeness by LC-MS (5-100, 3 min). The reaction solution was filtered and purified manually by pre-HPLC to obtain a white solid 33-6 (10 mg, 12.56%). LC-MS (ESI): m / z found [M+H] + =856.2.

[0581] Synthesis of compound 33:

[0582] Under ice bath conditions, 33-6 (6.1 mg, 0.0071 mmol) was dissolved in DMF (2.5 mL), and HATU (3.2 mg, 0.0085 mmol) was added. The mixture was reacted under ice bath conditions for 10 min, followed by the addition of DIEA (2.5 μL, 0.0142 mmol) and compound 2a (3.0 mg, 0.0071 mmol). The mixture was stirred at room temperature for 2 h. The reaction was monitored for completeness by LC-MS (5-100, 3 min). The reaction solution was filtered and purified manually by pre-HPLC to obtain a white solid compound 33 (2.45 mg, 27.35%). LC-MS (ESI): m / z found [M+H] + =1261.34.

[0583] Example 34:

[0584] Synthesis route:

[0585] Synthesis of intermediate 34-2:

[0586] Compound 11a (18.3 mg, 0.043 mmol) was dissolved in DCM (3 mL) at room temperature, followed by the addition of compound 34-1 (78.66 mg, 0.21 mmol) and TFA (25 μL). The reaction was allowed to proceed for 4 h at room temperature. LCMS (5-100, 3 min) was used to determine the completeness of the reaction. The reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by pre-HPLC to obtain a white solid compound 34-2 (13.5 mg, 40.17%). LCMS (ESI): m / z found [M+H] + =787.2.

[0587] Synthesis of intermediate 34-3:

[0588] Compound 34-2 (13.5 mg, 0.017 mmol) was dissolved in DCM (4 mL) at room temperature, and diethylamine (1 mL) was added. The reaction was allowed to proceed for 1.5 h at room temperature. LC-MS (5-100, 3 min) showed that the reaction proceeds were completely reacted. The reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by pre-HPLC to obtain a white solid compound 34-3 (9.7 mg, 100%). LCMS (ESI): m / z found [M+H] + =565.2.

[0589] Synthesis of intermediate 34-5:

[0590] Compound 34-4 (11.68 mg, 0.023 mmol) was dissolved in DMF (2 mL) under ice bath conditions. HATU (10.48 mg, 0.028 mmol) was added, and the mixture was reacted under ice bath conditions for 10 min. Then, DIEA (6 μL, 0.034 mmol) and compound 34-3 (13 mg, 0.023 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. The reaction was monitored for completeness by LC-MS (5-100, 3 min). The reaction solution was filtered and purified by pre-HPLC to obtain a yellow solid compound 35-5 (4 mg, 19.86%). LCMS (ESI): m / z found [M+H] + =1056.2.

[0591] Synthesis of compound 34:

[0592] Compound 34-5 (4 mg, 0.001 mmol) was dissolved in a mixed solution of EtOH (1.5 mL) and THF (0.5 mL) at room temperature. Compound 31-6 (3 mg, 0.001 mmol), copper sulfate pentahydrate (1.14 mg, 0.0012 mmol), and vitamin C (0.8 mg, 0.0012 mmol) were added. The mixture was purged three times with nitrogen and reacted at room temperature for 2 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was dried under reduced pressure, dissolved in a small amount of DMF, and purified by pre-HPLC to obtain a yellow solid compound 34 (0.3 mg, 4.28%). LC-MS (ESI): m / z found [M+H / 2] + =925.0.

[0593] Example 35:

[0594] Synthesis route:

[0595] Synthesis of intermediate 35-1:

[0596] Compound 25a (135 mg, 0.331 mmol) was dissolved in a mixed solvent of DMF (1 mL) and DMSO (1 mL), and bis(p-nitrobenzene) carbonate (301 mg, 0.993 mmol) and DIEA (59 μL, 0.331 mmol) were added. The reaction was carried out at room temperature for 3 h. The reaction was monitored by LCMS until complete. The product was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by normal-phase column chromatography to give a yellow solid product (100 mg, 52.9%). LCMS (ESI): m / z found [M+H] + =574.0.

[0597] Synthesis of intermediate 35-3:

[0598] Compound 35-2 (150 mg, 0.239 mmol) was dissolved in DMA (4 mL), and N,N'-dimethylethylenediamine (26 μL, 0.239 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 1.5 h. LCMS analysis showed the reaction was complete. The product was purified by reversed-phase column chromatography, concentrated under reduced pressure by distillation, and lyophilized to give a yellow solid (100 mg, 41.3%). LCMS (ESI): m / z found [M+H] + =577.2.

[0599] Synthesis of intermediate 35-4:

[0600] Compounds 35-3 (100 mg, 0.174 mmol) and 35-4 (100 mg, 0.174 mmol) were dissolved in DMA (2.5 mL) and reacted in an ice bath for 1.5 h. The reaction was confirmed to be complete by LCMS. The product was purified by reversed-phase column chromatography, concentrated under reduced pressure by distillation, and lyophilized to give a yellow solid product (55 mg, 31.4%). LCMS (ESI): m / z found [M+H] + =1011.2.

[0601] Synthesis of compound 35:

[0602] Compounds 35-4 (20 mg, 0.020 mmol), 31-6 (15.7 mg, 0.020 mmol), copper sulfate pentahydrate (5.9 mg, 0.024 mmol), and ascorbic acid (4.2 mg, 0.024 mmol) were dissolved in a mixed solvent of anhydrous ethanol (1.5 mL) and tetrahydrofuran (0.5 mL). The reaction was carried out under nitrogen protection at room temperature for 2.5 h. The reaction was confirmed to be complete by LCMS. The solvent was evaporated under reduced pressure, and the solution was prepared by HPLC and lyophilized to give a yellow solid compound 35 (7.04 mg, 19.7%). LCMS (ESI): m / z found [M / 2+H] + =902.8.

[0603] Example 36:

[0604] Synthesis route:

[0605] Synthesis of intermediate 36-1:

[0606] Compound 35-1 (40 mg, 0.070 mmol) was dissolved in DMA (2.5 mL), and N-BOC-N,N'-dimethylethylenediamine (13.6 μL, 0.070 mmol) was added. The reaction was allowed to proceed at room temperature for 1.5 h. The reaction was monitored by LCMS until complete. The product was purified by reversed-phase column chromatography, concentrated under reduced pressure by distillation, and lyophilized to give a yellow solid product (40 mg, 92.0%). LCMS (ESI): m / z found [M+H] + =623.2.

[0607] Synthesis of intermediate 36-2:

[0608] Compound 36-1 (40 mg, 0.064 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 h. LCMS analysis showed that the reaction was complete. The system was concentrated under reduced pressure to obtain the crude product, which was directly added to the next reaction (35 mg). LCMS (ESI): m / z found [M+H] + =523.2. Synthesis of compound 36:

[0609] Compound 36-3 (40 mg, 0.028 mmol) was dissolved in DMA (3 mL), and HATU (12.8 mg, 0.034 mmol) was added. After reacting at room temperature for 15 min, compound 36-2 (14.8 mg, 0.028 mmol) and DIEA (7.6 μL, 0.042 mmol) were added, and the reaction was carried out at room temperature for 1 h. The reaction was monitored by LCMS until complete. The product was prepared by HPLC (0.1% formic acid-water system), lyophilized, and a yellow solid product 36 (8.6 mg, 16.1%) was obtained. LCMS (ESI): m / z found [M / 2+H] + =954.2.

[0610] Example 37:

[0611] Synthesis route:

[0612] Synthesis of intermediate 37-1:

[0613] Compound 24a (80 mg, 0.172 mmol) was dissolved in toluene (2.5 mL), and compound 34-1 (316 mg, 0.858 mmol) and zinc acetate (63 mg, 0.343 mmol) were added. The reaction was carried out at room temperature for 3 h. The reaction was confirmed to be complete by LCMS. The product was purified by pre-HPLC, lyophilized, and given as a yellow solid (25 mg, 18.8%). LCMS (ESI): m / z found [M+H] + =775.2.

[0614] Synthesis of intermediate 37-2:

[0615] Compound 37-2 (25 mg, 0.032 mmol) was dissolved in DMF (1 mL), and diethylamine (0.2 mL) was added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by LCMS until complete. The product was purified by pre-HPLC, lyophilized, and yielded a yellow solid (5 mg, 28.1%). LCMS (ESI): m / z found [M+H] + =553.0.

[0616] Synthesis of compound 37:

[0617] Compound 29-5 (5 mg, 0.009 mmol) was dissolved in DMF (0.5 mL), and HATU (4 mg, 0.011 mmol) was added. After stirring at room temperature for 15 min, compound 37-2 (316 mg, 0.858 mmol) and DIEA (1.16 mg, 0.343 mmol) were added. The reaction was allowed to proceed at room temperature for 2 h. The reaction was confirmed to be complete by LCMS. The product was purified by HPLC and lyophilized to give a yellow solid, 37 (1.95 mg, 11.5%). LCMS (ESI): m / z found [M / 2+H] + =940.8.

[0618] Example 38:

[0619] Synthesis route:

[0620] Synthesis of intermediate 38-1:

[0621] Compound 24a (64 mg, 0.137 mmol) was dissolved in DMF (0.6 mL), and DIEA (48 μL) and (PNP)₂CO (167 mg, 0.5494 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction was confirmed to be complete by LCMS. The product was purified by reversed-phase column chromatography to give a yellow solid (40 mg, 46.2%). LCMS (ESI): m / z found [M+H] + =632.0.

[0622] Synthesis of intermediate 38-2:

[0623] Compound 38-1 (20 mg, 0.137 mmol) was dissolved in DMA (0.6 mL), and DIEA (11 μL), HOBT (5 mg, 0.035 mmol), and N,N'-dimethylethylenediamine (3.5 μL) were added. The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS until complete. The product was purified by reversed-phase column chromatography (42% ACN in H2O) to give a yellow solid (22 mg, 27.6%). LCMS (ESI): m / z found [M+H] + =581.2.

[0624] Synthesis of compound 38:

[0625] Compound 36-3 (24 mg, 0.017 mmol) was dissolved in DMA (0.6 mL), followed by the addition of DIEA (4.5 μL), HATU (7.9 mg, 0.021 mmol), and 38-2 (10 mg, 0.017 mmol). The mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by LC-MS. The reaction solution was filtered, concentrated, and purified by HPLC to give a yellow solid product 38 (0.71 mg). LC-MS (ESI): m / z found [M / 2+H] + =983.9.

[0626] Except for replacing the corresponding raw materials, Example 39 was synthesized according to the synthesis method of Example 34. The structure and LC-MS information are shown in Table 3.

[0627] Table 3. Structure and LC-MS of Example 39

[0628] Example 40:

[0629] Synthesis route:

[0630] Synthesis of compound LP-4:

[0631] Linker 3 (10 mg, 8.33 μmol) was dissolved in DMF (1 mL), and HATU (5 mg, 9.16 μmol) was added. The mixture was reacted at room temperature for 2 h, followed by the addition of DIEA (1 mg, 16.67 μmol) and 9-4 (3.73 mg, 8.33 μmol), and then reacted again at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The product was purified by pre-HPLC and lyophilized to give a yellow solid (3.69 mg, 25.2%). LC-MS (ESI): m / z found [M / 2+H] + =897.85.

[0632] Example 41:

[0633] Synthesis route:

[0634] Synthesis of intermediate 41-3:

[0635] 41-2 (1 g, 0.824 mmol) was dissolved in DMF (4 mL), and 41-1 (280 mg, 0.824 mmol) and DIEA (150 μL, 0.906 mmol) were added. The mixture was reacted at room temperature for 4 hours. After the reaction was complete, the product was purified by reversed-phase column chromatography and concentrated under reduced pressure to obtain a colorless oily product (1.15 g, 97.0%). LC-MS (ESI): m / z found [M+1] + =1440.2.

[0636] Synthesis of intermediate 41-4:

[0637] Compound 41-3 (1.15 g, 0.799 mmol) was dissolved in DMF (5 mL), and HOSU (124 mg, 1.079 mmol) and EDCI (206 mg, 1.079 mmol) were added. After reacting at room temperature for 2 hours, DIEA (132 μL, 0.799 mmol) and GGFG-AM (457 mg, 1.079 mmol) were added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by LC-MS until complete, and the product was purified by reversed-phase column chromatography and concentrated under reduced pressure to give a colorless oily product (1.1 g, 78.6%). LC-MS (ESI): m / z found [M / 2-36] + =885.0.

[0638] Synthesis of intermediate 41-5:

[0639] Compound 41-4 (500 mg, 0.271 mmol) was dissolved in DMF (5 mL), and 11 (138.5 mg, 0.326 mmol, synthesized according to WO2024230752A1), HATU (124 mg, 0.326 mmol), and DIEA (90 μL, 0.542 mmol) were added. The reaction was carried out at room temperature for 2.5 hours. After the reaction was monitored by LC-MS until complete, the product was purified by reversed-phase column chromatography and lyophilized to give a yellow solid product (341 mg, 55.9%). LC-MS (ESI): m / z found [M / 2+1] + =1127.35.

[0640] Synthesis of intermediate 41-6:

[0641] Compound 41-5 (341 mg, 0.151 mmol) was dissolved in DMF (5 mL), and diethylamine (76 μL) was added. The reaction was carried out at room temperature for 2.5 hours. After the reaction was monitored by LC-MS until complete, the product was purified by reversed-phase column chromatography and concentrated under reduced pressure to give a yellow oily product (150 mg, 48.9%). LC-MS (ESI): m / z found [M / 2+1] + =1016.20.

[0642] Synthesis of intermediate 41-7:

[0643] Azideacetic acid (13.4 mg, 0.133 mmol) was dissolved in DMF (2 mL), followed by the addition of DMTMM (61 mg, 0.222 mmol), TEA (29 μL, 0.222 mmol), and compounds 1-6 (150 mg, 0.074 mmol). The reaction was carried out at room temperature for 3 hours. After the reaction was confirmed to be complete by LC-MS, the product was prepared by pre-HPLC and lyophilized to obtain a yellow solid product (32 mg, 20.5%). LC-MS (ESI): m / z found [M / 2+1] + =1057.75.

[0644] Synthesis of compound 41:

[0645] Compounds 41-7 (30 mg, 0.014 mmol), 41-8 (15.7 mg, 0.014 mmol), copper sulfate pentahydrate (4.2 mg, 0.017 mmol), and ascorbic acid (4.8 mg, 0.029 mmol) were dissolved in DMSO (1.5 mL). The reaction was carried out at room temperature for 1.5 h under nitrogen protection. The reaction was confirmed to be complete by LCMS. The final product was prepared by HPLC and lyophilized to give a yellow solid, compound 41 (0.93 mg, 2.2%). LCMS (ESI): m / z found [M / 2+H] + =1454.5.

[0646] Example 42:

[0647] Synthesis route:

[0648] Synthesis of intermediate 42-2:

[0649] Compound 42-1 (5.0 g, 5.24 mmol) was dissolved in DCM (50 mL), and ethylene glycol (8.4 g, 52.4 mmol) and PPTS (6.8 g, 10.86 mmol) were added sequentially. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, dissolved in a small amount of DMF, purified by reversed-phase column chromatography, and concentrated under reduced pressure to give a white solid (3.2 g, 61.3%).

[0650] Synthesis of intermediate 42-3:

[0651] Compound 2-2 (500 mg, 1.61 mmol) was dissolved in DCM (35 mL), and PNP2CO (1.96 g, 6.11 mmol) and DIEA (208.18 mg, 1.61 mmol) were added in portions. The mixture was reacted overnight at room temperature. The reaction proceeded to completion as monitored by TLC. The mixture was purified by normal-phase column chromatography and concentrated under reduced pressure to give a yellow oil (320 mg, 44.26%).

[0652] Synthesis of intermediate 42-4:

[0653] Compound 42-3 (251.72 mg, 0.468 mmol) was dissolved in DMF (2 mL). HOBt (69.8 mg, 0.516 mmol) was added under ice bath conditions, and the mixture was reacted at room temperature for 15 min. Then, 11 (200 mg, 0.468 mmol) and DIEA (121.24 mmol, 0.94 mmol) were added sequentially, and the reaction was continued at room temperature for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The mixture was purified by reversed-phase column chromatography and lyophilized to give a yellow solid (180 mg, 46.13%). LC-MS (ESI): m / z found [M+1] + =822.0.

[0654] Synthesis of intermediate 42-5:

[0655] Compound 42-4 (50 mg, 0.06 mmol) was dissolved in DMF (1 mL), and piperidine (30.9 μL, 0.3 mmol) was added. The mixture was reacted at room temperature for 1 h. The reaction was monitored by LC-MS until complete. The mixture was purified by reverse-phase column chromatography and lyophilized to give a yellow solid (7 mg, 19.38%). LC-MS (ESI): m / z found [M+1] + =600.4.

[0656] Synthesis of intermediate 42-7:

[0657] At room temperature, 42-6 (1 g, 1.7 mmol) was dissolved in DMF (4 mL), and HOSU (215.2 mg, 1.87 mmol) and EDCI (358 mg, 1.87 mmol) were added. The reaction was carried out at room temperature for 6 hours, followed by the addition of 1-1 (578 mg, 1.7 mmol) and DIEA (444.3 μL, 2.55 mmol), and the reaction was carried out at room temperature for 2 hours. The reaction mixture was checked by LC-MS to confirm complete reaction. The reaction solution was filtered, and the filtrate was purified by reversed-phase column chromatography and lyophilized to give a white oily substance (1.142 g, 73.77%). LC-MS (ESI): m / z found [M+H] + =911.8.

[0658] Synthesis of intermediate 42-8:

[0659] At room temperature, 42-7 (1.142 g, 1.25 mmol) was dissolved in ACN (10 mL), and HOSU (216.4 mg, 1.88 mmol) and DCC (388 mg, 1.88 mmol) were added. The reaction was carried out at room temperature for 2 hours, and then the reaction solution was filtered. The filtrate was collected and concentrated under reduced pressure. The crude product was dissolved in DMF (5 mL), and DIEA (327.5 μL, 1.88 mmol) and GGF (420 mg, 1.5 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction mixture was monitored by LC-MS to ensure complete reaction of the starting material. The reaction solution was filtered, and the filtrate was purified by reversed-phase column chromatography and concentrated under reduced pressure to give a white oily substance (1.076 g, 73.22%). LC-MS (ESI): m / z found [M+H / 2] + =587.2.

[0660] Synthesis of intermediate 42-9:

[0661] At room temperature, 42-8 (400 mg, 0.34 mmol) was dissolved in DMF (2 mL), and piperidine (337 μL, 3.41 mmol) was added. The reaction was carried out at room temperature for 2 hours. LC-MS analysis showed that the reaction proceeded completely. The reaction solution was purified by automated pre-HPLC and concentrated under reduced pressure to obtain a white oil (159.3 mg, 49.14%). LC-MS (ESI): m / z found [M+H] + =950.7.

[0662] Synthesis of intermediate 42-10:

[0663] At room temperature, 42-9 (45 mg, 0.047 mmol) was dissolved in DMF (2.5 mL), followed by the addition of NHS azidoacetate (18.8 mg, 0.095 mmol) and DIEA (16.5 μL, 0.095 mmol). The reaction was allowed to proceed for 1.5 hours at room temperature. The reaction was monitored by LC-MS until complete. Pre-HPLC purification was performed, and the product was lyophilized to obtain a white oil (19.4 mg, 39.65%). LC-MS (ESI): m / z found [M+H] + =1033.75.

[0664] Synthesis of intermediate 42-11:

[0665] At room temperature, 42-10 (19.4 mg, 0.019 mmol) was dissolved in a mixed solution of EtOH (3 mL) and THF (1 mL), followed by the addition of 42-8 (13.54 mg, 0.017 mmol), CuSO4·5H2O (4.3 mg, 0.017 mmol), and ascorbic acid (3 mg, 0.017 mmol). The mixture was purged with nitrogen three times and reacted at room temperature for 3 h. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, dissolved in a small amount of methanol, purified by pre-HPLC, and lyophilized to give a yellow solid compound (19.1 mg, 61.24%). LC-MS (ESI): m / z found [M+H / 2] + =914.45. Synthesis of compound 42:

[0666] Compound 42-11 (10 mg, 0.005 mmol) was dissolved in DMF (2 mL) under ice bath conditions. HATU (2.5 mg, 0.007 mmol) was added, and the mixture was stirred under ice bath conditions for 20 min. Then, 42-5 (3.3 mg, 0.005 mmol) and DIEA (1.43 μL, 0.008 mmol) were added sequentially, and the mixture was reacted at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was filtered, and the filtrate was purified by Pre-HPLC and lyophilized to give a yellow solid product (2.07 mg, 15.7%). LC-MS (ESI): m / z found [M+H / 2] + =1205.35.

[0667] Example 43:

[0668] Synthesis route:

[0669] Synthesis of intermediate 43-1:

[0670] At room temperature, 41-3 (488.5 mg, 0.339 mmol) was dissolved in ACN (5 mL), and HOSU (58.58 mg, 0.509 mmol) and DCC (105 mg, 0.509 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The crude product was dissolved in DMF (3 mL), and DIEA (88.6 μL, 0.509 mmol) and GGF (113.7 mg, 0.407 mmol) were added. The mixture was reacted at room temperature for 2 hours. LC-MS analysis showed that the reaction was complete. The reaction solution was filtered, and the filtrate was purified by reversed-phase column chromatography and concentrated under reduced pressure to obtain a colorless oil (456.3 mg, 79.11%). LC-MS (ESI): m / z found [M+H / 2] + =851.85.

[0671] Synthesis of intermediate 43-2:

[0672] At room temperature, 43-1 (200 mg, 0.1176 mmol) was dissolved in DMF (2 mL), and piperidine (116.2 μL, 1.176 mmol) was added. The reaction was carried out at room temperature for 2 hours. LC-MS analysis showed that the reaction proceeded completely. The reaction solution was purified by Pre-HPLC and concentrated under reduced pressure to obtain a white oil (48.7 mg, 32.8%). LC-MS (ESI): m / z found [M+H] + =1479.25.

[0673] Synthesis of intermediate 43-3:

[0674] At room temperature, 43-2 (48.7 mg, 0.033 mmol) was dissolved in DMF (2.5 mL), followed by the addition of NHS azidoacetate (13 mg, 0.066 mmol) and DIEA (11.5 μL, 0.066 mmol). The reaction was allowed to proceed for 1.5 hours at room temperature. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was purified by Pre-HPLC and concentrated under reduced pressure to obtain a colorless oil (33.7 mg, 65.52%). LC-MS (ESI): m / z found [M+H] + =1562.25.

[0675] Synthesis of intermediate 43-4:

[0676] At room temperature, compound 43-3 (33.7 mg, 0.022 mmol) was dissolved in a mixed solution of EtOH (3 mL) and THF (1 mL), followed by the addition of compound 41-8 (15.56 mg, 0.020 mmol), copper sulfate pentahydrate (4.9 mg, 0.020 mmol), and ascorbic acid (3.5 mg, 0.020 mmol). The mixture was purged with nitrogen three times and reacted at room temperature for 2.5 h. After the reaction was complete, the reaction solution was dried under reduced pressure, dissolved in a small amount of methanol, purified by pre-HPLC, and lyophilized to give a yellow solid compound (28.8 mg, 56.66%). LC-MS (ESI): m / z found [M+H / 2] + =1178.85.

[0677] Synthesis of compound 43:

[0678] Under ice bath conditions, 43-4 (10 mg, 0.004 mmol) was dissolved in DMF (2 mL), and HATU (1.94 mg, 0.005 mmol) was added. After stirring in an ice bath for 30 min, 42-5 (2.55 mg, 0.004 mmol) and DIEA (1.11 μL, 0.006 mmol) were added sequentially, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was purified by pre-HPLC and lyophilized to give a yellow solid product (2.82 mg, 22.7%). LC-MS (ESI): m / z found [M+H / 2] + =1469.6.

[0679] Example 44

[0680] Except for replacing the corresponding reaction raw materials, Example 44 was synthesized according to the synthesis method of Example 32. The structure and LC-MS information are shown in Table 4.

[0681] Table 4. Structure and LC-MS of Example 44

[0682] Example 45:

[0683] Synthesis route:

[0684] Synthesis of intermediate 45-2:

[0685] At room temperature, 2-1 (100 mg, 0.272 mmol) was dissolved in DCM (2 mL), followed by the addition of 45-1 (42.38 mg, 0.543 mmol) and PPTS (136.44 mg, 0.543 mmol). The mixture was stirred at room temperature for 3 h under N2 protection. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure, dissolved in an appropriate amount of MeOH, purified by reversed-phase column chromatography, concentrated under reduced pressure, and lyophilized to obtain a white powder (45.9 mg, 43.7%). LC-MS (ESI): m / z found [M+H] + =617.40.

[0686] Synthesis of intermediate 45-3:

[0687] At room temperature, 45-2 (275.4 mg, 0.752 mmol) was dissolved in DMF (2 mL), followed by the addition of diethylamine (75 μL). The mixture was stirred at room temperature for 2 h under N2 protection. The reaction was monitored by LC-MS until complete. The product was purified by reversed-phase column chromatography, concentrated under reduced pressure, and lyophilized to obtain a yellow oil (127.2 mg, 100%). LC-MS (ESI): m / z found [M+H] + =163.2.

[0688] Synthesis of intermediate 45-6:

[0689] Under ice bath conditions, 45-4 (100 mg, 0.343 mmol) was dissolved in DMF (1 mL), followed by HOSU (47.41 mg, 0.412 mmol) and EDCI (79.09 mg, 0.412 mmol). The reaction was maintained on ice for 1 h. Then, 45-5 (95.88 mg, 0.343 mmol) and TEA (34.67 mg, 0.343 mmol) were added, and the reaction was continued at room temperature for 3 h. The reaction was monitored by LC-MS until complete. The reaction solution was purified by reversed-phase column chromatography, concentrated under reduced pressure, and lyophilized to give a yellow oily product (83.5 mg, 44%). LC-MS (ESI): m / z found [M+H] + =553.2.

[0690] Synthesis of intermediate 45-7:

[0691] At room temperature, 45-6 (168.3 mg, 0.305 mmol) was dissolved in THF (3 mL), followed by the addition of DCC (75.5 mg, 0.366 mmol) and HOSU (42.10 mg, 0.366 mmol). The mixture was stirred at room temperature for 2 h. LC-MS showed complete reaction. After stirring in an ice bath for 10 min, a large amount of white solid precipitated. The solid was filtered, washed with THF, and the filtrate was reserved. At room temperature, 45-3 (60 mg, 0.366 mmol) was dissolved in an aqueous solution of NaHCO3 (3 mL) and added dropwise to the above filtrate. The mixture was stirred at room temperature for 2 h. LC-MS showed complete reaction. The reaction solution was concentrated under reduced pressure, a small amount of water was added, and the pH was adjusted to 3 with a saturated sodium citrate solution. The solution was filtered, collected, concentrated under reduced pressure, and lyophilized to obtain a yellow oily substance (271.9 mg, 100%). LC-MS (ESI): m / z found [M+H] + =698.2.

[0692] Synthesis of intermediate 45-8:

[0693] At room temperature, 45-7 (100 mg, 0.143 mmol) was dissolved in DMSO (1 mL), followed by the addition of 1-8 (91 mg, 0.115 mmol), CuSO4·5H2O (35.82 mg, 0.143 mmol), and Vc (25.21 mg, 0.143 mmol). The mixture was stirred at room temperature for 5 min under N2 protection. The reaction was monitored by LC-MS until complete. The reaction solution was purified by reversed-phase column chromatography, concentrated under reduced pressure, and lyophilized to give a yellow solid product (83.5 mg, 29.8%). LC-MS (ESI): m / z found [M+H] + =1491.2.

[0694] Synthesis of compound 45:

[0695] At room temperature, 45-8 (108.2 mg, 0.073 mmol) was dissolved in DMF (1 mL), followed by the addition of HATU (33.10 mg, 0.087 mmol) and DIEA (25.27 μL, 0.145 mmol). The mixture was stirred at room temperature for 5 min under N2 protection, then 11 (30.87 mg, 0.0725 mmol) was added, and the mixture was stirred at room temperature for 2 h under N2 protection. The reaction was confirmed to be complete by LC-MS. Pre-HPLC was performed, and the product was lyophilized to obtain a yellow solid (7.3 mg, 5.2%). LC-MS (ESI): m / z found [M+H] + =950.2.

[0696] Example 46:

[0697] Synthesis route:

[0698] Synthesis of Example 46:

[0699] 5-1 (316 mg, 0.211 mmol) was dissolved in DMAc (3 mL), and HATU (88 mg, 0.232 mmol) was added. After reacting at room temperature for 15 minutes, 5-2 (100 mg, 0.211 mmol) and DIEA (27.2 mg, 0.211 mmol) were added, and the reaction was continued at room temperature for 1 hour. After the reaction of the starting materials was complete as monitored by LC-MS, the mixture was prepared by Pre-HPLC and lyophilized to obtain a yellow solid (139 mg, 33.8%). LC-MS (ESI): m / z found [M+H] + =973.2

[0700] Example 47:

[0701] Except for replacing the corresponding raw materials, the synthesis was carried out according to Example 35. The structure and LC-MS results are shown in the table below:

[0702] Examples 48-49:

[0703] Synthesized according to WO2024230752A1 and Example 43, the structure and LC-MS are shown in the table below:

[0704] Example 50:

[0705] Except for replacing the corresponding raw materials, Example 50 was synthesized according to the synthesis method of Example 38. The structure and LC-MS information are shown in the table below.

[0706] Example 51: B7H3 ADC Coupling

[0707] 1. Preparation of solution:

[0708] 1) Prepare 1mM EDTA-PBS buffer with 0.5M EDTA: 20μL EDTA + 10ml PBS.

[0709] 2) Dilute 0.5M TCEP to 5mM: 10μL TCEP + 990μL EDTA-PBS.

[0710] 3) Prepare a 10% DMSO solution: 100 μL DMSO + 900 μL EDTA-PBS.

[0711] 4) Dilute the antibody Ifinatamab to 10 mg / ml.

[0712] 2. TCEP reduction and breakage of disulfide bonds:

[0713] When synthesizing an ADC with a DAR value of 8: antibody: TCEP = 1:8 (molar ratio);

[0714] When synthesizing an ADC with a DAR value of 4: antibody: TCEP = 1:5 (molar ratio);

[0715] 3. Incubate at 37℃ on a shaker for 2 hours (normal shaking speed is 210-230 rpm), and place on ice after shaking.

[0716] 4. Dissolve the Linker-payload (referring to the linker and small molecule drug portions in the ligand-drug conjugate, excluding the ligand portion): Dissolve in pure DMSO to a 5 mg / ml solution.

[0717] 5. Add the Linker-payload to the antibody at a ratio of 1:8 (molar ratio) or 1:5.

[0718] 6. Mix thoroughly using a rotary mixer for 2 hours.

[0719] 7. After mixing, desalinate using a desalination column and ultrafilter 3 times.

[0720] 8. The concentration of ADC coupling products was determined using the BCA method for the samples obtained after ultrafiltration.

[0721] 9. Determine whether the coupling was successful by HPLC-HIC analysis.

[0722] 10. Antibody purity was determined by SEC-HPLC.

[0723] 11. Detect DAR value using LC-MS.

[0724] Positive antibody Ifinatamab heavy chain SEQ ID NO: 1

[0725] Positive antibody Ifinatamab light chain SEQ ID NO: 2

[0726] The names and specific structures of the obtained antibody-drug conjugates are shown in Table 5.

[0727] B7H3 target antibody 1 heavy chain SEQ ID NO: 3

[0728] B7H3 target antibody 1 light chain SEQ ID NO: 4

[0729] Table 5. Names and structural formulas of ligand-drug conjugates

[0730] Note: The antibody used in B7H3-ADC-1 is Ifinatamab, while the antibody used in other ADCs is B7H3 target antibody 1;

[0731] After ultrafiltration, the concentration of the ADC conjugation product was determined using absorbance measurements at 280 nm and 365 nm; successful conjugation was confirmed by HPLC-HIC analysis; antibody purity was determined by SEC-HPLC; and the DAR value was determined by LC-MS. The conjugation results are shown in Table 6.

[0732] Table 6. B7H3-ADC Coupling Results

[0733] Test Example 1: In vitro inhibition test of the disclosed compound on tumor cell proliferation

[0734] The control compound used in this experiment was DXd, with the following structural formula:

[0735] 1. Instruments and reagents

[0736] 2. Experimental Procedure

[0737] a. Plating & Culture: MDA-MB-453 (purchased from: Xiehe, catalog number: 1101HUM-PUMCO00016) / T47D (Kebai, CBP60397) / HT1376 cells (purchased from: Kebai, catalog number: CBP60310) at 1×10 3 / 2×10 3 / 1×10 3 Seed cells at a density of 100 μL into 96-well plates, add 200 μL of PBS to the outermost well (to reduce the volatilization of the culture medium), and incubate at 37°C and 5% CO2 for 24 h.

[0738] b. Adding the drug and incubating: Remove the 96-well plate, aspirate the culture medium from the 96-well plate, add 100 μL of the compound diluted with the culture medium, and treat at 37°C and 5% CO2 for 5 days.

[0739] 3. Detection and Data Processing

[0740] a. Remove the 96-well plate, remove the culture medium, and add 100 μL of detection solution (CCK8: culture medium = 1:9) to each well; place in a 37℃, 5% CO2 incubator for 4 hours;

[0741] b. Read the values ​​at 450nm using an ELISA reader (CEY0017) and record them using Excel;

[0742] c.Graphpad Prism 9.0 analyzes and organizes data.

[0743] The experimental results are shown in Table 7.

[0744] Table 7 shows the IC50 of the disclosed compounds in vitro against cancer cell proliferation. 50 Note: NA indicates not detected.

[0745] Conclusion: The compound exhibits significant inhibitory activity against the proliferation of MDA-MB-453, MDA-MB-468, and HT1376, indicating its potential as a drug.

[0746] Test Example 2: In vitro proliferation inhibition test of the ligand-drug conjugate of this disclosure on tumor cells targeting B7H3. The cell lines used in this experiment were human A375 (ATCC, catalog number: CRL-1619), NCI-H358 (ATCC, catalog number: CRL-5807), and NCI-H345 cell lines (BIOBW Beijing Bio-Tech Biotechnology Co., Ltd., catalog number: bio-133296) that highly express B7H3. Cell suspensions were prepared using fresh cell culture medium containing 10% FBS and then diluted to a density of 2 × 10⁻⁶ cells / mL. 4 cells / mL, 4×10 4 cells / mL and 2×10 4 The cells / mL were added at 100 μL per well to a 96-well cell culture plate (Thermo catalog number: 167425) and incubated at 37°C with 5% CO2 for 24 h.

[0747] The ADC sample was prepared at 10 μM using PBS. This was used as the initial concentration, and the samples were serially diluted five-fold with PBS to obtain nine different concentrations. 50 μL of culture medium was aspirated from each well, and then 50 μL of the above ADC solution was added to each well, resulting in an initial ADC concentration of 5 μM and a final volume of 100 μL per well. The samples were incubated at 37°C with 5% CO2 for 3 days. 100 μL of CTG was added to each well. The Luminescent Cell Viability Assay (Promega, catalog number: G7573) was mixed on a decolorizing shaker at room temperature for 30 min, incubated for 10 min, and the chemiluminescence was read on a microplate reader (TECAN, Spark). Data analysis was performed using Graphpad Prism 5 software. The results are shown in Table 8.

[0748] Table 8 shows the IC50 of the ligand-drug conjugate disclosed in this publication on the in vitro proliferation inhibition of cancer cells. 50 value "~" indicates an approximate value.

[0749] Conclusion: The ligand-drug conjugate targeting B7H3 in this invention exhibits significant inhibitory activity against the proliferation of A375, NCI-H358, and NCI-H345.

[0750] The present invention has been described through the above embodiments. However, it should be understood that the above embodiments are for illustrative purposes only and are not intended to limit the invention to the scope of the described embodiments. Furthermore, those skilled in the art will understand that the present invention is not limited to the above embodiments, and many variations and modifications can be made based on the teachings of the present invention, all of which fall within the scope of protection claimed by the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. The ligand-drug conjugate shown in Formula III or a pharmaceutically acceptable salt thereof, in, Ab represents the ligand, L represents the linker, and D represents the drug moiety; n is any integer or decimal from 1 to 15; preferably, n is any integer or decimal from 1 to 13; preferably, n is any integer or decimal from 3 to 10. The connector is -L 1 -L 2 -L 3 -L 4 -L 5 -; where L 1 The end is connected to the ligand, L 5 The end is connected to the drug portion; L 2 Selected from single bonds, alkyne groups, alkenyl groups, and -NR groups. 1L Combinations of one, two, three, or more of -, -O-, -C(O)-, alkylene, and heteroalkylene, wherein the ynylene, alkenylene, alkylene, and heteroalkylene are optionally represented by one or more R 1L replace; L 3 for Where r1 is selected from integers between 0 and 20; r2 is selected from 0, 1, and 2; * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites; L 4 It is a peptide residue containing 2 to 7 amino acid residues, wherein the amino acid is optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl; L 5 Selected from single key, * L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -C(=O)-* G 、* L4 -NR 2L (CR 3L R 4L ) t -* G 、* L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -Z1-C(=O)-* G and* L4 -NR 2L -Ar 2 -(CR 3L R 4L ) t -Z1-C(=O)-* G ;* L4 Indicates with L 4 The connection site, * G Indicates the connection site with G; Wherein, t is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; Z1 is independently selected as a single bond, O, S, or NH each time it appears; Ar 2 Each occurrence is independently an arylene or heteroarylene, the heteroarylene containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the arylene or heteroarylene is optionally surrounded by one or more atoms selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Substitution of alkyl group 2; R 1L R 2L and R 5L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH; R 3L and R 4L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-6 alkylene-OH and R 2H ; R 1H and R 2H Each occurrence is independently -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w Z2 is selected from single bonds, O, and NR. 7L and NR 7L C(O), W1 is selected from CH2CH2O and C(O)CH2N(R) 8L j1 and j2 are each independently selected from integers from 0 to 6 each time they appear, j3 is each independently selected from 0 or 1 each time it appears, and r3 is each independently selected from integers from 1 to 30 each time it appears. R w Selected from hydrogen, hydroxyl, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -NR7R 8L -C 1-6 Alkylene-NR7R 8L and -C(O)-NR7R 8L ; R 6L R 7L and R 8L Each time it appears, it is independently selected from hydrogen and C. 1-6 alkyl; Ar 1 and Ar 3 Each of the following groups is independently selected from 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl, wherein each of the 3-10-membered heterocyclic and 5-10-membered heteroaryl groups independently comprises one, two, or three heteroatoms independently selected from N, O, S, and P, wherein the 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl groups are optionally substituted by one or more substituents selected from oxo, hydroxy, cyano, amino, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, and cycloalkyl groups; In the formula, when r2 is 0, R 3L and R 4L At least one of them is R 2H R 2H -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w And j3 is not 0, and r3 is not 0; L 1 Selected from Among them, L p’ Selected from single bonds, 6-10 arylene groups, and 5-8 heteroarylene groups, wherein the 5-8 heteroarylene group comprises one, two, or three heteroatoms each independently selected from N, O, and S, wherein the 6-10 arylene group and the 5-8 heteroarylene group are optionally separated by one or more R atoms. 5L replace;* L2 Indicates with L 2 The connection site, Indicates the connection site.

2. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, Each occurrence of t is independently 0, 1, or 2; and / or L p’ Selected from single-bonded, phenyl, fluorinated phenyl and pyridyl groups; and / or Each occurrence of Z1 is independently a single bond, O, or S; preferably a single bond or O; more preferably O; and / or Z2 is selected from single bonds, O, NH, N(C) 1-3 Alkyl), NHC(O) and N(C) 1-3 Alkyl)C(O), preferably, Z2 is selected from single bond, O, NH and NHC(O); and / or W1 is selected from CH2CH2O and C(O)CH2N(C 1-3 Alkyl); preferably, W1 is CH2CH2O or C(O)CH2N(CH3); and / or j1 and j2 are each independently selected from 0, 1, 2, 3, 4, and 5 each time they appear; preferably, j1 and j2 are 0, 1, or 2; and / or Each occurrence of r3 is an independent integer selected from 6-30, preferably from 8-24, more preferably 8, 12, or 24; and / or R w C 1-6 Alkyl or -C(O)-C 1-6 Alkyl group, preferably C 1-3 Alkyl or -C(O)-C 1-3 Alkyl groups, more preferably -CH3 or -C(O)CH3; and / or R 1H and R 2H Each time it appears, it is selected independently. Among them, R 7L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups, j1, each time appearing independently selected from 0, 1, 2, 3, 4, 5, and 6; j2, each time appearing independently selected from 0, 1, 2, 3, 4, 5, and 6; preferably, R 1H and R 2H Each time it appears, it is selected independently. In this context, j1 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears. Preferably, R 1H and R 2H Each time it appears, it is selected independently. and / or Ar 1 and Ar 3 Each of these groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 Substituents of cycloalkyl groups; Preferably, Ar 1 and Ar 3 Each of the following groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, and C. 1-6 Alkyl substituents; Preferably, Ar 1 and Ar 3 Each time it appears, it is selected independently. Preferably, Ar 1 and Ar 3 Each time it appears, it is independent.

3. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in claim 1 or 2, wherein, The drug fraction D is camptothecin or a derivative thereof; preferably, the drug fraction D has the structure shown in formula (II-1) or (II-2): R1, R3, R4, R5, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Alkoxy group; preferably, R1, R3 and R5 are hydrogen; R2 and R6 are each independently selected from C(R1)2 and NR1; preferably, R2 and R6 are each independently C(R1)2; preferably, R2 and R6 are each independently CH2. n1 and n2 are each independently selected from 1, 2, 3, 4, 5 and 6; preferably, n1 and n2 are each independently 1, 2 or 3; preferably, n1 and n2 are each independently 1, 2 or 3. R4 and R8 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, preferably, R4 and R8 are each independently selected from hydrogen, fluorine and methyl; preferably, R4 is methyl and R8 is fluorine; Preferably, the drug portion D is: and / or L 1 Selected from and / or L p’ Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein the phenylene and the 5-8-membered heteroaryl group are each independently optionally separated by one or more R groups. 5L replace; Preferably, L p’ Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, and wherein the phenylene and 5-8-membered heteroaryl groups are each independently selected by 1, 2, 3, 4, 5, or 6 R atoms. 5L replace; Preferably, L p’ Selected from single bonds, phenylene, and pyridylene; wherein each of the phenylene and pyridylene groups is independently optionally surrounded by 1, 2, 3, or 4 R groups. 5L Replace; and / or R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 cycloalkyl; Preferably, R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl and -OC 1-3 alkyl; Preferably, R 5L Each occurrence is independently selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3, preferably R. 5L For F; Preferably, L p’ The group is selected from single bonds, phenylene, and pyridinyl groups; wherein the phenylene and pyridinyl groups are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3; Preferably, L p’ Selected from single bonds, in,* Lj Indicates with L j The connection site, * L2 Indicates with L 2 Connection sites; and / or L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 Alkylene and C 1-6 One, two, or three or more of the heteroalkyl groups, wherein the C 1-6 Alkylene and C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. 1L replace; Preferably, L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 A combination of one or more alkylene groups, wherein the C 1-6 Alkylene is optionally surrounded by one or more R 1L replace; Preferably, L 2 Selected from single bond, -O-, * LL1 -NR 1L -C(O)-* L3 、* L1 -C 1-6 Alkylene-C(O)-NR 1L -* L3 、* L1 -C 1-6 Alkylene-OC(O)-NR 1L -* L3 and* L1 -C 1-6 Alkylene-NR 1L -C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; among which, * L1 Indicates with L 1 The connection site, * L3 Indicates with L 3 Connection sites; Preferably, L 2 Selected from single bond, -O-, * L1 -NH-C(O)-* L3 、* L1 -C 1-6 Alkylene-C(O)-NH-* L3 、* L1 -C 1-6 Alkylene-OC(O)-NH-* L3 and* L1 -C 1-6 Alkylene-NH-C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; and / or R 1L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH; Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -C. 1-6 Alkylene-NH2; Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -methylene-NH2; Preferably, L 2 Selected from single bond, -O-, * L1 -NH-C(O)-* L3 , and / or L 3 for Among them, Ar 1 R 1H R 6L As defined in claim 1 or 2; r1 is selected from 0, 1, 2, 3, 4, or 5; r2 is 0 or 1; where, * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites; Preferably, L 3 Selected from * L2 -(CH2CH2O) r1 -CH2-Ar 1 -CH2-C(O)-* L4 , Preferably, R 1H Each time it appears, it is selected independently. Wherein, j1 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; preferably, j1 is independently 0, 2 or 4 each time it appears; preferably, j2 is independently 0, 1 or 2 each time it appears. Preferably, R 1H Each time it appears, it is independent. Preferably, L 3 Selected from and / or L 4 It is a peptide containing 2, 3, 4, 5 or 6 amino acids, wherein the amino acids are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl. Preferably, L 4 A peptide containing 2, 3, 4, 5, or 6 amino acids, wherein said amino acids are optionally converted by one or more groups selected from halogen, hydroxyl, cyano, amino, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 Substituents of cycloalkyl groups; Preferably, L 4 A peptide containing 2, 3, 4, 5 or 6 amino acid residues selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid and aspartic acid. Preferably, L 4 It is a dipeptide, tripeptide or tetrapeptide composed of amino acid residues selected from alanine, phenylalanine, glycine, lysine and citrulline. Preferably, L 4 The peptide is selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine, glycine-glycine-phenylalanine-glycine, valine-citrulline and valine-alanine. The amino acid is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, and cycloalkyl groups, preferably, optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, and C6 groups. 1-6 Alkyl substituents; Preferably, L 4 Selected from in,* L3 Indicates with L 3 The connection site, * L5 Indicates with L 5 The connection site.

4. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, wherein, Each occurrence of t is independently 0, 1, or 2; and / or Each occurrence of Z1 is independently a single bond, O, or S; preferably a single bond or O; more preferably O; and / or Ar 2 Each occurrence is independently a phenylene group, which is optionally oxidized by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2 is substituted; preferably, Ar 2 Each time it appears independently and / or R 1L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups; preferably selected from hydrogen and C. 1-3 Alkyl groups, preferably hydrogen; and / or R 3L and R 4L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl and R 2H ;wherein, j1 is independently selected from 0, 1, 2, 3, and 4 each time it appears, preferably 1; r3 is selected from integers from 1 to 30; and / or L 5 -D is selected from R 2H Selected from In this case, j1 is independently 0, 1, or 2 each time it appears; Preferably, L5-D is selected from Each time r3 appears, it is independently selected from an integer between 8 and 24, preferably 8, 12, or 24.

5. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, wherein, The connector L is selected from: Among them, n17 is selected from 8, 12, and 24 each time; Indicates the connection site.

6. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 1-5, wherein, The ligand-drug conjugate is selected from the following structures: Wherein, n is an integer or decimal from 1 to 10; preferably, n is an integer or decimal from 3 to 8; Ab is a ligand.

7. The linker compound shown in Formula I or a pharmaceutically acceptable salt thereof, L j -L p -L 2 -L 3 -L 4 -L 5 -G(Formula I); In the formula, G is a leaving group; L j for in, X S For single bonds or N(C) 1-6 alkyl); Each time R appears, it is an independent thiol reactive group; L p Selected from single bonds, 6-10 arylene groups, and 5-8 heteroarylene groups, wherein the 5-8 heteroarylene group comprises one, two, or three heteroatoms each independently selected from N, O, and S, wherein the 6-10 arylene group and the 5-8 heteroarylene group are optionally separated by one or more R atoms. 5L replace; L 2 Selected from single bonds, alkyne groups, alkenyl groups, and -NR groups. 1L Combinations of one, two, three, or more of -, -O-, -C(O)-, alkylene, and heteroalkylene, wherein the ynylene, alkenylene, alkylene, and heteroalkylene are optionally represented by one or more R 1L replace; L 3 for Where r1 is selected from integers between 0 and 20; r2 is selected from 0, 1, and 2; * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites; L 4 It is a peptide residue containing 2 to 7 amino acid residues, wherein the amino acid is optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl; L 5 Selected from single key, * L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -C(=O)-* G 、* L4 -NR 2L (CR 3L R 4L ) t -* G 、* L4 -NR 2L (CR 3L R 4L ) t -Z1-(CR 3L R 4L ) t -Z1-C(=O)-* G and* L4 -NR 2L -Ar 2 -(CR 3L R 4L ) t -Z1-C(=O)-* G ;* L4 Indicates with L 4 The connection site, * G Indicates the connection site with G; Wherein, t is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; Z1 is independently selected as a single bond, O, S, or NH each time it appears; Ar 2 Each occurrence is independently an arylene or heteroarylene, the heteroarylene containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the arylene or heteroarylene is optionally surrounded by one or more atoms selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Substitution of alkyl group 2; R 1L R 2L and R 5L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH; R 3L and R 4L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-6 alkylene-OH and R 2H ; R 1H and R 2H Each occurrence is independently -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w Z2 is selected from single bonds, O, and NR. 7L and NR 7L C(O), W1 is selected from CH2CH2O and C(O)CH2N(R) 8L j1 and j2 are each independently selected from integers from 0 to 6 each time they appear, j3 is each independently selected from 0 or 1 each time it appears, and r3 is each independently selected from integers from 1 to 30 each time it appears. R w Selected from hydrogen, hydroxyl, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -NR7R 8L -C 1-6 Alkylene-NR7R 8L and -C(O)-NR7R 8L ; R 6L R 7L and R 8L Each time it appears, it is independently selected from hydrogen and C. 1-6 alkyl; Ar 1 and Ar 3 Each of the following groups is independently selected from 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl, wherein each of the 3-10-membered heterocyclic and 5-10-membered heteroaryl groups independently comprises one, two, or three heteroatoms independently selected from N, O, S, and P, wherein the 3-10-membered cycloalkylene, 3-10-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl groups are optionally substituted by one or more substituents selected from oxo, hydroxy, cyano, amino, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, and cycloalkyl groups; In the formula, when r2 is 0, R 3L and R 4L At least one of them is R 2H R 2H -(CH2) j1 -(Ar 3 ) j3 -(CH2) j2 -Z2-(W1) r3 -R w And j3 is not 0, and r3 is not 0.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein, Z2 is selected from single bonds, O, NH, N(C) 1-3 Alkyl), NHC(O) and N(C) 1-3 Alkyl)C(O), preferably, Z2 is selected from single bond, O, NH and NHC(O); and / or W1 is selected from CH2CH2O and C(O)CH2N(C 1-3 Alkyl); preferably CH2CH2O or C(O)CH2N(CH3); and / or j1 and j2 are each independently selected from 0, 1, 2, 3, 4, and 5 each time they appear, preferably 0, 1, or 2; and / or Each occurrence of r3 is an independent integer selected from 6-30, preferably from 8-24, more preferably 8, 12, or 24; and / or R w C 1-6 Alkyl or -C(O)-C 1-6 Alkyl group, preferably C 1-3 Alkyl or -C(O)-C 1-3 Alkyl groups, more preferably -CH3 or -C(O)CH3; and / or R 1H and R 2H Each time it appears, it is selected independently. Among them, R 7L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups, j1 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; Preferably, R 1H and R 2H Each time it appears, it is selected independently. In this context, j1 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5, and 6 each time it appears. Preferably, R 1H and R 2H Each time it appears, it is selected independently.

9. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein, Ar 1 and Ar 3 Each of these groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 Substituents of cycloalkyl groups; Preferably, Ar 1 and Ar 3 Each of the following groups, when appearing independently, is selected from triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl, wherein the triazolyl, phenyl, pyrrolyl, piperidinyl, cyclohexyl, thiazolyl, and dihydropyridazinyl groups are optionally replaced by one or more groups selected from oxo, hydroxyl, cyano, amino, and C. 1-6 Alkyl substituents; Preferably, Ar 1 and Ar 3 Each time it appears, it is selected independently. Preferably, Ar 1 and Ar 3 Each time it appears, it is independent.

10. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-9, wherein, X S It is a single bond or N(CH3); each time R appears, it is an independently reactive mercapto group; Preferably, each occurrence of R is independently selected from halogens and -S-Ar. 4 More preferably, each occurrence of R is independently selected from F, Cl, Br, I, and -S-Ar; Ar 4 Selected from phenyl, C 1-6 Alkylphenyl-, C 1-6 Alkoxyphenyl-, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl, C 1-6 Alkylphenyl-, C 1-6 alkoxyphenyl-, 2-pyridyl, 2-pyrimidinyl, and 1-methylimidazol-2-yl are optionally surrounded by 1, 2, 3, or 4 R groups. a Substitution; preferably, Ar is selected from phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl The phenyl, C 1-3 Alkylphenyl, C 1-3 Alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, and 1-methylimidazol-2-yl are optionally surrounded by 1, 2, or 3 R groups. a replace; W2 is selected from amino, -NR a -C 1-6 Alkyl, -NR a -C 1-6 Alkoxy, -NR a -C 1-6 Alkylene-NR b R c -NR a -C 1-6 Alkylene-C 1-6 Alkoxy and 5 to 8-membered heterocyclic alkyl groups, wherein the 5 to 8-membered heterocyclic alkyl groups contain 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms, wherein the S atom may optionally be substituted by 1 or 2 oxo groups; R a Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH; R b R c Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Alkoxy; Preferably, W2 is selected from amino, -NR a -C 1-6 alkyl, Preferably, R is independently selected from halogens each time it appears. More preferably, R is selected independently each time it appears, choosing chlorine, bromine, Preferably, L j Selected from More preferably, L j Selected from 11. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-10, wherein, L p Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein the phenylene and the 5-8-membered heteroaryl group are each independently optionally separated by one or more R groups. 5L replace; Preferably, L p Selected from single bonds, phenylene, and 5-8-membered heteroaryl groups; wherein the 5-8-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein the phenylene and the 5-8-membered heteroaryl group are each independently optionally separated by 1, 2, 3, 4, 5, or 6 R atoms. 5L replace; Preferably, L p Selected from single bonds, phenylene, and pyridylene; wherein each of the phenylene and pyridylene groups is independently optionally surrounded by 1, 2, 3, or 4 R groups. 5L Replace; and / or R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and C 3-8 cycloalkyl; Preferably, R 5L Each time it appears, it is independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl and -OC 1-3 alkyl; Preferably, R 5L Each occurrence is independently selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3, preferably R. 5L For F; Preferably, L p The group is selected from single bonds, phenylene, and pyridinyl groups; wherein the phenylene and pyridinyl groups are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from Cl, Br, F, -OH, -CN, methyl, and -OCH3; Preferably, L p Selected from single bonds, in,* Lj Indicates with L j The connection site, * L2 Indicates with L 2 The connection site.

12. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-11, wherein, L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 Alkylene and C 1-6 One, two, or three or more of the heteroalkyl groups, wherein the C 1-6 Alkylene and C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. 1L replace; Preferably, L 2 For single bonds, or selected from -NR 1L -、-O-、-C(O)-、C 1-6 A combination of one or more alkylene groups, wherein the C 1-6 Alkylene is optionally surrounded by one or more R 1L replace; Preferably, L 2 Selected from single bond, -O-, * Lp -NR 1L -C(O)-* L3 、* Lp -C 1-6 Alkylene-C(O)-NR 1L -* L3 、* Lp -C 1-6 Alkylene-OC(O)-NR 1L -* L3 and* Lp -C 1-6 Alkylene-NR 1L -C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; among which, * Lp Indicates with L p The connection site, * L3 Indicates with L 3 Connection sites; Preferably, L 2 Selected from single bond, -O-, * Lp -NH-C(O)-* L3 、* Lp -C 1-6 Alkylene-C(O)-NH-* L3 、* Lp -C 1-6 Alkylene-OC(O)-NH-* L3 and* Lp -C 1-6 Alkylene-NH-C(O)-* L3 The C 1-6 Alkylene is optionally surrounded by 1, 2 or 3 R 1L Replace; and / or R 1L Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, carboxyl, -C 1-6 Alkyl-NH2 and -C 1-6 alkylene-OH; Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -C. 1-6 Alkylene-NH2; Preferably, R 1L Each time it appears, it is independently selected from hydrogen, carboxyl, and -methylene-NH2; Preferably, L 2 Selected from single bond, -O-, * Lp -NH-C(O)-* L3 , 13. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-12, wherein, L 3 for Among them, Ar 1 R 1H R 6L As defined in any one of claims 7-9; r1 is selected from 0, 1, 2, 3, 4, or 5; r2 is 0 or 1; where, * L2 Indicates with L 2 The connection site, * L4 Indicates with L 4 Connection sites; Preferably, L 3 Selected from * L2 -(CH2CH2O) r1 -CH2-Ar 1 -CH2-C(O)-* L4 , Preferably, R 1H Each time it appears, it is selected independently. Wherein, j1 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; j2 is independently selected from 0, 1, 2, 3, 4, 5 and 6 each time it appears; preferably, j1 is independently 0, 2 or 4 each time it appears; preferably, j2 is independently 0, 1 or 2 each time it appears. Preferably, R 1H Each time it appears, it is independent. Preferably, L 3 Selected from 14. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-13, wherein, L 4 It is a peptide containing 2, 3, 4, 5 or 6 amino acids, wherein the amino acids are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, haloalkoxy and cycloalkyl. Preferably, L 4 A peptide containing 2, 3, 4, 5, or 6 amino acids, wherein said amino acids are optionally converted by one or more groups selected from halogen, hydroxyl, cyano, amino, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 Substituents of cycloalkyl groups; Preferably, L 4 A peptide containing 2, 3, 4, 5 or 6 amino acid residues selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid and aspartic acid. Preferably, L 4 It is a dipeptide, tripeptide or tetrapeptide composed of amino acid residues selected from alanine, phenylalanine, glycine, lysine and citrulline. Preferably, L 4 The peptide is selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine, glycine-glycine-phenylalanine-glycine, valine-citrulline and valine-alanine. The amino acid is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, deuteroalkyl, alkoxy, and cycloalkyl groups, preferably, optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, and C6 groups. 1-6 Alkyl substituents; Preferably, L 4 Selected from in,* L3 Indicates with L 3 The connection site, * L5 Indicates with L 5 The connection site.

15. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-14, wherein, Each occurrence of t is independently 0, 1, or 2; and / or Each occurrence of Z1 is independently a single bond, O, or S; preferably a single bond or O; more preferably O; and / or Ar 2 Each occurrence is independently a phenylene group, which is optionally oxidized by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl, -OC 1-6 Alkyl, amino, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2 is substituted; preferably, Ar 2 Each time it appears independently and / or R 1L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups; preferably selected from hydrogen and C. 1-3 Alkyl groups, preferably hydrogen; and / or R 3L and R 4L Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl and R 2H ; where j1 is selected independently from 0, 1, 2, 3 and 4 each time it appears, preferably 1; r3 is selected from integers from 1 to 30; Preferably, L5-G is selected from Preferably, R 2H Selected from In this case, j1 is independently 0, 1, or 2 each time it appears; Preferably, L5-G is selected from Each time r3 appears, it is independently selected from an integer between 8 and 24, preferably 8, 12, or 24.

16. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 7-15, wherein, G is selected from halogens, hydroxyl groups, -Ots, -O-(4-nitrophenyl) and -ONO2.

17. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: in, Each time r3 appears, it is independently selected from an integer from 1 to 30, preferably from an integer from 6 to 30, more preferably from an integer from 8 to 24, and even more preferably from 8, 12 or 24; Preferably, the compound is selected from:

18. A compound as shown in Formula II or a pharmaceutically acceptable salt thereof, L j -L p -L 2 -L 3 -L 4 -L 5 -D (Formula II); In the formula, L j L p L 2 L 3 L 4 L 5 As defined in any one of claims 7-16; in, D is a drug; preferably, the drug D is a drug for treating cancer, preferably, the drug D is camptothecin or a derivative thereof; preferably, the drug D has the structure shown in formula (II-1) or (II-2): R1, R3, R4, R5, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Alkyl group; R2 and R6 are each independently selected from C(R1)2 and NR1; preferably C(R1)2; preferably CH2; n1 and n2 are each independently selected from 1, 2, 3, 4, 5 and 6; preferably 1, 2 or 3; Preferably, R1, R3, and R5 are hydrogen; and / or R4 and R8 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, preferably, R4 and R8 are each independently selected from hydrogen, fluorine and methyl; preferably, R4 is methyl and R8 is fluorine; Preferably, the drug portion D is:

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

20. A compound or a pharmaceutically acceptable salt thereof, selected from...

21. A ligand-drug conjugate with the structure shown in Formula 3-1 or a pharmaceutically acceptable salt thereof, in, Abs is the ligand, Ls is the linker moiety, and Ds is the drug moiety; ns is any integer or decimal from 1 to 15; preferably, ns is any integer or decimal from 1 to 13; preferably, ns is any integer or decimal from 3 to 10. The drug component Ds can be any of the following structures. Indicates the connection site.

22. A ligand-drug conjugate with the structure shown in Formula 3-2 or a pharmaceutically acceptable salt thereof, in, Abs is the ligand, Ls is the linker moiety, and Ds is the drug moiety; ns is any integer or decimal from 1 to 15; preferably, ns is any integer or decimal from 1 to 13; preferably, ns is any integer or decimal from 3 to 10. The connecting portion Ls is a connector L as defined in any one of claims 1-4; or the Ls includes -L 1s -; L 1s Selected from -(succinimide-3-yl-N)-, -(succinimide-3-yl-N)-Ws-C(=O)-, The left side connects to the ligand portion; Among them, Ws is selected from C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Ws is C 1-8 Alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 The heteroalkylene group comprises 1 to 3 heteroatoms independently selected from N, O, or S, wherein the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups. Preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, C groups, and S groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 The cycloalkyl group is substituted with one or more substituents; more preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally selected from halogens, -OH, -CN, and C. 1-3 Alkyl and -OC 1-3 The alkyl substituents are substituted, preferably, the alkylene, cycloalkylene and heteroalkylene are unsubstituted or optionally substituted with substituents selected from Cl, Br, F, -OH, -CN, methyl and -OCH3; Xs is selected from single bond, C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Xs is selected from single bond, C 1-8 Alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 Heteroalkyl; The drug component Ds can be any of the following structures. Indicates the connection site.

23. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in claim 21 or 22, wherein the linker Ls is -L 1s -L 2s -L 3s -L 4s -; L 1s Selected from -(succinimide-3-yl-N)-, -(succinimide-3-yl-N)-Ws-C(=O)-, Preferably, L 1s Selected from in, Ws is selected from C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Ws is C 1-8 Alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 The heteroalkylene group comprises 1 to 3 heteroatoms independently selected from N, O, or S, wherein the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups. Preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, C groups, and S groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 The cycloalkyl group is substituted with one or more substituents; more preferably, the alkylene, cycloalkylene, and heteroalkylene groups are unsubstituted or optionally selected from halogens, -OH, -CN, and C. 1-3 Alkyl and -OC 1-3 The alkyl substituents are substituted, preferably, the alkylene, cycloalkylene and heteroalkylene are unsubstituted or optionally substituted with substituents selected from Cl, Br, F, -OH, -CN, methyl and -OCH3; Xs is selected from single bond, C 1-10 Alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 Heteroalkyl, C 1-10 alkylene-cyclohexaalkylene, or C 1-10 Heteroalkyl-cycloalkylene, preferably Xs is selected from single bond, C 1-8 Alkylene, C 1- 8-alkylene-cycloalkylene or C 1-8 Heteroalkyl; Preferably, L 1s Selected from Preferably, L 1s Selected from L 2s Choice-(CH2CH2O) rs CH2CH2C(=O)-, -(CH2CH2O) rs C(=O)-, -NR 1Ls (CH2CH2O) rs C(=O)-, -(CH2CH2O) rs CH2C(=O)-, -NR 1Ls (CH2CH2O) rs CH2CH2C(=O)-, -NR 1Ls (CH2CH2O) rs CH2C(=O)-, -NR 1Ls CH2-Ar 1s -(CH2CH2O) rs CH2 CH2NR 1Ls C(=O)CH2OCH2C(=O)-, -NR 1Ls (CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) r sCH2CH2C(=O)-, -S-(CH2) rs C(=O)-, -O-(CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) rs CH2CH2C(=O)-, -O-(CH2CH2O) rs CH2-Ar 1s -CH2C(=O)-, -CH(CH2NH2)NR 1Ls C(=O)-(CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) rs CH2CH2C(=O)-, Or a single key, where rs is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and n17s is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 each time it appears; js is independently selected from 0, 1, 2, 3, 4, 5, 6 each time it appears; preferably rs is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; preferably, L 2s Selected from Where rs is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and n17s is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 each time it appears; js is independently selected from 0, 1, 2, 3, 4, 5, 6 each time it appears; preferably, rs is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; preferably, L 2s Selected from -NR 1Ls (CH2CH2O) rs CH2CH2C(=O)-、-O-(CH2CH2O) rs CH2-Ar 1s -(CH2CH2O) rs CH2CH2C(=O)-、-O-(CH2CH2O) rs CH2-Ar 1s -CH2C(=O)-; rs is an integer of 1, 2, 3, 4, or 5; preferably, L 2s Selected from Ar 1s Selected from 6-10 aryl groups, 5-10 heteroaryl groups containing 1-3 heteroatoms independently selected from N, O, P, and S, 3-10 cycloalkyl groups, or 3-10 heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, P, and S; preferably, Ar 1s Selected from Preferably, Ar 1s Selected from L 3s A peptide consisting of 2 to 7 amino acid residues, preferably L 3s A peptide consisting of 2, 3, 4, 5, or 6 amino acid residues, wherein the amino acids are unsubstituted or optionally further substituted by one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups, preferably, optionally further substituted by substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, C groups, and cycloalkyl groups. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy and C 5-8 The cycloalkyl group is substituted by one or more substituents; L 4s Selected from -NR 2Ls (CR 3L R 4L ) ts -Z-(CR 3Ls R 4Ls ) ts -C(=O)-, -NR 2Ls (CR 3Ls R 4Ls ) ts -, -NR 2Ls (CR 3Ls R 4Ls ) ts -Zs-(CR 3Ls R 4L ) ts -Zs-C(=O)-, -NR 2s -Ar 2s -(CR 3Ls R 4Ls ) ts -Zs-C(=O)-、-NR 2s -Ar 2s -(CR 3Ls R 4Ls ) ts -Zs-C(=O)-NR 2s -(CR 3Ls R 4Ls ) ts -NR 2s -、-NR 2s -(CR 3Ls R 4Ls ) ts -NR 2s - or single bond, where ts is an integer of 0, 1, 2, 3, 4, 5, or 6 each time it appears; Zs is a single bond, O, S, or -NH- each time it appears; Ar 2s It is an arylene or heteroarylene, preferably selected from 6-membered arylene or 5-8-membered heteroarylene, wherein the heteroarylene contains 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S; the arylene or heteroarylene is unsubstituted or optionally selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), and -N(C) 1-6 Alkyl)2 is substituted; preferably, L 4s Selected from -NR 2Ls (CR 3Ls R 4Ls ) ts -、-NR 2Ls -Ar 2s -(CR 3Ls R 4Ls ) ts -ZC(=O)-;-NR 2Ls -Ar 2s -(CR 3Ls R 4Ls ) ts -Zs-C(=O)-NR 2Ls -(CR 3Ls R 4sL ) ts -NR 2Ls -C(=O)-、-NR 2Ls -(CR 3Ls R 4Ls ) ts -NR 2Ls -C (=O)- or single key, where ts is an independent integer of 1, 2, or 3 each time it appears; Zs is an independent integer of 0 each time it appears; Ar 2s The arylene group is unsubstituted or optionally selected from H, halogen, -OH, -CN, C. 1-3 Alkyl, C 1-3 Alkyl group substitution; preferably, L 4s Selected from single bonds, -NH-CH2-, -NH-phenylene-CH2-O-CO-, -NH-phenylene-CH2-O-CO-N(CH3)-CH2-CH2-N(CH3)-CO-, -N(CH3)-CH2-CH2-N(CH3)-CO-; R 1Ls and R 2Ls Whether the elements are the same or different, and each occurrence is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and -C 1-6 alkylene-OH; R 3Ls and R 4Ls Whether the elements are the same or different, and each occurrence is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and -C 1-6 alkylene-OH; and L 1s The end is connected to the ligand, L 4s The end is connected to the drug portion.

24. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 21-23, wherein L 3s It is a peptide residue composed of 2-6 amino acids selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid, and aspartic acid; preferably, it is a dipeptide, tripeptide, or tetrapeptide residue composed of alanine, phenylalanine, glycine, lysine, and citrulline; preferably, L 3s The peptide residues are selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine-glycine, valine-citrulline, and valine-alanine. in, The peptide residues are unsubstituted or optionally further substituted with one or more substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, alkyl groups, haloalkyl groups, deuteralkyl groups, alkoxy groups, and cycloalkyl groups, preferably, optionally further substituted with substituents selected from halogens, hydroxyl groups, -CN groups, amino groups, and C groups. 1-6 Alkyl substituent substitution.

25. The ligand-drug conjugate of any one of claims 21-24 or a pharmaceutically acceptable salt thereof, wherein the linker Ls is selected from: Preferably, in Indicates the connection site.

26. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 21-25, wherein the ligand-drug conjugate is selected from the following structures: Preferably: in, ns is an integer or decimal from 1 to 10; preferably, ns is an integer or decimal from 3 to 8; Abs is a ligand.

27. A compound as shown in Formula 5-1 or a pharmaceutically acceptable salt thereof, L js -L 2s -L 3s –L 4s -Ds(Equation 5-1); Where -L 2s -、-L 3s -、-L 4s -, -Ds are as defined in any one of claims 22-26; L js Selected from And Ws, Xs as defined in any one of claims 22-26, preferably, L js Selected from 28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, Preferably, 29. The ligand-drug conjugate according to any one of claims 14-19 or 21-26, wherein the Ab or Abs is an antibody or its antigen-binding fragment or polypeptide, wherein the antibody is selected from chimeric antibodies, humanized antibodies and fully human antibodies; Preferably, the antibody or its antigen-binding fragment is selected from anti-TROP-2 antibody, anti-HER2 antibody, anti-NECTIN4 antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis antibody, etc. The antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody, or an antigen-binding fragment thereof; preferably, the antibody or antigen-binding fragment thereof is selected from anti-B7-H3 antibody or an antigen-binding fragment thereof; preferably, the amino acid sequence pair of the anti-B7-H3 antibody is selected from SEQ ID NO:1 and SEQ ID NO:2, and SEQ ID NO:3 and SEQ ID NO:

4.

30. Ligand-drug conjugates, wherein, The compound of claim 20 is used as the small molecule toxin portion of the drug.

31. A ligand-drug conjugate comprising a covalently linked antibody or its antigen-binding fragment and a linker-small molecule toxin moiety, wherein, The compound according to any one of claims 18-19 or 27-28 is used as the linker-drug moiety in the drug.

32. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 7-20 or 27-28, or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate according to any one of claims 1-6, 21-26, 29, or 30-31, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

33. Use of the compound of any one of claims 7-20 or 27-28, or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate of any one of claims 1-6, 21-26, or 29-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32, in the preparation of a medicament for treating or preventing tumors; preferably, the tumor is melanoma, non-small cell lung cancer, small cell lung cancer, prostate cancer, or breast cancer.

34. A method for preventing or treating tumors, comprising administering to a subject in need an effective amount of a compound of claims 7-20 or any one of claims 27-28 or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate of claims 14-19 or any one of claims 21-26 or 29-31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32; preferably, the tumor is melanoma, non-small cell lung cancer, small cell lung cancer, prostate cancer, or breast cancer.

35. The compound of any one of claims 7-20 or 27-28, or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate of any one of claims 1-6 or 21-26 or 29-31, or the pharmaceutical composition of claim 32, for the prevention or treatment of tumors; preferably, the tumor is melanoma, non-small cell lung cancer, small cell lung cancer, prostate cancer, or breast cancer.

36. The use of the compound of claim 20 or a salt thereof, characterized in that, Toxins are used as ingredients in antibody-drug conjugates to prepare antibody-drug conjugates.

37. Use of the compound of any one of claims 18-19 or 27-28 for the preparation of a ligand-drug conjugate, said ligand-drug conjugate comprising a covalently linked antibody or antigen-binding fragment thereof and a linker-drug moiety, wherein, The linker-drug portion is a compound as described in any one of claims 18-19 or 27-28.

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