Deuterated camptothecin derivatives and antibody-drug conjugates thereof

Abstract

The present invention discloses deuterated camptothecin derivatives and antibody-drug conjugates thereof. By applying deuteration technology to camptothecin-based ADCs, it is possible to discover superior deuterated camptothecin-based ADC drugs with higher safety and efficacy, which can better meet clinical needs.

Description

[Technical Field]

[0001] The present invention relates to deuterated camptothecin derivatives and antibody-drug conjugates thereof. [Background technology]

[0002] As a new form of targeted drug, antibody-drug conjugates (ADCs) are typically composed of three parts: an antibody or antibody-based ligand, a small molecule drug, and a binding unit that connects the ligand and drug. Antibody-drug conjugates utilize the specific recognition of antibodies against antigens to transport drug molecules to target cells, effectively releasing the drug molecules and achieving the therapeutic goal. In August 2011, the U.S. Food and Drug Administration (FDA) approved AdcetrIs, a new ADC drug developed by Seattle Genetics for the treatment of Hodgkin's lymphoma and recurrent degenerative large cell lymphoma (ALCL). TM The safety and effectiveness of this drug have been demonstrated in clinical use.

[0003] The advantages of antibody-drug conjugates (ADCs) include increased water solubility, improved targeting, specific antigen binding, drug transport to the target cell periphery, tumor cell death due to drug release near the target cell, and reduced toxic side effects. Camptothecin-based drugs show considerable promise among ADC drugs. Currently, the antibody-conjugated drug trastuzumab deruxtecan (trade name: Enhertu), which uses exatecan as the toxin, was approved for marketing by the US FDA on December 20, 2019. As the first commercially available camptothecin-based ADC drug, the drug discovery capabilities and application prospects of such drugs in the ADC field have been fully demonstrated.

[0004] Camptothecins (including irinotecan, exatecan, and SN38) are small molecule compounds with antitumor properties that exert their antitumor effects by inhibiting DNA topoisomerase I. Many camptothecin drugs are widely used in clinical settings, primarily for the treatment of bone cancer, prostate cancer, breast cancer, and pancreatic cancer. Unlike irinotecan, which is currently in clinical use, exatecan does not require enzymatic activation. Furthermore, compared with SN-38, the active ingredient of irinotecan, and the clinically used topotecan, exatecan exhibits stronger inhibitory activity against DNA topoisomerase I, resulting in stronger damage to various cancer cells in vitro. In particular, P-glycoprotein expression has been shown to be effective against cancer cells resistant to SN-38 and other drugs. Exatecan has not been successfully marketed as a standalone chemotherapy drug, and its high cellular activity is thought to narrow the therapeutic window. Furthermore, camptothecin-based drugs have a short plasma half-life, and therefore, in order to maintain their efficacy in clinical use, the dosage and frequency of administration must be increased, which may cause tolerance problems in patients.

[0005] Deuterium is a naturally occurring, non-radioactive, stable isotope of hydrogen. Its atomic mass is 6–9 times greater than that of hydrogen, making C–D bonds more stable than C–H bonds. Replacing hydrogen with deuterium in drug molecules can block metabolic sites and reduce the production of toxic metabolites. Deuterated drugs also remain stable under various metabolic enzymes, slowing their clearance rate and extending their half-life in the body. Therefore, deuterated drug therapy can achieve the goal of reducing drug toxicity and side effects by reducing the single dose without affecting the drug's pharmacological activity. In 2017, the US FDA approved the first deuterated drug, Teva's Austedo, and it was approved for sale in China in May 2020. Austedo is deuterated tetrabenazine. Its prototype, tetrabenazine, has become the mainstream treatment for Huntington's disease, but it suffers from drawbacks such as a short half-life and poor patient compliance. Deuterated tetrabenazine is produced by replacing the hydrogen atoms of the two methoxy groups on the benzene ring of tetrabenazine with deuterium atoms, which significantly slows the rate of drug metabolism and lengthens the drug half-life, thereby reducing the drug dosage and suppressing withdrawal reactions due to reduced blood drug concentrations. Summary of the Invention

[0006] The problem to be solved by the present invention is to discover superior deuterated camptothecin-based ADC drugs that have higher safety and efficacy and that better meet clinical needs by applying deuterium technology to camptothecin-based ADCs.

[0007] Based on a comprehensive understanding of ADC drugs, the present inventors have designed a series of deuterium-substituted camptothecin-based antibody-drug conjugates by introducing deuterium atoms into linker-drug compounds containing camptothecin, and have found through experiments that the molecules exhibit high drug activity and safety in vivo and in vitro, resulting in unexpected technical advantages.

[0008] According to the present invention, there is provided a hydrogenated camptothecin derivative represented by the general formula D, or a pharmaceutically acceptable salt or solvate thereof. [ka] In the formula, R1, R7, R 10 are independently hydrogen atoms, deuterium atoms, and C 1-6 Alkyl, C substituted with one or more deuterium atoms 1-6 selected from alkyl, substituted alkyl, aryl, aryl substituted with one or more deuterium atoms, heteroaryl, heteroaryl substituted with one or more deuterium atoms; R2, R3, R4, R5, R8, and R9 are each independently selected from hydrogen or deuterium; X is -C(O)-CR a R b -(CR c R d ) n -O-, -C(O)-CR a R b -(CR c R d ) n -NH- or -C(O)-CR a R b -(CR c R d ) n -S- is selected from R a , R b are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R a , R b and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R c , R d may be the same or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen, or C 1-6 Alkyl, alkyl halide, C substituted with one or more deuterium atoms 1-6 alkyl, alkoxy, alkoxy substituted with one or more deuterium atoms, hydroxyl, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms; or R c , R d and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, n is selected from the integers 0-4.

[0009] Preferably, X is -C(O)-CR a R b -(CR 3 R 4 ) n -O-. R a is selected from a hydrogen atom, a deuterium atom, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R bis selected from a hydrogen atom, a deuterium atom, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl or a heteroaryl; or R a , R b and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R c , R d may be the same or different and each independently represent a hydrogen atom, a deuterium atom, an alkyl, an alkyl substituted with one or more deuterium atoms, an alkoxy, an alkoxy substituted with one or more deuterium atoms, a hydroxyl, an amino, a cyano, a nitro, a hydroxyalkyl, a cycloalkyl, or a heterocyclyl; R c , R d and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms; n is selected from 0 or 1.

[0010] R1, R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R7, R8, R9, R 10 and X contains at least one deuterium atom.

[0011] More preferably, the camptothecin derivative comprises a structure represented by formula D2. [ka] In the formula, R 10 is a C substituted with a hydrogen atom, one or more deuterium atoms 1-6 alkyl, R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R8 and R9 are each independently selected from hydrogen or deuterium; R a is selected from a hydrogen atom, a deuterium atom, an alkyl, and a deuterated alkyl substituted with one or more deuterium atoms; R b is selected from a hydrogen atom, a deuterium atom, an alkyl, or a deuterated alkyl substituted with one or more deuterium atoms; R a , R b and the carbon atoms to which they are attached are perhydro-substituted alkyl, C substituted with one or more deuterium atoms. 3-6 cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, The wavy line in formula D2 represents a hydrogen atom or is covalently attached to a joint unit or a ligand unit of an antigen expressed on a binding target cell.

[0012] Preferably, but not limited to, X [ka] wherein Y is selected from a hydrogen or deuterium atom.

[0013] Preferably, the compound includes a tautomer, a meso-isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof.

[0014] Preferably, but not limited to, [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0015] The present invention further provides a drug-linker compound represented by the general formula (-LX-D2), or a pharmaceutically acceptable salt or solvate thereof. [ka] In the formula, R1, R7, R 10 is a hydrogen atom, a deuterium atom, or a C substituted with one or more deuterium atoms 1-6 Alkyl, C 1-6 selected from alkyl, substituted alkyl, aryl, deuterated aryl substituted with one or more deuterium atoms, heteroaryl, heteroaryl substituted with one or more deuterium atoms; R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R8 and R9 are each independently selected from hydrogen or deuterium; X is -C(O)-CR a R b -(CR c R d ) n -O-, R a , R bare each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, perhydro-substituted alkyl, cycloalkyl substituted with one or more deuterium atoms, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, alkoxyalkyl, alkoxyalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, aryl, aryl substituted with one or more deuterium atoms, substituted aryl, heteroaryl, heteroaryl substituted with one or more deuterium atoms; or R a , R b and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R c , R d may be the same or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen, an alkyl, an alkyl halide, a perhydro-substituted alkyl, or a C substituted with one or more deuterium atoms. 1-6 Alkyl, fully deuterated C 1-6 alkyl, alkoxy, alkoxy substituted with one or more deuterium atoms, hydroxyl, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms; or R c , R d and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, n is selected from the integers 0-4.

[0016] R1, R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R7, R8, R9, R 10 and X contains at least one deuterium atom.

[0017] L is a binding unit, where the wavy line in the formula -LX-D2 represents a hydrogen atom or is covalently bound to a joint unit or antibody of an antigen expressed on a binding target cell.

[0018] Preferably, the O end of X is attached to a linking unit L.

[0019] More preferably, the linking unit L- is -L1-L2-L3-L4-, with the L1 end attached to the antibody and the L4 end attached to X. where L1 is -(succinimide-3-yl-N)-YC(O)-, -CH2-C(O)-NR 5 -YC(O)- or -C(O)-YC(O)-. Y is C 1-8 Alkyl, C 1-8 alkyl-cycloalkyl or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, wherein the heteroalkyl contains 1 to 3 atoms selected from N, O, or S, and the C 1-8 The alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl are each independently substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy, or cycloalkyl. L2 is -NR 6 (CH2CH2O) p CH2CH2C(O)-, -NR 6 (CH2CH2O) p CH2C(O)-, -S(CH2) pC(O)- or a chemical bond, and p is selected from an integer of 0-20. L3 is selected from peptide residues consisting of 2-7 amino acids, optionally substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy, and cycloalkyl or substituted cycloalkyl. L4 -NR 7 (CR 8 R 9 ) q -, -C(O)NR 7 , -C(O)NR 7 (CH2) q - or a chemical bond, where q is selected from an integer from 0-6. R 5 , R 6 and R 7 may be the same or different and are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl; R 8 and R 9 may be the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl.

[0020] More preferably, L1 is -(succinimide-3-yl-N)-YC(O)-, -CH2-C(O)-NR 5 -YC(O)- or -C(O)-YC(O)-. Y is C 1-8 Alkyl, C 1-8 alkyl-cycloalkyl or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, wherein the heteroalkyl contains 1 to 3 atoms selected from N, O, or S, and the C 1-8The alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl are each independently substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy, or cycloalkyl. L2 is -NR 6 (CH2CH2O) p CH2CH2C(O)-, -NR 6 (CH2CH2O) p CH2C(O)-, -S(CH2) p C(O)- or a chemical bond, and p is selected from an integer of 0-20.

[0021] L3 is a polypeptide residue consisting of an amino acid selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (D), preferably an amino acid residue consisting of one, two, or more amino acids selected from phenylalanine and glycine, and most preferably a tetrapeptide residue consisting of glycine-glycine-phenylalanine-glycine. L4 -NR 7 CR 8 R 9 -, preferably -NHCH2-. R 5 , R 6 and R 7 may be the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl. R 8 and R 9 may be the same or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl.

[0022] According to the present invention, there is provided a drug-linker compound represented by general formula (LX-D2), or a pharmaceutically acceptable salt or solvate thereof. [ka] In the formula, Z is -YC(O)-, -CH2-C(O)-NR 5 -YC(O)- or -C(O)-YC(O)-, where Y is selected from, but not limited to, C 1-8 Alkyl, C 1-8 alkyl-cycloalkyl or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, wherein the heteroalkyl contains 1 to 3 atoms selected from N, O, or S, and the C 1-8 The alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl are each independently substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, nitro, amino, alkyl, heteroalkyl, substituted alkyl, alkoxy, carboxyl, or cycloalkyl. L2 is -NR 6 (CH2CH2O) p CH2CH2C(O)-, -NR 6 (CH2CH2O) p CH2C(O)-, -S(CH2) p C(O)- or a chemical bond, p is selected from an integer from 0-20, and any alkyl in the structure is substituted with one or more deuterium atoms. L3 is selected from peptide residues consisting of 2-7 amino acids, optionally substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy, and cycloalkyl or substituted cycloalkyl. R is a deuterium atom, C 1-6 It is selected from alkyl, substituted alkyl, aryl, substituted aryl, or heteroaryl. R 11is selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl. R 12 is selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a halogenated alkyl, a deuterated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R 11 , R 12 and the carbon atom to which they are attached, C 3-6 It comprises cycloalkyl, cycloalkylalkyl or heterocyclyl. R 5 , R 6 are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl. R1, R7, R 10、 R 15 are each independently hydrogen, alkyl, or C substituted with one or more deuterium atoms. 1-4 alkyl. R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R8, and R9 are each independently selected from hydrogen or deuterium. R1, R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R7, R8, R9, R 10 , R 11 and R 12 contains at least one deuterium atom.

[0023] Preferably, the general formula (L b -X-D2), or a pharmaceutically acceptable salt or solvate thereof. [ka] In the formula, R 11 , R 12 are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, a heterocyclyl, a heterocyclyl substituted with one or more deuterium atoms, an aryl, an aryl substituted with one or more deuterium atoms, a substituted aryl, a heteroaryl, a heteroaryl substituted with one or more deuterium atoms; or R 11 , R 12 and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 It comprises cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms. R1, R7, R 10、 R 15 are each independently hydrogen, alkyl, or C substituted with one or more deuterium atoms. 1-4 Alkyl, fully deuterated C 1-4 alkyl, substituted alkyl. R2, R 2' , R3, R 3' , R4, R 4' , R5, R 5' , R8, and R9 are each independently selected from hydrogen or deuterium. Ac has a hydrophilic structural unit represented by formula c, which contains both amino and carboxyl groups, and X is a scaffold connecting the amino and carboxyl groups, and C 1-10 Ac is a hydrocarbylene group or a substituted hydrocarbylene group. The hydrocarbylene group or the substituted hydrocarbylene group may be substituted with one or more deuterium atoms. Ac is a group having the structural formula L bIt is bonded to the 2-position methylene carbon shown as -X-D2. [ka]

[0024] More preferred are tautomers, meso isomers, racemates, enantiomers, diastereomers or mixtures thereof, wherein Ac is selected from glycine, α-alanine, β-alanine and (D / L) glutamic acid.

[0025] Preferably, the deuterated camptothecin derivative, or a pharmaceutically acceptable salt or solvate thereof, is [ka] Selected from JPEG0007753372000010.jpg216120JPEG0007753372000011.jpg216136JPEG0007753372000012.jpg187147.

[0026] According to the present invention, there is provided an antibody-drug conjugate represented by the general formula (Ab-LX-Dr), in which a camptothecin derivative, a camptothecin-linker compound, a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof is bound to a ligand unit, or a pharmaceutically acceptable salt or solvate thereof. [ka] In the formula, R1, R7, R 10 each independently represents a hydrogen atom, a deuterium atom, or a C substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-6 It is selected from alkyl, substituted alkyl, aryl, aryl substituted with one or more deuterium atoms, heteroaryl, heteroaryl substituted with one or more deuterium atoms. R2, R 2' , R3, R 3' , R4, R4' , R5, R 5' , R8, and R9 are each independently selected from hydrogen or deuterium. X is -C(O)-CR a R b -(CR c R d ) n -O-. R a , R b are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R a , R b and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6 It comprises cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms. R c , R d may be the same or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen, or C 1-6 Alkyl, alkyl halide, C substituted with one or more deuterium atoms 1-6 alkyl, alkoxy, alkoxy substituted with one or more deuterium atoms, hydroxyl, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms; or R c , R d and the carbon atom to which they are attached, C 3-6 Cycloalkyl, C substituted with one or more deuterium atoms 3-6It comprises cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms. n is selected from the integers 0-4. L is a linking unit. The wavy line in formula -LX-D2 represents a hydrogen atom or is covalently attached to an antibody of an antigen expressed on a joint unit or binding target cell.

[0027] Preferably, the linking unit L- is -L1-L2-L3-L4-, with the L1 end attached to the antibody and the L4 end attached to X. L1 is -(succinimide-3-yl-N)-YC(O)-, -CH2-C(O)-NR 5 -YC(O)- or -C(O)-YC(O)-. Y is C 1-8 Alkyl, C 1-8 alkyl-cycloalkyl or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, wherein the heteroalkyl contains 1 to 3 atoms selected from N, O, or S, and the C 1-8 The alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl are each independently substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy, or cycloalkyl. L2 is -NR 6 (CH2CH2O) p CH2CH2C(O)-, -NR 6 (CH2CH2O) p CH2C(O)-, -S(CH2) p C(O)- or a chemical bond, where p is selected from an integer of 0-20. L3 is a peptide residue consisting of 2-7 amino acids, optionally substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy, and cycloalkyl or substituted cycloalkyl. L4 -NR 7 (CR 8 R 9 ) q -, -C(O)NR 7 , -C(O)NR 7 (CH2) q - or a chemical bond, and q is selected from an integer of 0-6. R 5 , R 6 and R 7 may be the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl. R 8 and R 9 may be the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl. m is selected from integers or decimals from 1 to 10. Ab is an antibody, antibody fragment, target protein or Fc-fusion protein. L is a linking unit.

[0028] More preferably, the Ab is an antibody capable of forming a linking bond with the binding unit via its heteroatom, said antibody being selected from a murine antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an antibody fragment, a bispecific antibody, and a multispecific antibody.

[0029] More preferably, the antibodies include anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti-TDGF1 antibody, anti-ETBR antibody, anti-MSLN antibody, anti-TIM-1 antibody, anti-LRRC15 antibody, anti-LIV-1 antibody, anti-CanAg / AFP antibody, anti-cladin antibody. 18.2 antibody, anti-Mesothelin antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-c-MET antibody, anti-SLITRK6 antibody, anti-KIT / CD117 antibody, anti-STEAP1 antibody, anti-SLAMF7 / CS1 antibody, anti-NaPi2B / SLC34A2 antibody, anti-G PNMB antibody, anti-HER3 (ErbB3) antibody, anti-MUC1 / CD227 antibody, anti-AXL antibody, anti-CD166 antibody, anti-B7-H3 (CD276) antibody, anti-PTK7 / CCK4 antibody, anti-PRLR antibody, anti-EFNA4 antibody, anti-5T4 antibody, anti-NOTCH3 antibody, anti-Nectin and antibodies targeting one or more targets selected from the group consisting of anti-CD47 antibody, anti-CD142 antibody, anti-CA6 antibody, anti-GPR20 antibody, anti-CD174 antibody, anti-CD71 antibody, anti-EphA2 antibody, anti-LYPD3 antibody, anti-FGFR2 antibody, anti-FGFR3 antibody, anti-FRα antibody, anti-CEACAMs antibody, anti-GCC antibody, anti-Integrin Av antibody, anti-CAIX antibody, anti-P-cadherin antibody, anti-GD3 antibody, anti-Cadherin 6 antibody, anti-LAMP1 antibody, anti-FLT3 antibody, anti-BCMA antibody, anti-CD79b antibody, anti-CD19 antibody, anti-CD33 antibody, anti-CD56 antibody, anti-CD74 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD37 antibody, anti-CD138 antibody, anti-CD352 antibody, anti-CD25 antibody, anti-CD123 antibody, and anti-CD47 antibody.

[0030] Preferably, the antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, is [ka] Selected from JPEG0007753372000015.jpg233160JPEG0007753372000016.jpg169160JPEG0007753372000017.jpg222158JPEG0007753372000018.jpg105162. Here, m is selected from integers or decimals from 1 to 10. Ab is an antibody, an antibody fragment, a target protein, an Fc-fusion protein, etc.

[0031] According to the present invention, there is provided a method for producing compound (LX-D2), which comprises the following synthetic steps: [ka]

[0032] According to the present invention, the general formula (Ab-L a The present invention provides a method for producing an antibody-drug conjugate represented by formula (I)-X-Dr, or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: [ka] A compound of the general formula (Ab-L) is obtained by coupling an antibody, antibody fragment, target protein, Fc-fusion protein, etc. with a compound of the general formula (La-X-D2). a -X-D2) is obtained.

[0033] According to the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0034] According to the present invention, there is provided use of a camptothecin derivative, an antibody-drug conjugate thereof, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient in the manufacture of a drug for treating or preventing a tumor.

[0035] Preferably, the tumor is selected from a solid tumor or a hematological tumor, such as, but not limited to, breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urinary tract cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, melanoma, glioma, neuroblastoma, glioblastoma multiforme, sarcoma, lymphoma or leukemia. DETAILED DESCRIPTION OF THE INVENTION

[0036] Abbreviations and Definitions Unless otherwise defined, all technical and scientific terms used herein are the same as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. In describing and claiming the present invention, the following terms will be used in accordance with the definitions set forth below.

[0037] When trade names are used herein, they are intended to include formulations, generic drugs, and active ingredient portions of the products covered by the trade name.

[0038] Unless otherwise defined, the following terms and phrases used herein are intended to have the following meanings: When a trade name is used herein, unless the context dictates otherwise, the trade name includes the formulation, commonly used drug and active drug ingredients of the product bearing that trade name.

[0039] Unless stated to the contrary, terms used in the specification and claims have the same meaning as set forth below.

[0040] The term "ligand" refers to a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell. The role of the ligand is to present a drug to a target cell population to which the ligand binds. Such ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, or other molecules capable of binding to cells. In an embodiment of the present invention, the ligand is represented by Ab. The ligand can be bound to the binding unit via a heteroatom on the ligand. Preferably, it is an antibody or an antigen-binding fragment thereof. The antibody is selected from a chimeric antibody, a humanized antibody, a fully human antibody, and a murine antibody, and is preferably a monoclonal antibody.

[0041] The Ligand unit is a targeting agent that specifically binds to a target moiety. The Ligand can specifically bind to a cellular component or to a cellular component or other target molecule. The targeting moiety or target is typically on the cell surface. In some embodiments, the function of the Ligand unit is to deliver the Drug unit to a specific target cell population that interacts with the Ligand unit. Ligands include, but are not limited to, non-proteins such as proteins, polypeptides, peptides, and sugars. Suitable Ligand units include, for example, antibodies, such as full-length (intact) antibodies and antigen-binding fragments thereof. In embodiments where the Ligand unit is a non-antibody targeting agent, it may be a peptide or polypeptide, or a non-protein molecule. Examples of such targeting agents include interferons, lymphokines, hormones, growth and colony-stimulating factors, vitamins, nutrient transport molecules, or any other cell-binding molecule or substance. In some embodiments, the Binding unit is covalently bound to a sulfur atom of the Ligand. In some aspects, the sulfur atom is the sulfur atom of a cysteine ​​residue, forming an interchain disulfide bond of an antibody. In another aspect, the sulfur atom is the sulfur atom of a cysteine ​​residue into which a Ligand unit has been introduced, forming an interchain disulfide bond of the antibody. In another aspect, the sulfur atom is the sulfur atom of a cysteine ​​residue into which a Ligand unit has been introduced (e.g., by site-directed mutagenesis or chemical reaction). In another aspect, the sulfur atom attached to the Linking unit is selected from a cysteine ​​residue of an interchain disulfide bond of the antibody and a cysteine ​​residue into which a Ligand unit has been introduced (e.g., by site-directed mutagenesis or chemical reaction). In some embodiments, the EU index numbering system as described in Kabat EA et al., (1991), Sequences of proteins of Immunologic Interest, Fifth Edition, NIH Publication No. 91-3242.2 is used.

[0042] As used herein, the terms "antibody" or "antibody unit" include within their scope any portion of an antibody structure. This unit can bind, reactively associate, or form a complex with a receptor, antigen, or other receptor unit possessed by a target cell population. An antibody may be any protein or protein-like molecule capable of binding, complexing, or reacting with a portion of a cell population to be treated or biologically modified. In the present invention, the antibody conjugates can maintain their original, wild-type antigen-binding ability. Therefore, the antibodies of the present invention preferably can specifically bind to antigens. Such antigens include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules associated with tissue growth and differentiation (with known or predictable functionality), lymphokines, cytokines, molecules involved in cell cycle regulation, molecules involved in angiogenesis, and molecules associated with angiogenesis (with known or predictable functionality). As described herein, tumor-associated factors may be cluster differentiation factors (e.g., CD proteins).

[0043] Antibodies used in antibody-drug conjugates include, but are not limited to, antibodies against cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are well known in the art and can be prepared using methods and information well known in the art for preparing antibodies. To develop effective cellular targets for cancer diagnosis and treatment, researchers have identified transmembrane or other tumor-associated polypeptides. These targets can be expressed specifically on the surface of one or more cancer cells, but with little or no expression on the surface of one or more non-cancerous cells. Typically, such tumor-associated polypeptides are more overexpressed on the surface of cancer cells than on the surface of non-cancerous cells. Identifying such tumor-associated factors can significantly improve the specific targeting properties of antibody-based cancer therapy. For convenience, antigen-related information (such as names, other names, and GenBank accession numbers) well known in the art is provided below. Nucleic acid and protein sequences corresponding to tumor-associated antigens can be found in public databases such as GenBank. The tumor-associated antigen corresponding to the antibody target has at least 70%, 80%, 85%, 90%, or 95% identity to the sequence identified in the reference, including all amino acid sequence variants and isotypes, or has biological properties and characteristics that are completely identical to the sequence of the tumor-associated antigen described in the reference.

[0044] The terms "inhibit" or "suppress" refer to reducing the detectable amount or preventing it altogether.

[0045] The term "cancer" refers to a physiological condition or disease characterized by unregulated cell growth. "Tumor" includes cancerous cells.

[0046] The term "autoimmune disease" refers to a disease or disorder that results from the targeting of an individual's own tissues or proteins.

[0047] The term "drug" refers to a cytotoxic drug, which may be designated as D, and is a chemical molecule that can potently interfere with the normal growth of tumor cells. Cytotoxic drugs can, in principle, kill tumor cells at sufficiently high concentrations, but due to their lack of specificity, they may cause apoptosis of normal cells while killing tumor cells, potentially resulting in serious side effects. The term also includes toxins, such as small molecule toxins or enzymatically active toxins derived from bacteria, fungi, plants, or animals; radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , B.I. 212 , P 32 and radioactive isotopes of Lu), toxic drugs, chemotherapeutic drugs, antibiotics, and ribolysin, although toxic drugs are preferred.

[0048] The term "linker," "binding fragment," or "binding unit" refers to a chemical structural fragment or bond that is attached to a ligand at one end and to a drug at the other end, and may be attached to another binding unit which in turn is attached to the drug.

[0049] The linking unit includes a stretcher, a spacer, and an amino acid unit and can be synthesized according to methods known in the art (e.g., the method described in US2005-0238649A1). The linking unit can be a "cleavable linking unit" that facilitates intracellular drug release. For example, an acid-labile linking unit (e.g., hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linking unit, a photolabile linking unit, a dimethyl linking unit, or a disulfide-containing linking unit can be used (Charl et al. Cancer Research 52:127-131, 1992; US Patent No. 5,208,020).

[0050] Depending on the mechanism of intracellular drug release, the "binding unit" or "binding unit of an antibody-drug conjugate" described herein can be divided into two types: non-cleavable binding units and cleavable binding units. The drug release mechanism of antibody-drug conjugates containing non-cleavable binding units is as follows: After the conjugate binds to an antigen and is taken up by the cell, the antibody is enzymatically hydrolyzed in the lysosome, releasing the active molecule consisting of the small molecule drug, the binding unit, and antibody amino acid residues. This change in the drug molecule structure does not reduce its cytotoxicity, and the active molecule, being charged (amino acid residues), does not penetrate into neighboring cells. Therefore, such drugs do not kill neighboring tumor cells that do not express the target antigen (antigen-negative cells) (bystander effect) (Ducry et al., 2010, BIoconjugate Chem. 21:5-13).

[0051] The term "ligand drug conjugate" refers to an antibody conjugated to a biologically active drug via a stable binding unit. In the present invention, "ligand drug conjugate" refers to an antibody drug conjugate (ADC), preferably a monoclonal antibody or antibody fragment, conjugated to a biologically active drug via a stable binding unit.

[0052] The three-letter and one-letter codes for amino acids used herein are as described in J. Boy. Chem. 1968, 243, 3558.

[0053] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight or branched chain groups having 1 to 20 carbon atoms, preferably alkyl groups having 1 to 12 carbon atoms, more preferably alkyl groups having 1 to 10 carbon atoms, and most preferably alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and branched isomers thereof.More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment. The substituents are preferably each independently one or more selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxyl group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxy group.

[0054] The term "substituted alkyl" refers to an alkyl group in which a hydrogen atom is replaced with a substituent. Unless the context dictates otherwise, alkyl group substituents are selected from -halogen, -OR', -NR'R'', -SR', -SIR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)R', -NH-C(NH)=NH, -NR'C(NH)=NH, -NH-C(NH)=NR', -S(O)R', -S(O)R', -S(O)NR'R'', -NR'S(O)R'', -CN and -NO. The number of substituents is 0-(2m'+1), where m' is the total number of carbon atoms in the group. R', R'', and R''' are each independently hydrogen, unsubstituted C 1-8Alkyl groups, unsubstituted aryl groups, aryl groups substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl group, C 1-8 Alkoxy group or C 1-8 Thioalkoxy group or unsubstituted aryl group -C 1-4 When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl groups.

[0055] The term "heteroalkyl" refers to an alkyl group containing one or more heteroatoms selected from N, O and S. Alkyl group is as defined above.

[0056] The term "alkylene" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having two residues obtained by removing two hydrogen atoms from the same or different carbon atoms of a host alkane, including straight-chain or branched groups containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH)-, 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCHCH-), 1,4-butylene (-CHCHCHCHCH-), and 1,5-butylene (-CHCHCHCHCHCH-). The alkylene group may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably each independently one or more selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxy groups.

[0057] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl) groups. The alkyl and cycloalkyl groups are defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably each independently one or more selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0058] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20, preferably 3 to 12, more preferably 3 to 10, and most preferably 3 to 8 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Monocyclic cycloalkyl groups include spiro, fused, or bridged ring cycloalkyl groups.

[0059] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 members, each of which shares one atom (called a spiro atom) between two monocyclic rings, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the other ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl is divided into monoheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.

[0060] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3-20 ring atoms, one or more of which may be nitrogen, oxygen, or S(O). m (m is an integer of 0-2), except that the -OO-, -OS-, or -SS- ring moiety is excluded and the remaining ring atoms are carbon. Preferably, the cycloalkyl ring contains 3-12 ring atoms, of which 1-4 are heteroatoms. More preferably, the cycloalkyl ring contains 3-10 ring atoms. Examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinylalkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyl groups include spiro, fused, or bridged heterocyclyl groups.

[0061] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more, preferably one, cycloalkyl groups. The alkyl group and cycloalkyl group are as defined above.

[0062] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, alkyl being as defined above.

[0063] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms. Alkyl group is defined as above.

[0064] The term "hydroxyl" refers to an --OH group.

[0065] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0066] The term "amino" refers to -NH2. The term "nitro" refers to -NO2.

[0067] The term "amido" refers to a -C(O)N-(alkyl) or (cycloalkyl) group, where alkyl and cycloalkyl are defined above.

[0068] The term "carboxylic acid ester" refers to a -C(O)O-(alkyl) or (cycloalkyl) group, where alkyl and cycloalkyl are defined above.

[0069] The present invention further includes deuterated forms. Each hydrogen atom bonded to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated products according to the relevant literature. The deuterated products can be synthesized using commercially available deuterated starting materials or conventional deuterated reagents. Deuterated reagents include, but are not limited to, deuterated water, deuterated methanol, deuterated borane, trideuterated borane in tetrahydrofuran, lithium aluminum deuterated, deuterated iodoethane, and deuterated iodomethane.

[0070] The term "antibody" refers to an immunoglobulin, which has a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The antigenicity of immunoglobulins varies due to differences in the amino acid composition and sequence in the heavy chain constant region. This allows immunoglobulins to be divided into five types or isotypes: IgM, IgD, IgG, IgA, and IgE. The corresponding heavy chains are μ, δ, γ, α, and ε chains, respectively. Ig of the same type can be classified into different subclasses depending on the amino acid composition of their hinge regions and the number and location of disulfide bonds in the heavy chains. For example, IgG is divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as κ or λ chains depending on the constant region. Each of the five types of Ig can have either κ or λ chains. The antibodies described in the present invention are preferably specific for cell surface antigens on target cells.In non-limiting embodiments, the antibody is one or more of an anti-EGFRvIII antibody, an anti-DLL-3 antibody, an anti-PSMA antibody, an anti-CD70 antibody, an anti-MUC16 antibody, an anti-ENPP3 antibody, an anti-TDGF1 antibody, an anti-ETBR antibody, an anti-MSLN antibody, an anti-TIM-1 antibody, an anti-LRRC15 antibody, an anti-LIV-1 antibody, an anti-CanAg / AFP antibody, an anti-claudin 18.2 antibody, an anti-Mesothelin antibody, an anti-HER2 (ErbB2) antibody, an anti-EGFR antibody, an anti-c-MET antibody, an anti-SLITRK6 antibody, an anti-KIT / CD117 antibody, an anti-STEAP1 antibody, an anti-SLAMF7 / CS1 antibody, an anti-NaPi2B / SLC34A2 antibody, an anti-GPNMB antibody, an anti-HER3 (ErbB3) antibody, an anti-MUC1 / CD227 antibody, an anti-AXL antibody, an anti-CD166 antibody, an anti-B7-H3 (CD276) antibody, an anti-PTK7 / CCK4 antibody, an anti-PRLR antibody, an anti-EFNA4 antibody, an anti-5T4 antibody, an anti-NOTCH3 antibody, an anti-NectIn 4 antibody, an anti-TROP-2 antibody, an anti-CD142 antibody, an anti-CA6 antibody, an anti-GPR20 antibody, an anti-CD174 antibody, an anti-CD71 antibody, an anti-EphA2 antibody, an anti-LYPD3 antibody, an anti-FGFR2 antibody, an anti-FGFR3 antibody, an anti-FRα antibody, an anti-CEACAMs antibody, an anti-GCC antibody, an anti-Integrin αv antibody, an anti-CAIX antibody, an anti-P-cadherin antibody, an anti-GD3 antibody, an anti-Cadherin 6 antibody, an anti-LAMP1 antibody, an anti-FLT3 antibody, an anti-BCMA antibody, an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD33 antibody, an anti-CD56 antibody, an anti-CD74 antibody, an anti-CD22 antibody, an anti-CD30 antibody, an anti-CD37 antibody, an anti-CD138 antibody, an anti-CD352 antibody, an anti-CD25 antibody or an anti-CD123 antibody. Preferably, it is Trastuzumab (trade name Herceptin), Pertuzumab (also called 2C4; trade name Perjeta), NImotuzumab (trade name: Taixing Sheng), Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96 and Glematumamab.

[0071] The term "solvate" refers to a pharmaceutically acceptable solvate formed from a Ligand Drug Conjugate of the present invention and one or more solvent molecules. Examples of solvent molecules include, but are not limited to, water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0072] The term "drug loading" refers to the average number of cytotoxic drugs loaded on each antibody in a Formula I molecule, and may be expressed as the ratio of the drug amount to the antibody amount. Drug loading ranges from 0 to 12, preferably 1 to 10, cytotoxic drugs (D) can be conjugated to each antibody (Ab). In embodiments of the present invention, the drug loading is represented by n, which may be, for example, an average value of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The average number of drugs on each ADC molecule after the coupling reaction can be measured by standard methods, such as UV / visible spectroscopy, mass spectrometry, ELISA, and HPLC.

[0073] In one embodiment of the present invention, the cytotoxic drug is attached to the N-terminal amino acid of the ligand and / or the ε-amino acid of a lysine residue via a linking unit. Generally, the number of drug molecules that can be attached to an antibody in a coupling reaction is less than the theoretical maximum.

[0074] The loading of the ligand-cytotoxic drug conjugate can be controlled by the following non-limiting methods. (1) Controlling the molar ratio of binding unit reagent to monoclonal antibody. (2) Controlling the reaction time and temperature. (3) Select a different reaction reagent. For the preparation of conventional pharmaceutical compositions, please refer to the Chinese Pharmacopoeia.

[0075] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of the ligand-drug conjugate of the present invention or a salt of a compound described in the present invention. Such salts are safe and effective when used in mammals and have appropriate biological activity. The ligand-drug conjugate of the present invention has at least one carboxyl and can form salts with bases. Non-limiting examples of pharmaceutically acceptable salts include sodium salts, potassium salts, calcium salts, magnesium salts, etc.

[0076] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of the ligand-drug conjugate of the present invention or a salt of a compound described in the present invention. Such salts are safe and effective when used in mammals and have appropriate biological activity. The antibody-drug conjugate compounds of the present invention contain at least one amino group and can form salts with acids. Examples of pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0077] "Acidic amino acids" refer to amino acids with an isoelectric point of less than 7. Acidic amino acids typically have one or more acidic groups, such as carboxyl groups, and structurally can be effectively ionized to negative ions, thereby improving hydrophilicity. Acidic amino acids can be divided into natural amino acids and unnatural amino acids.

[0078] "Natural amino acids" refer to amino acids obtained by biosynthesis. Natural amino acids are generally L-configuration, but there are exceptions, such as glycine, and include both naturally occurring and those synthesized in vivo.

[0079] "Unnatural amino acid" refers to an amino acid obtained synthetically.

[0080] The present invention will be further described below with reference to specific examples. However, it should be understood that these examples are used only to illustrate the present invention and are not intended to limit the scope of the present invention. In the following examples, test methods for which no specific conditions are given generally follow conventional conditions or conditions suggested by the manufacturer. Unless otherwise specified, all percentages, proportions, ratios or parts are by weight.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly known in the art. Furthermore, any methods and materials similar or equivalent to those described can all be applied to the methods of the present invention. The preferred working methods and materials described herein are merely exemplary.

[0082] Example 1: Synthesis of Compound 1 and iso-1 [ka] Compound SM-1 (N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide, purchased) (6.26 g, 25.0 mmol), SM-2 ((S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyran-O[3,4-F]indoxazine-3,6,10(4H)-ketone, purchased) (7.90 g, 30.0 mmol), and pyridinium p-toluenesulfonate (1.26 g, 5.0 mmol) were placed in a 1 L round-bottom flask. 500 mL of toluene was added, the mixture was heated to reflux, and reacted for 6 hours. The reaction was monitored by HPLC until SM-2 was no longer present, and then the reaction was stopped. The mixture was cooled, crystallized in an ice-water bath with stirring for 2 hours, filtered, and dried under vacuum to obtain compound Ac-1 (11.02 g, 92%). The LC-MS results were [M+H] + :478.2.

[0083] Ac-1 (11.02 g, 23.0 mmol), methanesulfonic acid (55 mL), water (110 mL), and toluene (55 mL) were mixed in a 1 L round-bottom flask and heated to reflux. After 6 hours, the reaction was monitored by TLC. After the starting materials had completely reacted, 500 mL of methanol was slowly added dropwise to the reaction mixture at room temperature and stirred. After the addition was complete, the mixture was stirred overnight. The reaction mixture was then suction filtered, the filter cake was washed with methanol, the filtrate was collected, and the filter cake was dried to give compound 1 (6.58 g, 54%) as an off-white solid. LC-MS results showed [M+H] + The filtrate was concentrated under reduced pressure, purified by preparative liquid chromatography (mobile phase: MeCN / HO), and lyophilized to obtain a pale brown solid compound iso-1 (3.71 g, 37%). LC-MS results showed [M+H] + :436.2.

[0084] Example 2: Synthesis of Compounds D-D1 [ka] A 1000 ml three-neck flask (No. 1) was flushed with nitrogen and protected with a nitrogen balloon. A constant-pressure dropping funnel was attached, and heavy water (25 ml, 1.25 mol) was added to the flask using a syringe. The flask was stirred at 0°C and prepared for use. A 500 ml three-neck flask (No. 2) was flushed with nitrogen, and a 1.0 M LiHMDS THF solution (300 ml, 0.30 mol) was added. The mixture was cooled to 0°C with stirring. DSM1-1 (12.00 g, 54.0 mmol) was slowly added dropwise to the flask. After the addition was complete, the mixture was allowed to react for 5 minutes. The extract was then extracted with a syringe and slowly added dropwise to the cooled heavy water in the constant-pressure dropping funnel of the No. 1 flask. The addition took approximately 15 minutes. After the dropwise addition was completed, the mixture was stirred for 5 minutes, 300 ml of saturated ammonium chloride was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain 8.33 g of a colorless oily liquid, DSM1-2 (yield 69%). 1 The deuteration status was determined based on the integral of the hydrogen at the α-position of the carbonyl by H-NMR, and the non-deuterated portion was approximately 1.7%.

[0085] A 250 mL single-neck flask was charged with 50 mL of dichloromethane and DSM1-2 (8.33 g, 37.3 mmol). The mixture was stirred at 0 °C, 50 mL of TFA was added, and the mixture was warmed to room temperature and stirred for approximately 1 h. After confirming complete reaction by TLC, the reaction mixture was concentrated under reduced pressure at 30 °C, and the remaining TFA was removed with DCM. The mixture was then dried under reduced pressure on an oil pump for 15 min to obtain the crude oily product, which was used directly in the next reaction. The crude product was dissolved in 100 mL of methanol, 10% Pd / C (5.00 g) was added, and the mixture was purged with hydrogen. A hydrogen balloon apparatus was added, and the mixture was reacted at room temperature for approximately 2 h. After confirming complete reaction by TLC, the mixture was filtered with suction, and the filter cake was washed twice with methanol. The combined filtrate was concentrated under reduced pressure and dried under reduced pressure on an oil pump to obtain DSM-1 (2.85 g, 99%) as a pale yellow oil, which was used directly.

[0086] A 25 mL round-bottom flask was charged with compound 1 (100.3 mg, 0.19 mmol), DSM-1 (43.0 mg, 0.56 mmol), HATU (107.2 mg, 0.28 mmol), HOBt (38.1 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 min, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain a yellow solid, D-D1 (64.0 mg, 69% yield).

[0087] LC-MS result: [M+H]+: 495.2.

[0088] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=9.2 Hz, 1H), 7.64 (d, J=11.2 Hz, 1H), 7.25 (s, 1H), 6.51 (s, 1H), 5.60-5.41 (m, 2H), 5.39 (s, 2H), 5.09 (d, J=18.8 Hz, 1H), 4.92 (d, J=18.8 Hz, 1H), 3.97(s, 1H), 3.22-2.98 (m, 2H), 2.29 (s, 3H), 2.22-2.08 (m, 2H), 1.95-1.73 (m, 2H), 0.86 (t, J=7.2 Hz, 3H).

[0089] Example 3: Synthesis of Compounds D-D2 [ka] A 25 mL round-bottom flask was charged with compound iso-1 (82.5 mg, 0.19 mmol), DSM-1 (43.1 mg, 0.56 mmol), HATU (107.2 mg, 0.28 mmol), HOBt (38.2 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 min, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain a yellow solid, D-D2 (67.8 mg, 73% yield).

[0090] LC-MS result: [M+H]+: 495.1.

[0091] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=9.0 Hz, 1H), 7.65 (d, J=10.9 Hz, 1H), 7.25 (s, 1H), 6.51 (s, 1H), 5.53 (dt, J=9.1, 6.0 Hz, 1H), 5.41 (s, 2H), 5.12 (d, J=19.1 Hz, 1H), 4.92 (d, J=18.9 Hz, 1H), 3.99 (s, 1H), 3.10 (qt, J=16.7, 6.1 Hz, 2H), 2.29 (d, J=1.8 Hz, 3H), 2.16 (q, J=6.4 Hz, 2H), 2.00-1.81 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

[0092] Example 4: Synthesis of Compounds D-D3 [ka]

[0093] A 1000 mL three-neck flask (No. 1) was flushed with nitrogen and protected with a nitrogen balloon. A constant-pressure dropping funnel was attached, and heavy water (20 mL, 1.00 mol) was added to the flask using a syringe. The flask was stirred at 0°C and prepared for use. A 500 mL three-neck flask (No. 2) was flushed with nitrogen, and a 1.0 M LiHMDS THF solution (200 mL, 0.20 mol) was added. The mixture was cooled to 0°C with stirring. DSM2-1 (10.00 g, 42.3 mmol) was slowly added dropwise to the flask. After the addition was complete, the mixture was allowed to react for 5 minutes. The mixture was extracted with a syringe and slowly added dropwise to the cooled heavy water in the constant-pressure dropping funnel of the No. 1 flask. The addition took approximately 12 minutes. After the dropwise addition was completed, the mixture was stirred for 5 minutes, 200 ml of saturated ammonium chloride was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain 5.07 g of a colorless oily liquid, DSM2-2 (yield 50%). 1The deuteration status was determined based on the integral of the hydrogen at the α-position of the carbonyl using H-NMR. As a result, the hydrogen at the α-position of the carbonyl was almost completely gone, and the non-deuterated portion was approximately 1%.

[0094] A 150 mL single-neck flask was charged with 40 mL of dichloromethane and DSM2-2 (5.07 g, 21.4 mmol). The mixture was stirred at 0 °C, 20 mL of TFA was added, and the mixture was warmed to room temperature and stirred for approximately 1 h. After confirming complete reaction by TLC, the reaction mixture was concentrated under reduced pressure at 30 °C, and the remaining TFA was removed with DCM. The mixture was then dried under reduced pressure on an oil pump for 15 min to obtain the crude oily product, which was used directly in the next reaction. The crude product was dissolved in 50 mL of methanol, 10% Pd / C (2.00 g) was added, and the mixture was purged with hydrogen. A hydrogen balloon apparatus was added, and the mixture was reacted at room temperature for approximately 2 h. After confirming complete reaction by TLC, the mixture was filtered with suction, and the filter cake was washed twice with methanol. The combined filtrate was concentrated under reduced pressure and dried under reduced pressure on an oil pump to obtain DSM-2 (1.84 g, 94%) as a pale yellow oil, which was used directly.

[0095] A 25 mL round-bottom flask was charged with compound 1 (100.4 mg, 0.19 mmol), DSM-2 (51.3 mg, 0.56 mmol), HATU (107.1 mg, 0.28 mmol), HOBt (38.3 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 75.9 mg of a yellow solid (79% yield).

[0096] The LC-MS result was [M+H]+: 509.2.

[0097] 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=8.8 Hz, 1H), 7.64 (d, J=10.8 Hz, 1H), 7.26 (s, 1H), 6.53 (s, 1H), 5.56 (d, J=5.2 Hz, 1H), 5.48(dd, J=14.0, 6.4 Hz, 1H), 5.40(s, 2H), 5.09 (d, J=18.8 Hz, 1H), 4.89 (d, J=18.8 Hz, 1H), 3.22-3.11 (m, 1H), 3.11-3.00 (m, 1H), 2.29 (s, 3H), 2.22-2.09 (m, 2H), 1.92-1.78 (m, 2H), 1.32 (s, 3H), 0.87 (t, J=7.2 Hz, 3H).

[0098] Example 5: Synthesis of Compounds D-D4 [ka] A 25 mL round-bottom flask was charged with compound iso-1 (82.8 mg, 0.19 mmol), DSM-2 (50.9 mg, 0.56 mmol), HATU (107.4 mg, 0.28 mmol), HOBt (38.0 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 70.7 mg of a yellow solid (74% yield).

[0099] The LC-MS result was [M+H]+: 509.3.

[0100] 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=9.2 Hz, 1H), 7.71 (d, J=10.9 Hz, 1H), 7.29 (s, 1H), 6.53 (s, 1H), 5.68 (d, J=4.9 Hz, 1H), 5.54 (q, J=7.3 Hz, 1H), 5.42 (s, 2H), 5.20 (d, J=19.0 Hz, 1H), 4.93 (d, J=18.9 Hz, 1H), 3.25-3.01 (m, 2H), 2.32 (s, 3H), 2.14 (q, J=6.5 Hz, 2H), 1.96-1.80 (m, J=7.1 Hz, 2H), 1.42 (s, 3H), 0.90 (t, J=7.2 Hz, 3H).

[0101] Example 6: Synthesis of Compounds D-D5 [ka]

[0102] A 1000 mL three-neck flask (No. 1) was flushed with nitrogen, protected with a nitrogen balloon, and equipped with a constant-pressure dropping funnel. Heavy water (30 mL, 1.50 mol) was added to the flask using a syringe and stirred at 0°C. A 500 mL three-neck flask (No. 2) was flushed with nitrogen, and a 1.0 M LiHMDS THF solution (350 mL, 0.35 mol) was added. The mixture was cooled to 0°C with stirring. DSM3-1 (20.32 g, 70.0 mmol) was slowly added dropwise to the flask. After the addition was complete, the mixture was allowed to react for 5 minutes. The extract was then extracted with a syringe and slowly added dropwise to the cooled heavy water in the constant-pressure dropping funnel of the No. 1 flask. The addition took approximately 12 minutes. After the dropwise addition was completed, the mixture was stirred for 5 minutes, 350 ml of saturated ammonium chloride was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain 7.15 g of a pale yellow oily liquid, DSM3-2 (yield 35%). 1The deuteration status was determined based on the integral of the hydrogen at the α-position of the carbonyl using H-NMR. As a result, the hydrogen at the α-position of the carbonyl was almost completely gone, with the non-deuterated portion being 1%.

[0103] A 150 mL single-neck flask was charged with 40 mL of dichloromethane and DSM3-2 (7.15 g, 24.5 mmol). The mixture was stirred at 0 °C, 20 mL of TFA was added, and the mixture was warmed to room temperature and stirred for approximately 1 h. After confirming complete reaction by TLC, the reaction mixture was concentrated under reduced pressure at 30 °C, and the remaining TFA was removed with DCM. The mixture was then dried under reduced pressure on an oil pump for 15 min to obtain the crude oily product, which was used directly in the next reaction. The crude product was dissolved in 50 mL of methanol, 10% Pd / C (3.50 g) was added, and the mixture was purged with hydrogen. A hydrogen balloon apparatus was added, and the mixture was reacted at room temperature for approximately 2 h. After confirming complete reaction by TLC, the mixture was filtered with suction, and the filter cake was washed twice with methanol. The combined filtrate was concentrated under reduced pressure and dried under reduced pressure on an oil pump to obtain DSM-3 (3.54 g, 97%) as a pale yellow oil, which was used directly.

[0104] A 25 mL round-bottom flask was charged with compound 1 (100.8 mg, 0.19 mmol), DSM-3 (81.3 mg, 0.56 mmol), HATU (106.8 mg, 0.28 mmol), HOBt (38.5 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 63.1 mg of a yellow solid (59% yield).

[0105] The LC-MS result was [M+H]+: 562.1.

[0106] Example 7: Synthesis of Compounds D-D6 [ka] A 25 mL round-bottom flask was charged with compound iso-1 (82.3 mg, 0.19 mmol), DSM-3 (81.5 mg, 0.56 mmol), HATU (107.2 mg, 0.28 mmol), HOBt (38.3 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 66.1 mg of a yellow solid (62% yield).

[0107] The LC-MS result was [M+H]+: 562.2.

[0108] Example 8: Synthesis of Compounds D-D7 [ka] A 1000 mL three-neck flask (No. 1) was flushed with nitrogen and protected with a nitrogen balloon. A constant-pressure dropping funnel was attached, and heavy water (30 mL, 1.50 mol) was added to the flask using a syringe. The flask was stirred at 0°C and prepared for use. A 500 mL three-neck flask (No. 2) was flushed with nitrogen, and a 1.0 M LiHMDS THF solution (350 mL, 0.35 mol) was added. The mixture was cooled to 0°C with stirring. DSM4-1 (18.36 g, 70.0 mmol) was slowly added dropwise to the flask. After the addition was complete, the mixture was allowed to react for 5 minutes. The mixture was extracted with a syringe and slowly added dropwise to the cooled heavy water in the constant-pressure dropping funnel of the No. 1 flask. The addition took approximately 12 minutes. After the dropwise addition was completed, the mixture was stirred for 5 minutes, 350 ml of saturated ammonium chloride was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain 7.58 g of a pale yellow oily liquid, DSM4-2 (yield 41%). 1 The deuteration status was determined based on the integral of the hydrogen at the α-position of the carbonyl using H-NMR. As a result, the hydrogen at the α-position of the carbonyl was almost completely gone, and the non-deuterated portion was approximately 0.7%.

[0109] A 150 mL single-neck flask was charged with 60 mL of dichloromethane and DSM4-2 (7.58 g, 28.8 mmol). The mixture was stirred at 0 °C, 20 mL of TFA was added, and the mixture was warmed to room temperature and stirred for approximately 1 h. After confirming complete reaction by TLC, the reaction mixture was concentrated under reduced pressure at 30 °C, and the remaining TFA was removed with DCM. The mixture was then dried under reduced pressure on an oil pump for 15 min to obtain the crude oily product, which was used directly in the next reaction. This crude product was dissolved in 50 mL of methanol, and 10% Pd / C (4.01 g) was added. The mixture was purged with hydrogen and a hydrogen balloon apparatus was added. The mixture was reacted at room temperature for approximately 2 h. After confirming complete reaction by TLC, the mixture was filtered with suction, and the filter cake was washed twice with methanol. The combined filtrate was concentrated under reduced pressure and dried under reduced pressure on an oil pump to obtain DSM-4 (3.27 g, 97%) as a nearly colorless oily liquid, which was used directly.

[0110] A 25 mL round-bottom flask was charged with compound 1 (100.7 mg, 0.19 mmol), DSM-4 (65.9 mg, 0.56 mmol), HATU (107.8 mg, 0.28 mmol), HOBt (38.9 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 71.3 mg of a yellow solid (70% yield).

[0111] The LC-MS result was [M+H]+: 535.2.

[0112] Example 9: Synthesis of Compounds D-D8 [ka] A 25 mL round-bottom flask was charged with compound iso-1 (82.7 mg, 0.19 mmol), DSM-4 (65.6 mg, 0.56 mmol), HATU (107.3 mg, 0.28 mmol), HOBt (38.9 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 65.3 mg of a yellow solid (64% yield).

[0113] The LC-MS result was [M+H]+: 535.2.

[0114] Example 10: Synthesis of Compounds D-D9 [ka] A 1 L three-neck flask was protected with a nitrogen balloon and charged with 300 mL of freshly distilled THF and 1.0 M LiHMDS in THF (200 mL, 0.20 mol). The mixture was cooled to -78 °C with stirring. DSM1-1 (22.23 g, 0.10 mol) was slowly added dropwise. After the addition was complete, the mixture was allowed to react for 30 min, and then CD3I (10 mL, 0.20 mol) was added dropwise. After the addition was complete, the mixture was stirred for 15 min, warmed to room temperature, and stirred for another 15 min. The reaction was quenched by adding 300 mL of saturated ammonium chloride, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography. 13.88 g of DSM5-1 (58% yield) was obtained as a pale yellow oil.

[0115] A 150 mL single-neck flask was charged with 40 mL of dichloromethane and DSM5-1 (4.79 g, 20.0 mmol). The mixture was stirred at 0 °C, 20 mL of TFA was added, and the mixture was warmed to room temperature and stirred for approximately 1 h. After confirming complete reaction by TLC, the reaction mixture was concentrated under reduced pressure at 30 °C, and the remaining TFA was removed with DCM. The mixture was then dried under reduced pressure on an oil pump for 15 min to obtain the crude oily product, which was used directly in the next reaction. This crude product was dissolved in 50 mL of methanol, and 10% Pd / C (2.56 g) was added. The mixture was purged with hydrogen and a hydrogen balloon apparatus was added. The mixture was reacted at room temperature for approximately 2 h. After confirming complete reaction by TLC, the mixture was filtered with suction, and the filter cake was washed twice with methanol. The combined filtrate was concentrated under reduced pressure and dried under reduced pressure on an oil pump to obtain DSM-5 (1.83 g, 98%) as a nearly colorless oily liquid, which was used directly.

[0116] A 25 mL round-bottom flask was charged with compound 1 (100.5 mg, 0.19 mmol), DSM-5 (52.6 mg, 0.56 mmol), HATU (107.6 mg, 0.28 mmol), HOBt (38.7 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 66.9 mg of a yellow solid (69% yield).

[0117] The LC-MS result was [M+H]+: 511.2.

[0118] Example 11: Synthesis of Compounds D-D10 [ka]

[0119] A 25 mL round-bottom flask was charged with compound iso-1 (82.6 mg, 0.19 mmol), DSM-5 (52.3 mg, 0.56 mmol), HATU (107.4 mg, 0.28 mmol), HOBt (38.2 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 70.8 mg of a yellow solid (73% yield).

[0120] The LC-MS result was [M+H]+: 511.1.

[0121] Example 12: Synthesis of Compounds D-D11 [ka] A 500 ml three-neck flask (No. 1) was flushed with nitrogen and protected with a nitrogen balloon. A constant-pressure dropping funnel was attached, and heavy water (20 ml, 1.0 mol) was added to the flask using a syringe and stirred at 0°C. This flask was then prepared for use. A 250 ml three-neck flask (No. 2) was protected with a nitrogen balloon and charged with a 1.0 M LiHMDS THF solution (125 ml, 0.125 mol). The temperature was lowered while stirring at 0°C. DSM5-1 (5.99 g, 25.0 mmol) was slowly added dropwise to the flask. After the addition was complete, the mixture was allowed to react for 5 minutes. The mixture was then extracted with a syringe and slowly added dropwise to the cooled heavy water in the constant-pressure dropping funnel of the No. 1 flask. The addition took approximately 12 minutes. After the addition was complete, the mixture was stirred for 5 minutes, and then 150 ml of saturated ammonium chloride was added to the reaction mixture. The mixture was extracted three times with ethyl acetate. The combined organic phase was washed once with water, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain 3.11 g of pale yellow oily liquid DSM5-2 (yield 52%). 1 The deuteration status was determined based on the integral of the hydrogen at the α-position of the carbonyl using H-NMR. As a result, the hydrogen at the α-position of the carbonyl was almost completely gone, and the non-deuterated portion was approximately 1.5%.

[0122] A 100 mL single-neck flask was charged with 30 mL of dichloromethane and DSM5-2 (3.11 g, 12.6 mmol). The mixture was stirred at 0 °C, 10 mL of TFA was added, and the mixture was warmed to room temperature and stirred for approximately 1 h. After confirming complete reaction by TLC, the reaction mixture was concentrated under reduced pressure at 30 °C, and the remaining TFA was removed with DCM. The mixture was then dried under reduced pressure on an oil pump for 15 min to obtain a crude oily product, which was used directly in the next reaction. The crude product was dissolved in 30 mL of methanol, and 10% Pd / C (1.50 g) was added. The mixture was purged with hydrogen and a hydrogen balloon apparatus was added. The mixture was reacted at room temperature for approximately 2 h. After confirming complete reaction by TLC, the mixture was filtered with suction, and the filter cake was washed twice with methanol. The filtrates were combined, concentrated under reduced pressure, and dried under reduced pressure on an oil pump to obtain DSM-6 (1.15 g, 97%) as a nearly colorless oily liquid, which was used directly.

[0123] A 25 mL round-bottom flask was charged with compound 1 (101.1 mg, 0.19 mmol), DSM-6 (52.7 mg, 0.56 mmol), HATU (108.1 mg, 0.28 mmol), HOBt (38.7 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 66.1 mg of a yellow solid (68% yield).

[0124] The LC-MS result was [M+H]+: 512.2.

[0125] Example 13: Synthesis of Compounds D-D12 [ka] A 25 mL round-bottom flask was charged with compound iso-1 (82.7 mg, 0.19 mmol), DSM-6 (52.9 mg, 0.56 mmol), HATU (107.4 mg, 0.28 mmol), HOBt (38.2 mg, 0.28 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (95 μL, 0.57 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed for approximately 3 h until the starting material concentration was less than 5%. The reaction mixture was separated by preparative liquid chromatography and lyophilized to obtain 70.8 mg of a yellow solid (73% yield).

[0126] The LC-MS result was [M+H]+: 512.2.

[0127] Example 14: Synthesis of Compounds D-D13 [ka] Compound 1 (319.1 mg, 0.60 mmol) was placed in a 25 mL round-bottom flask, protected with argon, and cooled to -78 °C with 8 mL of freshly distilled THF. 14.8 mg of NaH was dissolved in 2.0 mL of freshly distilled THF and slowly added dropwise to the cooled solution of compound 1. The mixture was stirred at low temperature for 5 min. CD3I (50 µL, 0.80 mmol) was then added. The reaction mixture was then warmed to room temperature and stirred for 1 h. After confirming no significant progress by HPLC, the reaction was terminated. 5 mL of 3 M HCl solution was added to the reaction mixture, stirred overnight at room temperature, concentrated, and purified by preparative liquid chromatography to give a yellow solid, CD-1 (172.0 mg, 63%).

[0128] The LC-MS result was [M+H]+: 453.2.

[0129] A 25 mL round-bottom flask was charged with compound CD-1 (67.5 mg, 0.15 mmol), DSM-7 (35.2 mg, 0.45 mmol), HATU (114.2 mg, 0.30 mmol), HOBt (41.0 mg, 0.30 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (78 μL, 0.45 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC for approximately 6 hours. The reaction mixture was separated by preparative liquid chromatography so that the starting material was less than 5%. The mixture was then lyophilized to obtain 35.7 mg of a yellow solid (47% yield).

[0130] The LC-MS result was [M+H]+: 511.2.

[0131] Example 15: Synthesis of Compounds D-D14 [ka] A 25 mL round-bottom flask was charged with compound CD-1 (67.9 mg, 0.15 mmol), DSM-8 (40.5 mg, 0.45 mmol), HATU (113.9 mg, 0.30 mmol), HOBt (41.4 mg, 0.30 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 minutes, DIEA (78 μL, 0.45 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC and allowed to proceed overnight. The reaction mixture was separated by preparative liquid chromatography so that the starting material was less than 5%. The mixture was then lyophilized to obtain 38.9 mg of a yellow solid (49% yield).

[0132] The LC-MS result was [M+H]+: 525.2.

[0133] Example 16: Synthesis of Compounds D-D15 and D-D16 [ka] Compound D-D15 (33.5 mg) was obtained by referring to the synthetic route and method of Example 14. The LC-MS result was [M+H]: 511.2.

[0134] [ka] Compound D-D16 (37.5 mg) was obtained by referring to the synthetic route and method of Example 15. The LC-MS result was [M+H]: 525.1.

[0135] Example 17: Synthesis of Compounds D-D17 [ka] Compound 1 (320.5 mg, 0.60 mmol) was placed in a 25 mL round-bottom flask, protected with argon, and cooled to -78 °C with 8 mL of freshly distilled THF. 15.5 mg of NaH was dissolved in 2.0 mL of freshly distilled THF and slowly added dropwise to the cooled solution of compound 1. The mixture was stirred at low temperature for 5 min. CHCl (50 μL, 0.80 mmol) was then added, and the reaction mixture was warmed to room temperature and stirred for 1 h. After confirming no significant reaction progress by HPLC, the reaction was terminated. 5 mL of 3 M HCl solution was added to the reaction mixture, stirred overnight at room temperature, concentrated, and purified by preparative liquid chromatography to give a yellow solid, CH-1 (174.6 mg, 65%).

[0136] The LC-MS result was [M+H]+: 450.2.

[0137] A 25 mL round-bottom flask was charged with compound CH-1 (66.8 mg, 0.15 mmol), DSM-5 (42.2 mg, 0.45 mmol), HATU (114.2 mg, 0.30 mmol), HOBt (41.0 mg, 0.30 mmol), and 5 mL of ultra-dry DMF, and the flask neck was sealed. After stirring in an ice-water bath for 10 min, DIEA (78 μL, 0.45 mmol) was added and the mixture was allowed to warm to room temperature with stirring. The reaction progress was monitored by TLC, and after approximately 5 h, the reaction mixture was separated by preparative liquid chromatography so that the starting material was less than 5%. The mixture was then lyophilized to obtain 38.7 mg of a yellow solid (49% yield).

[0138] The LC-MS result was [M+H]+: 525.2.

[0139] Example 18: Synthesis of compounds D-D18, D-D19, and D-D20 [ka] Compound D-D18 (39.5 mg) was obtained by referring to the synthetic route and method of Example 17. The LC-MS result was [M+H]: 576.1.

[0140] [ka] Compound D-D19 (37.5 mg) was obtained by referring to the synthetic route and method of Example 17. The LC-MS result was [M+H]: 525.1.

[0141] [ka] Compound D-D16 (38.9 mg) was obtained by referring to the synthetic route and method of Example 17. The LC-MS result was [M+H]: 576.2.

[0142] Example 19: Synthesis of Compound M1 [ka] A 5000 mL single-neck flask was charged with N-fluorenylmethyloxycarbonyl-glycine-glycine (100 g, 282 mmol, 1.0 eq, purchased), lead tetraacetate (175 g, 553 mmol, 1.4 eq), 2000 mL dry tetrahydrofuran, and 670 mL toluene. The mixture was stirred uniformly and heated to 85°C under nitrogen gas protection for 2.5 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound M1 (87 g). LC-MS: [M+NH4] + 386.0.

[0143] Example 20: Synthesis of Compound M2 [ka] Compound SM-3 (49.9 g, 100.0 mmol, 1.0 eq, synthesized according to the method disclosed in our patent application CN108452321), pentafluorophenol (18.5 g, 110.0 mmol, 1.1 eq), DCC (20.64 g, 110.0 mmol, 1.1 eq), and THF (500 mL) were added to a 1000 mL single-neck flask and reacted at room temperature for 1 hour (monitored for complete reaction by TLC). The insoluble material was removed by filtration, and the filtrate, designated Filtrate A, was stored at 2-8 °C for further use (the solvent was used as is, calculated at 0.2 M). LC-MS: [M+H] + 565.2.

[0144] Example 21: Synthesis of Compound L-D1 [ka]

[0145] Step 1: Synthesis of compound 1a A 250 mL single-neck flask was charged with M1 (7.37 g, 20.0 mmol), 100 mL of THF, and p-toluenesulfonic acid monohydrate (0.38 g, 2.00 mmol). The mixture was cooled to 0 °C with stirring, and the benzyl ester (7.33 g, 40.0 mmol), a synthetic intermediate of DSM-5, was added dropwise. The mixture was then allowed to warm to room temperature and react for approximately 2-4 h. The reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated NaHCO3 solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1-5:1-1:1) to give 1a (5.32 g, 54% yield). LC-MS: [M+H] 492.2.

[0146] Step 2: Synthesis of compound 1b A 50 mL single-neck flask was charged with 1a (5.00 g, 10.2 mmol) and 20 mL of DMF, stirred at 0 °C, and DBU (1.64 mL, 11.0 mmol) was added. The reaction was allowed to proceed for 1 h and monitored by TLC. After Fmoc deprotection was complete, the mixture was allowed to stand and prepared for use. Another 50 mL single-neck flask was charged with M4 (4.55 g, 11.0 mmol, purchased), PyBOP (6.25 g, 12.0 mmol), HOBt (1.62 g, 12.0 mmol), and 10 mL of DMF. DIEA (2.00 mL, 12.0 mmol) was added in an ice-water bath and stirred for 30 min. The reaction mixture was then placed in a reaction flask and allowed to warm to room temperature. The reaction mixture was monitored by HPLC, and upon completion, the reaction mixture was purified by preparative liquid chromatography to obtain the product. The product was lyophilized to obtain solid 1b (4.61 g, 68% yield). LC-MS: [M+H] 665.3.

[0147] Step 3: Synthesis of compound 1c 1b (4.32 g, 6.50 mmol) and 15 mL of DMF were placed in a 50 mL single-neck flask and dissolved. After dissolving, 4.2 g of 5% Pd / C was added and the mixture was hydrogenated for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate and crude product 1c were obtained and used directly in the next reaction.

[0148] Step 4: Synthesis of compound 1d The crude product 1c was placed in an ice-water bath, DIPEA (1.22 mL, 7.00 mmol) was added, and compound M2 (35 mL, 7.0 mmol) was added. The mixture was then warmed to room temperature and reacted for 1 h. The reaction was monitored for completion by HPLC, and the liquid phase was purified. The fraction was lyophilized to give 1d (3.62 g). LC-MS: [M+H] 821.4.

[0149] Step 5: Synthesis of compound 1e A 50 mL single-neck flask was charged with 1d (500.0 mg, 0.60 mmol), compound 1 (310.6 mg, 0.58 mmol), PyBOP (448.3 mg, 0.94 mmol), HOBt (127.0 mg, 0.94 mmol), and 15 mL of DMF. DIEA (418 μL, 2.40 mmol) was added in an ice-water bath, and the mixture was allowed to warm to room temperature and react for 3 h. The reaction was monitored by HPLC, and after completion, the reaction mixture was purified by preparative liquid chromatography to obtain compound 1e. The resulting fraction was lyophilized to give 1e (497.9 mg, 67%). LC-MS: [M+H] + 1238.6;

[0150] Step 6: Synthesis of compound L-D1 A 25 mL single-neck flask was charged with 1e (100 mg, 0.081 mmol), zinc bromide (368 mg, 1.63 mmol), and 5 mL of nitromethane, and the reaction was carried out at 40°C for 1 hour. The reaction was monitored by HPLC, and after completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography to obtain a product fraction. The product was lyophilized to obtain solid compound L-D1 (63.1 mg). LC-MS: [M+H] + 1082.3.

[0151] Example 22: Synthesis of Compound L-D2 [ka] Compound L-D2 (59.8 mg) was obtained by following the synthetic route and method of Example 21. LC-MS: [M+H] + 1082.4.

[0152] Example 23: Synthesis of compound L-D3 [ka]

[0153] Step 1: Synthesis of compound 2a A 250 mL single-neck flask was charged with M1 (7.36 g, 20.0 mmol), 100 mL of THF, and p-toluenesulfonic acid monohydrate (0.38 g, 2.00 mmol). The mixture was cooled to 0 °C with stirring, and the benzyl ester (7.25 g, 40.0 mmol), a synthetic intermediate for DSM-2, was added dropwise. The mixture was allowed to warm to room temperature and react for approximately 2-4 h. The reaction was monitored by TLC. After completion of the reaction, the reaction was quenched by the addition of saturated NaHCO3 solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1-5:1-1:1) to give 2a (5.12 g, 52% yield). LC-MS: [M+H] + 490.2.

[0154] Step 2: Synthesis of compound 2b A 50 mL single-neck flask was charged with 2a (5.00 g, 10.2 mmol) and 20 mL of DMF, stirred at 0 °C, and then DBU (1.64 mL, 11.0 mmol) was added. The reaction was allowed to proceed for 1 h and monitored by TLC. After Fmoc deprotection was complete, the mixture was allowed to stand and prepared for use. Another 50 mL single-neck flask was charged with M4 (4.56 g, 11.0 mmol, purchased), PyBOP (6.26 g, 12.0 mmol), HOBt (1.64 g, 12.0 mmol), and 10 mL of DMF. DIEA (2.00 mL, 12.0 mmol) was added in an ice-water bath and stirred for 30 min. The reaction mixture was then placed in a reaction flask and allowed to warm to room temperature. The reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was purified by preparative liquid chromatography to obtain the product. The product was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 2b (4.58 g, 68% yield). LC-MS: [M+H] + 663.3.

[0155] Step 3: Synthesis of compound 2c 2b (4.31 g, 6.50 mmol) and 15 mL of DMF were added to a 50 mL single-neck flask and dissolved. After dissolving, 4.0 g of 5% Pd / C was added and the mixture was subjected to a hydrogenation reaction for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate and crude product 2c were obtained and used directly in the next reaction.

[0156] Step 4: Synthesis of compound 2d The crude product 2c was placed in an ice-water bath, DIPEA (1.22 mL, 7.00 mmol) was added, and compound M2 (35 mL, 7.0 mmol) was added. The mixture was then warmed to room temperature and reacted for 1 h. The reaction was monitored for completion by HPLC, and the liquid phase was purified. The fraction was lyophilized to give compound 2d (3.57 g). LC-MS: [M+H] 819.4.

[0157] Step 5: Synthesis of compound 2e A 50 mL single-neck flask was charged with 2d (500.0 mg, 0.61 mmol), compound 1 (320.1 mg, 0.60 mmol), PyBOP (448.5 mg, 0.94 mmol), HOBt (127.3 mg, 0.94 mmol), and 15 mL of DMF. DIEA (418 μL, 2.40 mmol) was added in an ice-water bath, and the mixture was allowed to warm to room temperature and react for 3 h. The reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was purified by preparative liquid chromatography to obtain compound 2e, which was then lyophilized to give compound 2e (482.3 mg, 64%). LC-MS: [M+H] + 1236.5.

[0158] Step 6: Synthesis of compound L-D3 A 25 mL single-neck flask was charged with 2e (100 mg, 0.081 mmol), zinc bromide (370 mg, 1.63 mmol), and 5 mL of nitromethane, and the reaction was allowed to proceed at 40°C for 1 h. The reaction was monitored by HPLC, and upon completion, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography to obtain a product fraction. The product was lyophilized to obtain solid compound L-D3 (48.3 mg). LC-MS: [M+H] + 1080.4.

[0159] Example 24: Synthesis of compound L-D4 [ka]

[0160] Compound L-D4 (49.8 mg) was obtained by following the synthetic route and method of Example 23. LC-MS: [M+H] + 1080.4.

[0161] Example 25: Synthesis of Compound L-D5 [ka]

[0162] Step 1: Synthesis of compound 3a A 250 mL single-neck flask was charged with M1 (11.05 g, 30.0 mmol), 150 mL of THF, and p-toluenesulfonic acid monohydrate (0.57 g, 3.00 mmol). The mixture was cooled to 0 °C with stirring, and the benzyl ester (9.41 g, 40.0 mmol), a synthetic intermediate of DSM-3, was added dropwise. The mixture was then allowed to warm to room temperature and react for approximately 2-4 h. The reaction was monitored by TLC. After completion of the reaction, the reaction was quenched by the addition of saturated NaHCO3 solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1-5:1-1:1) to give 3a (8.04 g, 37% yield). LC-MS: [M+H] + 544.2.

[0163] Step 2: Synthesis of compound 3b A 50 mL single-neck flask was charged with 3a (5.54 g, 10.2 mmol) and 20 mL of DMF, stirred at 0 °C, and then DBU (1.64 mL, 11.0 mmol) was added. The reaction was allowed to proceed for 1 h and monitored by TLC. After Fmoc deprotection was complete, the mixture was allowed to stand and prepared for use. Another 50 mL single-neck flask was charged with M4 (4.55 g, 11.0 mmol, purchased), PyBOP (6.27 g, 12.0 mmol), HOBt (1.66 g, 12.0 mmol), and 10 mL of DMF. DIEA (2.00 mL, 12.0 mmol) was added in an ice-water bath and stirred for 30 min. The reaction mixture was then placed in a reaction flask and allowed to warm to room temperature. The reaction was monitored by HPLC. Upon completion, the reaction mixture was purified by preparative liquid chromatography to obtain a product fraction. The fraction was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 3b (3.52 g, 48% yield). LC-MS: [M+H] + 717.3.

[0164] Step 3: Synthesis of compound 3c A 50 mL single-neck flask was charged with 3b (3.22 g, 4.50 mmol) and 10 mL of DMF. After dissolving, 3.0 g of 5% Pd / C was added and the mixture was hydrogenated for 2 hours. After completion of the reaction, the mixture was filtered to obtain the filtrate and crude product 3c, which were used directly in the next reaction.

[0165] Step 4: Synthesis of compound 3d The crude product 3c was placed in an ice-water bath, DIPEA (1.22 mL, 7.00 mmol) was added, and then compound M2 (25 mL, 5.0 mmol) was added. The mixture was then warmed to room temperature and reacted for 1 hour. The reaction completion was monitored by HPLC, and the liquid phase was purified. The fraction was lyophilized to give 3d (3.17 g). LC-MS: [M+H] + 873.3.

[0166] Step 5: Synthesis of compound 3e A 50 mL single-neck flask was charged with 3d (500.2 mg, 0.57 mmol), compound 1 (319.5 mg, 0.60 mmol), PyBOP (447.3 mg, 0.94 mmol), HOBt (126.9 mg, 0.94 mmol), and 15 mL of DMF. DIEA (418 μL, 2.40 mmol) was added in an ice-water bath, and the mixture was allowed to warm to room temperature and react for 3 h. The reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was purified by preparative liquid chromatography to obtain compound 3e, which was then lyophilized to give 3e (492.3 mg, 67%). LC-MS: [M+H] + 1290.5.

[0167] Step 6: Synthesis of compound L-D5 A 25 mL single-neck flask was charged with 3e (100 mg, 0.077 mmol), zinc bromide (370 mg, 1.63 mmol), and 5 mL of nitromethane, and the reaction was allowed to proceed at 40°C for 1 h. The reaction was monitored by HPLC, and upon completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography to obtain a product fraction. The product was lyophilized to obtain solid compound L-D5 (42.4 mg, 48%). LC-MS: [M+H] + 1134.4.

[0168] Example 26: Synthesis of Compound L-D6 [ka] Compound L-D6 (41.8 mg) was obtained by following the synthetic route and method of Example 25. LC-MS: [M+H] + 1134.4.

[0169] Example 27: Synthesis of Compound L-D7 [ka] Compound L-D7 (45.7 mg) was obtained by following the synthetic route and method of Example 23. LC-MS: [M+H] + 1083.4.

[0170] Example 28: Synthesis of Compound L-D8 [ka]

[0171] Step 1: Synthesis of compound 4a A 250 mL single-neck flask was charged with M1 (7.36 g, 20.0 mmol), 100 mL of THF, and p-toluenesulfonic acid monohydrate (0.38 g, 2.00 mmol). The mixture was cooled to 0 °C with stirring, and benzyl glycolate (6.65 g, 40.0 mmol) was added dropwise. The mixture was allowed to warm to room temperature and react for approximately 2-4 h. The reaction was monitored by TLC. After completion of the reaction, the reaction was quenched by the addition of saturated NaHCO3 solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1-5:1-1:1) to give 4a (5.29 g, 56% yield). LC-MS: [M+H] + 475.2.

[0172] Step 2: Synthesis of compound 4b A 50 mL single-neck flask was charged with 4a (5.00 g, 10.5 mmol) and 20 mL of DMF, stirred at 0 °C, and then DBU (1.64 mL, 11.0 mmol) was added. The reaction was allowed to proceed for 1 h and monitored by TLC. After Fmoc deprotection was complete, the mixture was allowed to stand and prepared for use. Another 50 mL single-neck flask was charged with M4 (4.57 g, 11.0 mmol, purchased), PyBOP (6.26 g, 12.0 mmol), HOBt (1.65 g, 12.0 mmol), and 10 mL of DMF. DIEA (2.00 mL, 12.0 mmol) was added in an ice-water bath and stirred for 30 min. The reaction mixture was then placed in a reaction flask and allowed to warm to room temperature. The reaction mixture was monitored by HPLC. Upon completion, the reaction mixture was purified by preparative liquid chromatography to obtain the product. The product was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 4b (4.68 g, 71% yield). LC-MS: [M+H] + 648.3.

[0173] Step 3: Synthesis of compound 4c 4b (3.00 g, 4.63 mmol) and 15 mL of DMF were placed in a 50 mL single-neck flask and dissolved. After dissolving, 2.0 g of 5% Pd / C was added and the mixture was hydrogenated for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate and crude product 4c were used directly in the next reaction.

[0174] Step 4: Synthesis of compound 4d The crude product 4c was placed in an ice-water bath, DIPEA (1.22 mL, 7.00 mmol) was added, and compound M2 (25 mL, 5.0 mmol) was added. The mixture was then warmed to room temperature and reacted for 1 hour. The reaction completion was monitored by HPLC, and the liquid phase was purified. The fraction was lyophilized to give 4d (2.57 g). LC-MS: [M+H] + 804.3.

[0175] Step 5: Synthesis of compound 4e A 50 mL single-neck flask was charged with 4d (500.0 mg, 0.62 mmol), compound CD-1 (289.1 mg, 0.64 mmol), PyBOP (448.5 mg, 0.94 mmol), HOBt (127.3 mg, 0.94 mmol), and 15 mL of DMF. DIEA (418 μL, 2.40 mmol) was added in an ice-water bath, and the mixture was allowed to warm to room temperature and react for 3 h. The reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was purified by preparative liquid chromatography to obtain compound 4e, which was then lyophilized to give 4e (412.3 mg, 48%). LC-MS: [M+H] + 1238.5.

[0176] Step 6: Synthesis of compound L-D8 A 25 mL single-neck flask was charged with 4e (100 mg, 0.081 mmol), zinc bromide (370 mg, 1.63 mmol), and 5 mL of nitromethane, and the reaction was allowed to proceed at 40°C for 1 h. The reaction was monitored by HPLC, and upon completion, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography to obtain a product fraction. The product was lyophilized to obtain solid compound L-D8 (48.7 mg). LC-MS: [M+H] +1082.4.

[0177] Example 29: Synthesis of Compound L-D9 [ka] Compound L-D9 (45.1 mg) was obtained by following the synthetic route and method of Examples 21 and 28. LC-MS: [M+H] + 1096.4.

[0178] Example 30: Synthesis of Compound L-D10 [ka] Compound L-D10 (45.9 mg) was obtained by following the synthetic route and method of Example 21. LC-MS: [M+H] + 1066.4.

[0179] Example 31: Synthesis of Compound L-D11 [ka] Compound L-D11 (55.2 mg) was obtained by following the synthetic route and method of Example 23. LC-MS: [M+H] + 1106.4.

[0180] Example 32: Synthesis of control compounds The following compounds were synthesized according to the methods described in Patent CN111689980 and WO2020063676. [Table 1] JPEG0007753372000056.jpg93149

[0181] Example 33: Synthesis of Compound L-H1 [ka]

[0182] Step 1: Synthesis of compound 1f A 50 mL single-neck flask was charged with 1b (500.0 mg, 0.772 mmol), 5% Pd / C (500.0 mg, 100% m), and 10 mL of DMF. A hydrogen balloon was added to replace the atmosphere, and the mixture was allowed to react at room temperature for approximately 3 hours. The reaction was monitored by HPLC. After completion, the hydrogen gas was removed by ultrasound. The filtrate and crude product 1c were obtained. MC (280.1 mg, 0.9 mmol) and DIEA (235 mg, 1.8 mmol) were added to the filtrate in an ice-water bath, followed by nitrogen gas protection. The mixture was then warmed to room temperature and reacted for 1 hour. The reaction was monitored by HPLC, purified by preparative liquid chromatography, and lyophilized to give compound 1f (268.9 mg, 86%). MS: [M+H] + 617.2.

[0183] Step 2: Synthesis of compound L-H1 A 10ml single-neck flask was charged with 1f (268.9mg, 0.44mmol), exatecan mesylate (233.8mg, 0.44mmol, purchased), HATU (190.5mg, 0.50mmol), HOBt (67.8mg, 0.50mmol), and 5ml of DMF. The mixture was stirred in an ice-water bath for 10 minutes, and DIEA (140uL, 0.84mmol) was added dropwise to continue the reaction. After confirming complete reaction by HPLC, the mixture was separated and lyophilized to give 254.3mg of a yellow solid (56% yield). LC-MS: [M+H] + 1034.4.

[0184] Example 34: The following compounds were synthesized with reference to the synthetic route and method of Example 21. [Table 2] JPEG0007753372000059.jpg41148

[0185] Example 35: General method for preparing ADC drugs by coupling Pre-purified antibody molecules (Ab) with a monomer ratio of over 95% were transferred to phosphate buffer (10 mg / mL) using an ultrafiltration centrifuge tube. TCEP (20 times the moles of antibody) was added and incubated at room temperature for 10 hours to cleave the disulfide bonds between antibody chains. Payload (20 times the moles of antibody) was added and incubated at room temperature for 2 hours. After the reaction was complete, the solution was exchanged with PBS using an ultrafiltration centrifuge tube with a 30 kDa molecular weight cutoff to remove unbound payload. The ADC sample after the exchange was filtered through a 0.22 micron sterile filter and stored until use.

[0186] The coupling payload compounds L-D1, L-D2, L-D3, L-D4, L-D5, L-D6, L-D7, L-D8, L-D9, L-D10, L-D11, L-H1, L-H2, L-H3, L-H4, L-H5, L-H6, L-H7, and L-H8 were coupled to antibody molecules Ab (A: Trastuzumab antibody, B: Cetuximab antibody) using the general coupling method described in Example 35. The average drug-to-antibody ratio (DAR) of the coupled product was measured by reverse-phase high-performance liquid chromatography. The relevant information of the resulting ADC drug molecules and their corresponding payload molecules are shown in the table below. [Table 3] JPEG0007753372000061.jpg226160JPEG0007753372000062.jpg229160JPEG0007753372000063.jpg76160

[0187] Example 36: Elimination half-life study of deuterated camptothecin drug material Liver microsomes: Human liver microsomes (supplier: Xenotech) Chemical Reagents [Table 4] equipment [Table 5] Incubation System [Table 6]

[0188] Experimental procedure Preparation of phosphate buffer Appropriate amounts of KH2PO4 (MW = 136.09), K2HPO4·3H2O (MW = 228.22), and MgCl2·6H2O (MW = 203.3) were weighed and thoroughly dissolved in an appropriate volume of deionized water to prepare a 100 mM potassium phosphate buffer solution (containing 3 mM MgCl2) with a pH of 7.4 ± 0.05. The pH was adjusted with HCl as needed.

[0189] Preparation of stock and working solutions Preparation of stock solutions: The appropriate amount of test article or positive control compound was placed in a suitable container and a 10 mM stock solution was prepared in DMSO (or other suitable organic solvent).

[0190] Preparation of working solution: A working solution was prepared by diluting the 10 mM stock solution to 1.0 mM with acetonitrile (or other suitable solvent) and was ready for use.

[0191] Preparation of microsome test / positive control working solutions A stock solution of liver microsomes (concentration: 20 mg / mL) was diluted with 100 mM potassium phosphate buffer (pH 7.4) to the concentration (1.12 mg / mL) required for sample incubation.

[0192] Preparation of NADPH solution The NADPH coenzyme solution contained 10 mM NADPH and was prepared by diluting NADPH in 100 mM potassium phosphate buffer before incubating the samples.

[0193] Preparation of stop solution A stop solution was prepared by mixing equal volumes of methanol and acetonitrile (MeOH:ACN=1:1, v:v) and stored in a refrigerator at 4°C.

[0194] Sample incubation and processing 1. The test article working solution was added to the liver microsome working solution and pre-incubated at 37°C for 5 minutes. The prepared NADPH working solution was then added and mixed uniformly. The incubation volume was 200 μL, and the liver microsome protein concentration and test article incubation concentration in the incubation system were 1.0 mg / mL and 10 μM, respectively. The incubation tube was incubated in a 37°C water bath for 120 minutes. The test article incubation system required a minimum volumetric content of ≤1% total organic solvents (DMSO and acetonitrile or other organic solvents), and a DMSO content of ≤0.1%. All procedures were performed on ice. 2. To the blank sample, the corresponding volume of phosphate buffer solution was added instead of the test sample working solution. To the 0 min sample, the stop solution and liver microsome solution were added and mixed uniformly, and then the test sample working solution was added. 3. At the end of the incubation, 400 μL of stop solution was added to stop the reaction, and the incubated samples were removed from the water bath. After the reaction was stopped, the samples were shaken and then centrifuged at 4700 g for 10 minutes. After centrifugation, 200 μL of the supernatant was transferred to a 96-well plate and directly used for LC-MS analysis to determine the ratio of metabolites to the main drug.

[0195] The measurement results are shown in the table below. [Table 7] JPEG0007753372000068.jpg206143JPEG0007753372000069.jpg48143

[0196] As can be seen from the experimental results, the metabolic stability of deuterated drugs in liver microsomes was significantly improved.

[0197] Example 37: ADC drug antitumor cell activity test In this study, A431, Fadu, Bxpc-3, SW620, and N87 were used as in vitro efficacy testing systems. Appropriate amounts of tumor cell lines were uniformly seeded into 96-well plates and incubated in a CO2 incubator. After 24 hours, cells were confirmed to be normal under a microscope and then treated with drugs. Drugs (ADC drug initial concentration: 500 nM, diluted 7-fold, resulting in a total of eight concentration points; the theoretical toxin-antibody coupling ratio (DAR) is 8:1, whereas the actual coupling ratio is approximately 7.5:1) were diluted with medium and mixed evenly. Then, the toxin was added to the corresponding wells. The following two rows served as a control group (i.e., cells + medium, no drug treatment) and a blank group (i.e., no cells, containing medium only, for background elimination). The plates were then incubated in a CO2 incubator (37°C) for five days. After 5 days, 20 μL of MTS (Promega, G3581) was added to each well, and the incubation time was 2 hours. The absorbance at 490 nm was then measured using a microplate reader (Molecular Device, model number: SpectraMAX190). The inhibitory effect of the ADC drug on tumor cell proliferation was evaluated by calculating the IC50 by detecting the activity of mitochondrial dehydrogenase. The results are shown in the table below. [Table 8]

[0198] As can be seen from the above ADC cellular activity test, the deuterated camptothecin drug described in the present invention, after being coupled to an antibody via the linking unit L, also exhibits good antitumor activity in many antigen-positive tumor cell lines, and is highly valuable for clinical application.

[0199] Example 38: ADC in vivo efficacy testing In the present invention, an A431 tumor-bearing nude mouse model was established to evaluate the in vivo efficacy of deuterated camptothecin-based derivative ADC conjugates and non-deuterated ADC conjugates. 6 A431 cells were subcutaneously injected into the right shoulder of 4-6 week-old BALB / c nude mice, and the average volume of mouse tumors was 140-150 mm. 3 After reaching maturity, the mice were randomly assigned to groups of 5 mice per group. On days 0, 7, 14, and 21, a blank control (buffer blank) and 10 mg / kg doses of antibody-drug conjugates ADC-1, ADC-3, ADC-5, ADC-10, ADC-12, ADC-13, and ADC-15 were intravenously injected, respectively. Tumor volume was measured on days 0, 7, 14, 21, 24, 28, 32, and 36. The measured data were the average tumor volume at the time of measurement. Changes in mouse weight were also recorded, and the in vivo early toxicity of the ADC drugs was observed. The results are shown in the table below.

[0200] [Table 9]

[0201] [Table 10]

[0202] The above-mentioned ADC mouse in vivo efficacy experiment showed that the deuterated camptothecin drug described in the present invention, after being coupled to an antibody via the linking unit L, exhibited significant antitumor activity in tumor-bearing mice, with the average tumor volume being significantly smaller than that of the blank control, demonstrating significant tumor suppression. No significant rebound was observed during the observation period, and the efficacy was sustained. The body weight of the mice did not change significantly during the administration period. Except for the blank control, there was no significant change in body weight among the mice in the group, and no mice died. Therefore, the deuterated camptothecin drug described in the present invention has good safety.

Claims

1. A deuterated camptothecin derivative represented by the general formula D, or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 1】 (In the formula, R １ , R ７ , R １０ are each independently a hydrogen atom, a deuterium atom, or C １－６ Alkyl, C substituted with one or more deuterium atoms １－６ alkyl, substituted alkyl; R ２ , R ２' , R ３ , R ３' , R ４ , R ４' , R ５ , R ５' , R ８ , R ９ are each independently selected from hydrogen or deuterium; X is -C(O)-CR ａ R ｂ - (CR ｃ R ｄ ) ｎ -O-, -C(O)-CR ａ R ｂ - (CR ｃ R ｄ ) ｎ —NH— or —C(O)—CR ａ R ｂ - (CR ｃ R ｄ ) ｎ -S-; R ａ , R ｂ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R ａ , R ｂ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R ｃ , R ｄ may be the same or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen, or C １－６ Alkyl, halogenated alkyl, C substituted with one or more deuterium atoms １－６ alkyl, alkoxy, alkoxy substituted with one or more deuterium atoms, hydroxyl, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms; or R ｃ , R ｄ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, n is selected from an integer from 0 to 4; R ａ or R ｂ contains at least one deuterium atom.

2. X is -C(O)-CR ａ R ｂ - (CR ｃ R ｄ ) ｎ -O-, R ａ is selected from a hydrogen atom, a deuterium atom, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R ｂ is selected from a hydrogen atom, a deuterium atom, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl or a heteroaryl; or R ａ , R ｂ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl or heterocyclyl substituted with one or more deuterium atoms, heterocyclyl substituted with one or more deuterium atoms, R ｃ , R ｄ may be the same or different and each independently represent a hydrogen atom, a deuterium atom, an alkyl, an alkyl substituted with one or more deuterium atoms, an alkoxy, an alkoxy substituted with one or more deuterium atoms, a hydroxyl, an amino, a cyano, a nitro, a hydroxyalkyl, a cycloalkyl, or a heterocyclyl; R ｃ , R ｄ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms; 2. The camptothecin derivative according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1.

3. The camptothecin derivative is represented by the following formula D ２ 3. The camptothecin derivative according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, comprising a structure represented by the following formula: 【Chemistry 2】 (In the formula, R １０ is a C substituted with a hydrogen atom, one or more deuterium atoms １－６ alkyl, R ２ , R ２' , R ３ , R ３' , R ４ , R ４' , R ５ , R ５' , R ８ , R ９ are each independently selected from hydrogen or deuterium; R ａ is selected from a hydrogen atom, a deuterium atom, an alkyl, and a deuterated alkyl substituted with one or more deuterium atoms; R ｂ is selected from a hydrogen atom, a deuterium atom, an alkyl, or a deuterated alkyl substituted with one or more deuterium atoms; R ａ , R ｂ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, Formula D ２ The wavy lines in represent hydrogen atoms or are covalently linked to a joint unit or a ligand unit of an antigen expressed on a binding target cell.

4. X is 【Chemistry 3】 2. The camptothecin derivative according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of hydrogen and deuterium atoms.

5. 2. The camptothecin derivative according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, including a tautomer, a racemate, a diastereomer, or a mixture thereof. 【Request 6】 【Chemical 4】 2. The camptothecin derivative according to claim 1, which is a compound represented by the formula: or a pharmaceutically acceptable salt or solvate thereof.

7. General formula (-L-X-D ２ or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 5】 (In the formula, R １ , R ７ , R １０ is a hydrogen atom, a deuterium atom, or a C substituted with one or more deuterium atoms. １－６ Alkyl, C １－６ selected from alkyl, substituted alkyl, aryl, deuterated aryl substituted with one or more deuterium atoms, heteroaryl, heteroaryl substituted with one or more deuterium atoms; R ２ , R ２' , R ３ , R ３' , R ４ , R ４' , R ５ , R ５' , R ８ , R ９ are each independently selected from hydrogen or deuterium; X is -C(O)-CR ａ R ｂ - (CR ｃ R ｄ ) ｎ -O-, R ａ , R ｂ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, a heterocyclyl substituted with one or more deuterium atoms, an aryl, an aryl substituted with one or more deuterium atoms, a substituted aryl, a heteroaryl, a heteroaryl substituted with one or more deuterium atoms; or R ａ , R ｂ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R ｃ , R ｄ may be the same or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen, an alkyl, an alkyl halide, C １－６ Alkyl, C substituted with one or more deuterium atoms １－６ Alkyl or fully deuterated C １－６ alkyl, alkoxy, alkoxy substituted with one or more deuterium atoms, hydroxyl, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms; or R ｃ , R ｄ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, n is selected from an integer from 0 to 4; R ａ or R ｂ contains at least one deuterium atom, L is a linking unit, Here, the formula -L-X-D ２ The wavy lines in represent hydrogen atoms or covalent bonds to the antibody of the joint unit or antigen expressed on the binding target cell.

8. 8. The drug-linker compound of claim 7, wherein the O-end of X is bonded to a linking unit L, or a pharmaceutically acceptable salt or solvate thereof.

9. The linking unit L- is -L １ -L ２ -L ３ -L ４ -, where L １ The end is bound to an antibody, and the L ４ The end is bonded to X, L １ is -(succinimide-3-yl-N)-Y-C(O)-, -CH ２ —C(O)—NR ５ -Y-C(O)- or -C(O)-Y-C(O)-; Y is C １－８ Alkyl, C １－８ alkyl-cycloalkyl, or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, said heteroalkyl containing 1-3 atoms selected from N, O or S, said C １－８ each alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl is independently substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy, or cycloalkyl; L ２ is -NR ６ (CH ２ CH ２ O) ｐ CH ２ CH ２ C(O)-, -NR ６ (CH ２ CH ２ O) ｐ CH ２ C(O)-, -S(CH ２ ) ｐ C(O)— or a chemical bond, where p is selected from an integer from 0 to 20; L ３ is selected from peptide residues consisting of 2-7 amino acids, optionally further substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy, and cycloalkyl or substituted cycloalkyl; L ４ is -NR ７ (CR ８ R ９ ) ｑ -, -C(O)NR ７ , —C(O)NR ７ (CH ２ ) ｑ - or a chemical bond, where q is selected from an integer from 0 to 6; R ５ , R ６ and R ７ may be the same or different and are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl; R ８ and R ９ may be the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

10. L １ is -(succinimide-3-yl-N)-Y-C(O)-, -CH ２ —C(O)—NR ５ -Y-C(O)- or -C(O)-Y-C(O)-; Y is C １－８ Alkyl, C １－８ alkyl-cycloalkyl, or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, said heteroalkyl containing 1 to 3 atoms selected from N, O or S, said C １－８ each alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl is independently substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy, or cycloalkyl; L ２ is -NR ６ (CH ２ CH ２ O) ｐ CH ２ CH ２ C(O)-, -NR ６ (CH ２ CH ２ O) ｐ CH ２ C(O)-, -S(CH ２ ) ｐ C(O)— or a chemical bond, where p is selected from an integer from 0 to 20; L ３ is a polypeptide residue consisting of an amino acid selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), or aspartic acid (D); L ４ is -NR ７ CR ８ R ９ - and R ５ , R ６ and R ７ may be the same or different and are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl; R ８ and R ９ may be the same or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl, a deuterated alkyl, a halogenated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

11. L ３ is an amino acid residue consisting of one, two or more amino acids selected from phenylalanine and glycine, or a pharmaceutically acceptable salt or solvate thereof.

12. The drug-linker compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein L 3 is a tetrapeptide residue consisting of glycine-glycine-phenylalanine-glycine.

13. L ４ is -NHCH ２ 10. The drug-linker compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein

14. General formula (L-X-D ２ or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 6】 (L-X-D ２ ) (Wherein, Z is —Y—C(O)—, —CH ２ —C(O)—NR ５ -Y-C(O)- or -C(O)-Y-C(O)-, where Y is C １－８ Alkyl, C １－８ alkyl-cycloalkyl, or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, said heteroalkyl containing 1-3 atoms selected from N, O or S, said C １－８ each alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl is independently substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, alkyl, heteroalkyl, substituted alkyl, alkoxy, carboxyl, or cycloalkyl; L ２ is -NR ６ (CH ２ CH ２ O) ｐ CH ２ CH ２ C(O)-, -NR ６ (CH ２ CH ２ O) ｐ CH ２ C(O)-, -S(CH ２ ) ｐ C(O)— or a chemical bond, where p is selected from an integer from 0 to 20, and any alkyl in the structure is substituted with one or more deuterium atoms; L ３ is a peptide residue of 2-7 amino acids, optionally substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy, and cycloalkyl or substituted cycloalkyl; R １０ is a deuterium atom, C １－６ selected from alkyl or substituted alkyl, aryl, substituted aryl, or heteroaryl; R １１ is selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl; R １２ is selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a halogenated alkyl, a deuterated alkyl, a cycloalkyl, a cycloalkylalkyl, an alkoxyalkyl, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R １１ , R １２ and the carbon atom to which they are attached is C ３－６ cycloalkyl, cycloalkylalkyl or heterocyclyl, R 13 and R 14 are hydrogen atoms, R ５ , R ６ are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl; R １ , R ７ , R １０、 R １５ are each independently hydrogen, alkyl, or C substituted with one or more deuterium atoms. １－４ alkyl, R ２ , R ２' , R ３ , R ３' , R ４ , R ４' , R ５ , R ５' , R ８ , R ９ are each independently selected from hydrogen or deuterium; R １１ or R １２ contains at least one deuterium atom.

15. General formula (L ｂ -X-D ２ 15. The compound represented by the general formula (L-X-D) according to claim 14, or a pharmaceutically acceptable salt or solvate thereof. ２ ) or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 7】 (In the formula, R １１ , R １２ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, a heterocyclyl, a heterocyclyl substituted with one or more deuterium atoms, an aryl, an aryl substituted with one or more deuterium atoms, a substituted aryl, a heteroaryl, a heteroaryl substituted with one or more deuterium atoms; or R １１ , R １２ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R 13 and R 14 are hydrogen atoms, R １ , R ７ , R １０、 R １５ are each independently hydrogen, alkyl, C substituted with one or more deuterium atoms or fully deuterated １－４ selected from alkyl or substituted alkyl; R ２ , R ２' , R ３ , R ３' , R ４ , R ４' , R ５ , R ５' , R ８ , R ９ are each independently selected from hydrogen or deuterium; Ac has a hydrophilic structural unit represented by formula c, 【Chemistry 8】 This structure contains both amino and carboxyl, and X is a scaffold that connects the amino and carboxyl, and C １－１０ A hydrocarbylene group or a substituted hydrocarbylene group, wherein the hydrocarbylene group or the substituted hydrocarbylene group may be substituted with one or more deuterium atoms, and Ac is a group of the structural formula L ｂ -X-D ２ is bonded to the 2-position methylene carbon in

16. 16. The general formula (L-X-D) according to claim 15, wherein Ac is selected from glycine, α-alanine, β-alanine, and (D / L) glutamic acid. ２ ) or a pharmaceutically acceptable salt or solvate thereof.

17. 【Chemical 9】 【change】 【change】 【change】 【change】 【change】 The general formula (L-X-D) according to claim 14 is selected from ２ ) or a pharmaceutically acceptable salt or solvate thereof.

18. An antibody-drug conjugate represented by the general formula (Ab-L-X-Dr), in which the camptothecin derivative, camptothecin-linker compound, or tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof is bound to a ligand unit, or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 10】 (In the formula, R １ , R ７ , R １０ each independently represents a hydrogen atom, a deuterium atom, or a C substituted with one or more deuterium atoms. １－６ Alkyl, C １－６ selected from alkyl, substituted alkyl, aryl, aryl substituted with one or more deuterium atoms, heteroaryl, heteroaryl substituted with one or more deuterium atoms; R ２ , R ２' , R ３ , R ３' , R ４ , R ４' , R ５ , R ５' , R ８ , R ９ are each independently selected from hydrogen or deuterium; X is -C(O)-CR ａ R ｂ - (CR ｃ R ｄ ) ｎ -O-, R ａ , R ｂ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, an alkoxyalkyl, an alkoxyalkyl substituted with one or more deuterium atoms, a heterocyclyl, an aryl, a substituted aryl, or a heteroaryl; R ａ , R ｂ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R ｃ , R ｄ may be the same or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen, or C １－６ Alkyl, halogenated alkyl, C substituted with one or more deuterium atoms １－６ alkyl, alkoxy, alkoxy substituted with one or more deuterium atoms, hydroxyl, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms; or R ｃ , R ｄ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, n is selected from an integer from 0 to 4; L is a linking unit, R ａ or R ｂ contains at least one deuterium atom, Formula-L-X-D ２ The wavy lines in represent hydrogen atoms or covalent bonds to the antibody of the joint unit or antigen expressed on the binding target cell.

19. The linking unit L- is -L １ -L ２ -L ３ -L ４ - and L １ The end is bound to an antibody, and the L ４ The end is bonded to X, L １ is -(succinimide-3-yl-N)-Y-C(O)-, -CH ２ —C(O)—NR ５ -Y-C(O)- or -C(O)-Y-C(O)-; Y is C １－８ Alkyl, C １－８ alkyl-cycloalkyl or straight-chain or straight-chain-cyclic heteroalkyl having 1 to 8 atoms, said heteroalkyl containing 1-3 atoms selected from N, O or S, said C １－８ each alkyl, cycloalkyl, straight-chain or straight-chain-cyclic heteroalkyl is independently substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy, or cycloalkyl; L ２ is -NR ６ (CH ２ CH ２ O) ｐ CH ２ CH ２ C(O)-, -NR ６ (CH ２ CH ２ O) ｐ CH ２ C(O)-, -S(CH ２ ) ｐ C(O)— or a chemical bond, where p is selected from an integer from 0 to 20; L ３ is selected from peptide residues consisting of 2-7 amino acids, optionally substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy, and cycloalkyl or substituted cycloalkyl; L ４ is -NR ７ (CR ８ R ９ ) ｑ -, -C(O)NR ７ , —C(O)NR ７ (CH ２ ) ｑ - or a chemical bond, and q is selected from an integer from 0 to 6; R ５ , R ６ and R ７ may be the same or different and are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl; R ８ and R ９ may be the same or different and are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, or heteroaryl; m is selected from integers or decimals from 1 to 10; Ab is an antibody, antibody fragment, target protein, or Fc-fusion protein; 19. The antibody-drug conjugate of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a linking unit.

20. 20. The antibody-drug conjugate of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody and forms a linking bond with the binding unit via its heteroatom, and the antibody is selected from a murine antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an antibody fragment, a bispecific antibody, and a multispecific antibody.

21. Antibodies include anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, and anti-TDGF1 antibody. body, anti-ETBR antibody, anti-MSLN antibody, anti-TIM-1 antibody, anti-LRRC15 antibody, anti-LIV-1 antibody, anti-CanAg / AFP antibody, anti-cladin 18.2 antibody, anti-Mesothelin antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-c-MET antibody, anti-SLITRK6 antibody, anti-KIT / CD117 antibody, anti-STEAP1 antibody, anti-SLAMF7 / CS1 antibody, anti-NaPi2B / SLC34A2 antibody, anti-G PNMB antibody, anti-HER3 (ErbB3) antibody, anti-MUC1 / CD227 antibody, anti-AXL antibody, anti-CD166 antibody, anti-B7-H3 (CD276) antibody, anti-PTK7 / CCK4 antibody, anti-PRLR antibody, anti-EFNA4 antibody, anti-5T4 antibody, anti-NOTCH3 antibody, anti-Nectin 4 antibodies, anti-TROP-2 antibody, anti-CD142 antibody, anti-CA6 antibody, anti-GPR20 antibody, anti-CD174 antibody, anti-CD71 antibody, anti-EphA2 antibody, anti-LYPD3 antibody, anti-FGFR2 antibody, anti-FGFR3 antibody, anti-FRα antibody, anti-CEACAMs antibody, anti-GCC antibody, anti-Integrin antibody Av antibody, anti-CAIX antibody, anti-P-cadherin antibody, anti-GD3 antibody, anti-Cadherin 6 antibody, anti-LAMP1 antibody, anti-FLT3 antibody, anti-BCMA antibody, anti-CD79b antibody, anti-CD19 antibody, anti-CD33 antibody, anti-CD56 antibody, anti-CD74 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD37 antibody, anti-CD138 antibody, anti-CD352 antibody, anti-CD25 antibody, anti-CD123 antibody, and anti-CD47 antibody, or a pharmaceutically acceptable salt or solvate thereof.

22. [Chemical 11] 【change】 【change】 【change】 【change】 is selected from where m is selected from an integer or decimal number from 1 to 10; The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to claim 19 or 20, wherein Ab is an antibody, an antibody fragment, a target protein, or an Fc-fusion protein.

23. The compound (L-X-D) according to claim 15, comprising the steps represented by the following formula: ２ ) manufacturing method. 【Chemistry 12】

24. The general formula (Ab-L) according to any one of claims 18 to 21 ａ a method for producing an antibody-drug conjugate represented by the formula (I) or a pharmaceutically acceptable salt or solvate thereof, comprising: Antibodies, antibody fragments, target proteins, Fc-fusion proteins, etc., and ２ ) by a coupling reaction with a compound represented by the general formula (Ab-L ａ -X-D ２ obtaining a compound represented by the formula The reaction scheme of the coupling reaction is: 【Chemistry 13】 and In the formula, R １１ , R １２ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a substituted alkyl, a cycloalkyl, a cycloalkyl substituted with one or more deuterium atoms, a cycloalkylalkyl, a cycloalkylalkyl substituted with one or more deuterium atoms, a heterocyclyl, a heterocyclyl substituted with one or more deuterium atoms, an aryl, an aryl substituted with one or more deuterium atoms, a substituted aryl, a heteroaryl, a heteroaryl substituted with one or more deuterium atoms; or R １１ , R １２ and the carbon atom to which they are attached is C ３－６ Cycloalkyl, C substituted with one or more deuterium atoms ３－６ cycloalkyl, cycloalkylalkyl, cycloalkylalkyl substituted with one or more deuterium atoms, heterocyclyl, heterocyclyl substituted with one or more deuterium atoms, R 13 and R 14 are hydrogen atoms, R １５ is a C substituted with hydrogen, alkyl, one or more deuterium atoms １－４ selected from alkyl, Manufacturing method.

25. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

26. Use of a camptothecin derivative according to any one of claims 1 to 22, an antibody-drug conjugate thereof, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient in the manufacture of a drug for treating or preventing a tumor.

27. 27. The use according to claim 26, wherein the tumor is a solid tumor or a hematological tumor.

28. 28. The use of claim 27, wherein the tumor is selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urinary tract cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, melanoma, glioma, neuroblastoma, glioblastoma multiforme, sarcoma, lymphoma, or leukemia.

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