Exatecan derivatives and their uses

Abstract

The present invention provides a series of exatecan derivatives having novel structures, their pharmaceutically acceptable salts, stereoisomers or prodrugs, and their use in the anti-tumor field, wherein the exatecan derivatives have a structure represented by formula (I): JPEG2025526504000098.jpg58170

Description

[Technical Field]

[0001] The present invention relates to the field of biomedicine, and in particular to exatecan derivatives and their uses. [Background technology]

[0002] Exatecan, a fully synthetic derivative of camptothecin, possesses highly potent inhibitory activity against topoisomerase I (Top1), promotes tumor cell apoptosis, and has broad antitumor activity. Exatecan's severe side effects limit its application in the field of antitumor drugs. However, its hydroxyacetamide derivative (Dxd) is used as a toxin to form an antibody-drug conjugate (ADC) with trastuzumab (Herceptin), DS-8201a, which has excellent therapeutic efficacy against Her2-expressing tumors. DS-8201a is an ADC (antibody-drug conjugate) with excellent performance. ADC drugs targeting other antigens, such as B7-H3 and Trop2, are also being extensively studied.

[0003] The present invention provides a series of exatecan derivatives with binding sites by derivatizing the exatecan scaffold with hydroxylamine and hydrazine. These compounds have high antitumor activity, low toxic side effects, and high water solubility, making them potentially useful as antitumor monotherapy or antibody-drug conjugates. Summary of the Invention

[0004] The present invention provides a series of exatecan derivatives having novel structures, pharmaceutically acceptable salts, stereoisomers or prodrugs thereof, and uses thereof in the antitumor field.

[0005] One aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof: JPEG2025526504000002.jpg51170

[0006] During the ceremony, R is selected from -Z-R1, where Z is a single bond or C=O; R1 is -(CH2) n NR a R b , -CH2OR a , -NOR a , -(CH2) n ONR a R b or -R3, where n is selected from 0, 1, 2, or 3; R a , R b are each independently selected from hydrogen, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkylamino group, an amino C1-C6 alkyl group, or a C1-C6 alkoxy group; R3 is selected from a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group containing a heteroatom of N, O, or S, and R3 may optionally further comprise R c is replaced by R c is selected from hydrogen, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkylamino group, or a C1-C6 alkoxy group; provided that -Z-R1 is not -NH2, -CH2OH, -CH2NH2, or -CH2OCH2NH2.

[0007] In one embodiment, R1 is not -CH2ONH2 or a hydroxyoxetane group.

[0008] In one embodiment, R1 is -NR a R b , -CH2NR a R b , -CH2OR a , -NOR a , -(CH2) n ONR a Rb or -R3.

[0009] Preferably, R1 is -NR a R b , -C(O)NR a R b , -CH2NR a R b , -CH2ONR a R b or -R3.

[0010] In one embodiment, R a , R b are each independently selected from hydrogen, a hydroxy group, an amino group, a C1 to C6 alkyl group, a C1 to C6 alkylamino group, or a C1 to C6 alkoxy group.

[0011] Preferably, R a , R b are each independently selected from hydrogen, a hydroxy group, an amino group, a methyl group, a methylamino group, or a methoxy group.

[0012] In one embodiment, R3 is selected from a 3-6 membered heterocycloalkyl group containing an N, O, or S heteroatom, and R3 optionally further comprises R c wherein R is substituted with c is selected from hydrogen, a hydroxy group, an amino group, a C1 to C6 alkyl group, a C1 to C6 alkylamino group, or a C1 to C6 alkoxy group.

[0013] In one embodiment, R1 is selected from -NHNH2, -N(CH3)NH2, -N(CH3)NHCH3, -C(O)NHNH2, -C(O)N(CH3)NH2, -CH2NHOH, -CH2NHOCH3, -CH2ONH2, -CH2ONHCH3, -CH2NCH3NH2, -CH2N(CH3)NHCH3, -CH2N(CH3)OH, -CH2NHOCH2CH3, a hydroxyoxetane group, an aminooxetane group. JPEG2025526504000003.jpg35170

[0014] In one embodiment, R1 is selected from -NHNH2, -N(CH3)NH2, -N(CH3)NHCH3, -C(O)NHNH2, -C(O)N(CH3)NH2, -CH2NHOH, -CH2NHOCH3, -CH2ONHCH3, -CH2NCH3NH2, -CH2N(CH3)NHCH3, -CH2N(CH3)OH, -CH2NHOCH2CH3, an aminooxetane group. JPEG2025526504000004.jpg30170

[0015] In one embodiment, the compound of formula (I) is a compound of formula (Ia). JPEG2025526504000005.jpg64170

[0016] wherein R1 is defined as in the compound of formula (I).

[0017] Preferably, R1 is -NHNH2 or -N(CH3)NH2.

[0018] In one embodiment, the compound of formula (I) is a compound of formula (Ib). JPEG2025526504000006.jpg56170

[0019] In the formula, R2 is selected from -NHOH, -ONH2, -NHO (C1-C3 alkyl group), -ONH (C1-C3 alkyl group), -N (C1-C3 alkylamino group), -N (C1-C3 alkyl group)NH (C1-C3 alkyl group), -N (C1-C3 alkyl group)OH, or -NHO (C1-C3 alkyl group).

[0020] Preferably, R2 is selected from -NHOH, -NHOCH3, ONH2, -ONHCH3, -NCH3NH2, -N(CH3)NHCH3, -N(CH3)OH or -NHOCH2CH3.

[0021] In one embodiment, R2 is selected from -NHOH, -NHO(C1-C3 alkyl group), -ONH(C1-C3 alkyl group), -N(C1-C3 alkylamino group), -N(C1-C3 alkyl group)NH(C1-C3 alkyl group), -N(C1-C3 alkyl group)OH, or -NHO(C1-C3 alkyl group).

[0022] Preferably, R2 is selected from -NHOH, -NHOCH3, -ONHCH3, -NH3NH2, -N(CH3)NHCH3, -N(CH3)OH or -NHOCH2CH3.

[0023] In one embodiment, the compound of formula (I) is a compound of formula (Ic). JPEG2025526504000007.jpg60170

[0024] In the formula, R a , R b is defined as in compounds of formula (I), except that R a , R b is not H at the same time.

[0025] Preferably, R a , R b are each independently selected from hydrogen, an amino group, a C1 to C3 alkyl group, and a C1 to C3 alkylamino group.

[0026] Preferably, —NR a R b is selected from —NHNH2, —N(CH3)NH2, or —N(CH3)NHCH3.

[0027] In one embodiment, the compound of formula (I) is a compound of formula (Id). JPEG2025526504000008.jpg63170

[0028] wherein X is CH, NH, O, or S.

[0029] Preferably, X is CH2 or O, and more preferably, X is O.

[0030] In one embodiment, R c is selected from hydrogen, a hydroxy group, an amino group, a C1 to C6 alkyl group, a C1 to C6 alkylamino group, or a C1 to C6 alkoxy group.

[0031] Preferably, R c is selected from a hydroxy group or an amino group, and is more preferably an amino group.

[0032] In one embodiment, the compound of formula (I) is selected from the following compounds: JPEG2025526504000009.jpg183170JPEG2025526504000010.jpg51170

[0033] It is noteworthy that when R1 is -CH2ONH2, its IC20 in inhibiting the growth of OE33 cells was similar to that of compound 8 (R1 is -CH2ONHCH3). 50 The IC value of compound 8 is below 10 nM. 50 The IC values for the exatecan derivative compounds were still obtained when R1 was -CH2ONH2. 50 This is significantly lower than the value.

[0034] Another aspect of the present invention provides a method for preparing any of the compounds described above, selected from the following reaction pathways:

[0035] Reaction Pathway 1: Exatecan is reacted with N,N'-carbonyldiimidazole, followed by reaction with hydrazine or a substituted hydrazine to give the corresponding N-aminourea exatecan derivative.

[0036] For example, the following reaction pathways can be mentioned: JPEG2025526504000011.jpg39170

[0037] Reaction Pathway 2: Substituted hydrazines are reacted with oxalyl chloride, followed by reaction with exatecan to give the corresponding oxamide hydrazide exatecan derivatives.

[0038] For example, the following reaction pathways can be mentioned: JPEG2025526504000012.jpg34170

[0039] Reaction Pathway 3: Exatecan is reacted with bromoacetic acid to give bromoacetylexatecan, and bromoacetylexatecan is condensed with an amine compound to give the corresponding amideexatecan derivative.

[0040] For example, the following reaction pathways can be mentioned: JPEG2025526504000013.jpg50170

[0041] Reaction Pathway 4: Exatecan is reacted directly with a carboxylic acid compound to give the corresponding amide exatecan derivative.

[0042] For example, the following reaction pathways can be mentioned: JPEG2025526504000014.jpg46170

[0043] In the formula, R and L are defined as in the compound of formula (I).

[0044] A further aspect of the present invention provides a Drug-Linker Compound having the formula (II), or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof: JPEG2025526504000015.jpg51170

[0045] wherein R is defined as in the compound of formula (I).

[0046] In one embodiment, L is -L1-Q-L2, and R is partially linked to L1.

[0047] wherein L1 is selected from the group represented by the formula: JPEG2025526504000016.jpg28170Here, the positions indicated by the following symbols indicate connections to the R group, JPEG2025526504000017.jpg29170The positions indicated by the symbols below indicate connections to the Q group. JPEG2025526504000018.jpg28170

[0048] In one embodiment, L2 is selected from the group represented by the formula: JPEG2025526504000019.jpg34170

[0049] In one embodiment, Q is Val-Cit, Val-Ala, Ala-Ala-Asn, Gly-Gly-Phe-Gly, Gly-Lys, Gly-Gly-lys, (CH2) m1 O(CH2) m2 , (CH2) m3 wherein m1 and m2 are each independently selected from integers of 1 to 4.

[0050] Preferably, m1 is 2.

[0051] Preferably, m2 is 2.

[0052] Preferably, m3 is 6.

[0053] In one embodiment, Q is selected from Val-Cit, Gly-Gly-Phe-Gly, (CH2)2O(CH2)2, or (CH2)6.

[0054] Preferably, L1 is a group represented by the following formula: JPEG2025526504000020.jpg26170 or a group represented by the following formula: JPEG2025526504000021.jpg27170

[0055] Preferably, L2 is a group represented by the following formula: JPEG2025526504000022.jpg37170 or a group represented by the following formula: JPEG2025526504000023.jpg37170

[0056] A further aspect of the present invention provides a drug-antibody conjugate compound of formula (III), or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof: JPEG2025526504000024.jpg61170

[0057] wherein R is defined as in formula (I) or a compound thereof, and L is defined as in formula (II) or a compound thereof.

[0058] Ab is a tumor-associated antigen antibody, and n is an integer selected from 1-8.

[0059] Preferably, the tumor-associated antigen is selected from Her2, Trop2, 5T4, ROR1, or B7-H3.

[0060] Preferably, the Ab is Pertuzumab.

[0061] In one embodiment, the drug-antibody conjugate of formula (III) is selected from the following compounds: JPEG2025526504000025.jpg189170

[0062] Preferably, the drug-antibody conjugate of formula (II) is selected from the following compounds: JPEG2025526504000026.jpg122170

[0063] A further aspect of the present invention provides a pharmaceutical composition comprising the above-described compound, drug-linker compound, or a pharmaceutically acceptable salt, stereoisomer, prodrug, or antibody-drug conjugate thereof.

[0064] The pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant.

[0065] A further aspect of the present invention provides use of the above-mentioned compound, drug-linker compound or a pharmaceutically acceptable salt, stereoisomer, prodrug or antibody-drug conjugate, or pharmaceutical composition in the manufacture of a cancer therapeutic agent.

[0066] Preferably, the cancer is gastric cancer, esophageal cancer, breast cancer, or lung adenocarcinoma.

[0067] Another aspect of the present invention provides a method for treating cancer, comprising administering to a patient in need thereof the above-described compound or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition thereof.

[0068] In one embodiment, the amount of the compound or a pharmaceutically acceptable salt, stereoisomer, prodrug, antibody-drug conjugate, or pharmaceutical composition thereof administered is a therapeutically effective amount. DETAILED DESCRIPTION OF THE INVENTION

[0069] I. Definition In the present invention, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art unless otherwise specified. Furthermore, the relevant terms and experimental procedures used herein are terms and common steps commonly used in their respective fields. In addition, in order to better understand the present invention, the definitions and explanations of relevant terms are provided below.

[0070] As used herein, and unless otherwise specified, the terms "comprise," "include," "have," and "contain," including their grammatical equivalents, are to be generally understood as open-ended and non-limiting, e.g., not excluding other unrecited elements or steps.

[0071] The compounds of the present invention may be asymmetric and may, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included. The stereoisomers include geometric isomers (e.g., cis- and trans-configurations) and optical isomers (e.g., enantiomers), and are therapeutic agents consisting of individual compounds, racemates, racemic mixtures, and pharmaceutically acceptable salts thereof. Compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be isolated from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are within the scope of the present invention.

[0072] The compounds of the present invention also include tautomeric forms, which result from the swapping of a single bond with an adjacent double bond and involve the migration of one proton.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a corresponding amine compound and an inorganic or organic acid, a salt formed between a corresponding carboxylic acid compound and an alkali metal or alkaline earth metal, or a salt formed between a corresponding carboxylic acid compound and an organic amine. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc. Organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, etc. Alkali metal or alkaline earth metal salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, etc. Organic amine salts include, but are not limited to, salts made with ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, amino acids, and the like.

[0074] As used herein, the term "precursor" refers to a compound that, after being taken into the human body by an appropriate administration method, undergoes metabolism or simple chemical changes in the patient's body and is converted into the compound included in the general formula 1 of the present invention and its corresponding salt form. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonate esters, phosphate esters, sulfate esters, sulfonate esters, amino acid esters, gluconate esters, and various amides, acetals, hemiacetals, carbonic acid amide esters, etc.

[0075] Numerical ranges herein refer to individual integers within the specified range. For example, "C1-C6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and "C3-C6" means that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0076] When any variable (e.g., Rn) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 1 to 5 R, then that group may also be optionally substituted with up to 5 R, and each occurrence of R is an independent option. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0077] The term "alkyl group" means a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 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. groups, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 2,2-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, and carboxylic acid ester groups. In the present invention, preferred are methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, haloalkyl groups, deuterated alkyl groups, alkoxy-substituted alkyl groups, and hydroxy-substituted alkyl groups.

[0078] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the -OO-, -OS-, or -SS- ring moieties, with the remaining ring atoms being carbon. Preferably, it is a 3- to 8-membered heterocyclyl containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, and nitrogen-containing fused heterocyclyl groups.

[0079] The term "aryl group" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as, for example, phenyl and naphthyl groups.

[0080] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen, sulfhydryl groups, hydrogen groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, or carboxylic acid ester groups.

[0081] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydrogen groups, nitro groups, chloro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxylic acid groups, and carboxylic acid ester groups.

[0082] All hydrogen atoms described in the present invention can be substituted with their isotope, deuterium.

[0083] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are independently replaced with the corresponding number of substituents. Substituents are present only at chemically feasible positions, and it is obvious that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., alkene) bond.

[0084] The symbols below represent chemical bond sites. JPEG2025526504000027.jpg27170

[0085] Drug or pharmaceutical composition As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a corresponding amine compound and an inorganic or organic acid, a salt formed between a corresponding carboxylic acid compound and an alkali metal or alkaline earth metal, or a salt formed between a corresponding carboxylic acid compound and an organic amine. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc. Organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, etc. Alkali metal or alkaline earth metal salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, etc. Organic amine salts include, but are not limited to, salts made with ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, amino acids, and the like.

[0086] As used herein, the term "precursor" refers to a compound that, after being taken into the human body by an appropriate administration method, undergoes metabolism or simple chemical changes in the patient's body and is converted into the compound included in the general formula 1 of the present invention and its corresponding salt form. Precursors of the compound include, but are not limited to, various carboxylic acid esters, carbonate esters, phosphate esters, sulfate esters, sulfonate esters, amino acid esters, gluconate esters, and various amides, acetals, hemiacetals, carbonic acid amide esters, etc.

[0087] The drugs or pharmaceutical compositions of the present invention can be administered orally, topically, parenterally, or mucosally (e.g., sublingually, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. Oral administration is usually preferred. The active agents can be administered orally in the form of capsules, tablets, etc. (See Remington: The Science and Practice of Pharmacy, 20th Edition).

[0088] When administered orally in tablet or capsule form, the active drug component may be combined with non-toxic pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, and the like), disintegrants (e.g., potato starch or sodium hydroxyacetate starch), or wetting agents (e.g., sodium lauryl sulfate), colorants and flavors, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, gum tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. When administered orally in liquid form, the drug component may be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, ester oil, ethanol, or fractionated vegetable oil), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, citronellyl propionate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0089] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present invention containing a compound of Formula I as an active compound can also be incorporated into beads, microspheres, or microcapsules, for example, constructed from polyglycolic / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions, suspensions, etc., or can be dry preparations that are reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to provide controlled or delayed release of the active compound.

[0090] The term "treatment" includes inhibiting, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0091] The use of the term "inhibition" is relative to a control. One of ordinary skill in the art can readily determine an appropriate control for each experiment. For example, a reduction in a response in subjects or cells treated with a compound is compared to a response in subjects or cells not treated with the compound.

[0092] The term "pharmaceutical composition" means a composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one selected from pharmaceutically acceptable ingredients, including, depending on the method of administration and the nature of the formulation, carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspension aids, etc.

[0093] The term "effective amount" or "therapeutically effective amount" refers to a nontoxic but sufficient amount of a drug or agent to achieve a desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug to be administered will depend on many factors, such as the specific administration protocol, the type and severity of the disease or condition, and the specific characteristics (e.g., body weight) of the subject or host requiring treatment. However, dosages can be routinely determined by methods known in the art depending on the specific circumstances, including, for example, the specific drug employed, the route of administration, the condition being treated, and the subject or host being treated. Generally, dosages used in adult treatment typically range from 0.02 to 5000 mg / day, e.g., about 1 to 1500 mg / day. This required dose can conveniently be expressed as a single dose or as divided doses administered simultaneously (or shortly thereafter) or at appropriate intervals, e.g., two, three, four, or more divided doses per day. Although the above dosage ranges are given, it will be understood by those skilled in the art that the specific effective amount may be appropriately adjusted depending on the condition of the patient and in conjunction with the diagnosis of a physician.

[0094] The term "antibody-drug conjugate (ADC)" refers to a monoclonal antibody that is chemically linked to a biologically active small molecule drug, with the monoclonal antibody acting as a carrier to transport the small molecule drug to target cells.

[0095] As used herein, the terms "reduce," "inhibit," "attenuate," or "reduce" are used relative to a control. One of ordinary skill in the art can readily determine an appropriate control for each experiment. For example, the reduction in a response in subjects or cells treated with a compound is compared to the response in subjects or cells not treated with the compound.

[0096] Unless otherwise specified, the materials and equipment used in specific embodiments of the present invention are known products and can be obtained commercially.

[0097] Abbreviation CDI: N,N'-carbonyldiimidazole, EA: ethyl acetate, DCM: dichloromethane, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ester, DIPEA: N,N-diisopropylethylamine, NMP: N-methylpyrrolidone, HOBt: 1-hydroxybenzotriazole, Val: valine (the structural formula is as follows), JPEG2025526504000028.jpg44170JPEG2025526504000029.jpg40170JPEG2025526504000030.jpg36170JPEG2025526504000031.jpg37170JPEG2025526504000032.jpg56170JPEG2025526504000033.jpg55170JPEG2025526504000034.jpg40170 (Linking chains such as Val-Ala, Ala-Ala-Asn, Gly-Lys, and Gly-Gly-lys can be linked by amino acid condensation methods well known in the art.) -Pab- (the structural formula of which is as follows): JPEG2025526504000035.jpg33170JPEG2025526504000036.jpg34170JPEG2025526504 000037.jpg46170JPEG2025526504000038.jpg37170JPEG2025526504000039.jpg30170

[0098] II. Specific Examples In this example, the ADC is prepared using pertuzumab having the following heavy chain amino acid sequence (SEQ ID NO: 1) and light chain amino acid sequence (SEQ ID NO: 2), but is not limited thereto. [ka] [ka]

[0099] Example 1: Exatecan-N-aminourea (1) JPEG2025526504000042.jpg581701 ml of DMF was added with exatecan methanesulfonate (30 mg, 56.44 μmol) and triethylamine (11.42 mg, 112.88 μmol), and stirred thoroughly. CDI (9.15 mg, 56.44 μmol) was added, and the mixture was reacted at room temperature for 1 hour under argon gas protection. Triethylamine (80 mg) and hydrazine hydrochloride (19.33 mg, 0.28 mmol) were added sequentially, and the mixture was stirred and reacted at room temperature for 10 hours. 50 ml of EA was added, and the mixture was washed with saturated saline, extracted, and the phases were separated and dried over anhydrous sodium sulfate. The mixture was then purified by silica gel column chromatography to obtain compound 1 (25 mg, yield 90%). 1 H NMR(500MHz,DMSO-d6)δ7.77(d,J=10.9Hz,1H),7.54(s,1H),7.30(s,1H),6.52(m,1H),5.41(m,2H),5.39-5.33(m,1H),5.22(m,J=7.0Hz,2H) ),3.15(m,J=13.6,6.9Hz,2H),3.06(s,2H),2.38(s,3H),2.24-2.11(m,2H),1.86(m,J=21.4,7.0Hz,2H),0.87(t,J=7.3Hz,3H);LCMS:(M+1) + 493.98 (calculated value: 493.18).

[0100] Example 2: Exatecan-N-methyl-N-aminourea (2) JPEG2025526504000043.jpg551701 ml of DMF was added with exatecan methanesulfonate (30 mg, 56.44 μmol) and triethylamine (11.42 mg, 112.88 μmol), and stirred thoroughly. Then CDI (9.15 mg, 56.44 μmol) was added and the mixture was reacted at room temperature for 1 hour under argon gas protection. Triethylamine (80 mg) and 1-Boc-2-methylhydrazine (45.05 mg, 0.3 mmol) were added sequentially, and the mixture was stirred at room temperature for 10 hours. Then 50 ml of EA was added, washed with saturated saline, extracted, and the phases were separated and dried over anhydrous sodium sulfate. The product was then purified by silica gel column chromatography to obtain the compound Boc-product. This Boc-product was then separated by DCM. The solution was dissolved in 1 ml of the extract, and 0.5 ml of a 4 M hydrochloric acid solution in ethyl acetate was added thereto. The mixture was stirred at room temperature for 30 minutes to react, thereby obtaining Compound 2 (22 mg, yield 80%). 1 H NMR(500MHz,DMSO-d6)δ7.81(d,J=10.9Hz,1H),7.32(s,1H),6.54(s,1H),5.43(m,J=18Hz,3H),5.29(d,J=4.1Hz,2H),3.29(s,3H)3.17( t,J=6.4Hz,2H),2.41(d,J=1.7Hz,3H),2.20(m,J=13.0,6.9Hz,2H),1.86(m,J=20.7,13.7,6.8Hz,2H),0.87(t,J=7.3Hz,3H);LCMS:(M+1) + 508.02 (calculated value: 507.19).

[0101] Example 3: Exatecan-N',N-dimethylaminourea (3) JPEG2025526504000044.jpg551701 ml of DMF was added with exatecan methanesulfonate (30 mg, 56.44 μmol) and triethylamine (11.42 mg, 112.88 μmol). After stirring thoroughly, CDI (9.15 mg, 56.44 μmol) was added and the mixture was reacted at room temperature for 1 hour under argon gas protection. TEA (80 mg) and N'N-dimethylhydrazine hydrochloride (45.05 mg, 0.33 mmol) were added sequentially and the mixture was stirred at room temperature for 10 hours. 50 ml of EA was added, the mixture was washed with saturated brine, the phases were separated, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography to obtain compound 3 (18 mg, yield 62%). 1 H NMR(500MHz,DMSO-d6)δ7.76(d,J=10.9Hz,1H),7.48(d,J=9.2Hz,1H),7.30(s,1H) ,6.51(s,1H),5.41(s,2H),5.31(dd,J=17.0,8.5Hz,2H),5.16(s,1H),4.64(q,J=5. 7Hz,2H),3.09(dt,J=16.8,7.8Hz,2H),3.01(s,3H),2.38(s,3H),2.18(t,J=7.2Hz ,3H),1.86(dq,J=19.3,7.1Hz,2H),1.47(s,1H),0.86(d,J=8.2Hz,3H);LCMS:(M+1) + 522.02 (calculated value: 521.21).

[0102] Example 4: Exatecan-N'-aminooxamide (4) To 30 ml of DCM, Boc-hydrazine (5.93 g, 44.90 mmol) and TEA (6.2 g, 61.21 mmol) were added, and the mixture was stirred until clear. A DCM solution (50 ml) of oxalylmethyl chloride (5 g, 40.81 mmol) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hour. The mixture was then washed with saturated brine (20 ml × 3), dried over anhydrous sodium sulfate, and concentrated to give compound 4-a, i.e., N'-Boc-N-oxalylhydrazide monomethyl ester (7.1 g, 79% yield). LCMS: (M+1) +219.01 (calculated value: 218.21).

[0103] Compound 4-a (7.1 g, 32.56 mmol) was dissolved in 70 ml of ethanol, and then 32.53 ml of 1 M aqueous LiOH solution was added dropwise. The mixture was stirred at room temperature overnight. The pH of the reaction mixture was then adjusted to 5 by adding 0.5 M aqueous HCl dropwise. Water and ethanol were removed under reduced pressure, and 5 ml of methanol and 15 ml of DCM were added to the concentrated mixture. The mixture was stirred for 1 hour, filtered, and the filtrate was concentrated to give compound 4-b, i.e., N'-Boc-N-oxalylhydrazide (6 g, 89% yield). LCMS: (M+1) + 205.2 (calculated value: 204.18).

[0104] To 2 ml of DMF, exatecan methanesulfonate (200 mg, 0.37 mmol), diisopropylethylamine (6.15 mg, 0.047 mmol), N'-Boc-N-oxalohydrazide (164 mg, 0.8 mmol), and HATU (286 mg, 0.75 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 4 hours. The DMF was removed under reduced pressure, and the concentrate was added to 20 ml of DCM and purified by silica gel column chromatography to give compound 4-c, i.e., exatecan-N'-Boc-aminooxamide (180 mg, 77% yield). LCMS: (M+1) + 622.1 (calculated value: 621.22).

[0105] Exatecan-N'-Boc-aminooxamide (180 mg, 0.29 mmol) was dissolved in 2 ml of DCM, 1 ml of 4 M hydrochloric acid in ethyl acetate was added, and the reaction was stirred at room temperature for 30 minutes, reacted, and concentrated to give compound 4, i.e., exatecan-N'-aminooxamide (162 mg, 100%). 1HNMR(500MHz,DMSO-d6)δ9.54(d,J=8.9Hz,1H),7.77(m,J=11.3,4.1Hz,1H),7.30(s,1H),6.52(s,1H),5.53(m,J=8.3,5.0Hz,1H),5.39(s ,2H),5.12(d,J=4.0Hz,2H),3.23(s,1H),2.38(s,3H),2.28-2.15(m,2H),1.85(m,J=25.0,7.2Hz,2H),0.86(t,J=7.4Hz,3H);LCMS:(M+1) + 522.00 (calculated value: 521.17).

[0106] Example 5: Exatecan N'-amino-N-methyloxamide (5) 1-Methyl-2-Boc hydrazine (2.4 g, 26 mmol) and TEA (1.65 g, 16.3 mmol) were added to 20 ml of DCM and stirred until the mixture was clear. Then, a DCM solution (20 ml) of methyl oxalyl chloride (2 g, 16.3 mmol) was added dropwise at 0° C. and the mixture was stirred at room temperature for 1 hour to react. The mixture was then extracted, washed with saturated brine (10 ml × 3), dried over anhydrous sodium sulfate, and concentrated to give intermediate compound 5-a, i.e., 1-methyl-2-Boc-oxalyl hydrazide monomethyl ester (3.5 g, 92% yield). LCMS: (M+1) + 233.10 (calculated value: 232.24).

[0107] Compound 5-a (3.5 g, 15 mmol) was dissolved in 40 ml of ethanol, 16.37 ml of 1 M aqueous LiOH solution was added dropwise, and the mixture was stirred at room temperature overnight. The pH of the reaction mixture was then adjusted to 5 by adding 0.5 M aqueous HCl solution dropwise. Water and ethanol were removed under reduced pressure, and the concentrated mixture was added with 2 ml of methanol and 8 ml of DCM. The mixture was stirred for 1 hour, filtered, and the filtrate was concentrated to give intermediate compound 5-b, i.e., 1-methyl-2-Boc-oxalylhydrazide (3.21 g, 90% yield). LCMS: (M+1) + 219.01 (calculated value: 218.21).

[0108] To 2 ml of DMF, exatecan methanesulfonate (100 mg, 0.19 mmol), DIPEA (48.58 mg, 0.37 mmol), compound 5-b (82 mg, 0.37 mol), and HATU (118 mg, 0.32 mmol) were added in sequence, and the reaction mixture was stirred at room temperature for 4 hours to allow the reaction to proceed. The DMF was removed under reduced pressure, and the mixture was purified by silica gel paper chromatography to obtain intermediate compound 5-c, i.e., exatecan-N'-Bocamino-N-methyloxamide (91 mg, 75% yield). LCMS: (M+1) + 636.14 (calculated value: 635.65).

[0109] Compound 5-c (91 mg, 0.14 mmol) was dissolved in 2 ml of DCM, 1 ml of 4 M hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 30 minutes, reacted, and concentrated to give compound 5, i.e., exatecan N'-amino-N-aminooxamide (85 mg, 100% yield). 1 H NMR(500MHz,DMSO-d6)δ8.87(d,J=8.7Hz,1H),7.79(d,J=10.9Hz,1H),7.31(s,1H),5.59-5.62(m,J=18Hz,1H),5.46-5.32(m,J=84Hz,4H),3.16- 3.10(m,2H),2.95(s,2H),2.40(s,3H),2.17(ddq,J=28.2,14.0,5.5,4.9 Hz,2H),1.86(dp,J=20.9,7.0Hz,2H),0.86(t,J=7.4Hz,3H);LCMS:(M+1) + 536.03 (calculated value: 535.53).

[0110] Example 6: 2-hydroxyaminoacetylexatecan (6) JPEG2025526504000047.jpg501701 ml of DMF was added with exatecan methanesulfonate (100 mg, 0.19 mmol) and TEA (25 mg, 0.28 mmol), and the mixture was stirred until clear. Bromoacetic acid (40 mg, 0.37 mol) and HATU (85 mg, 0.22 mmol) were then added, and the mixture was stirred at room temperature for 1 hour to allow the reaction to proceed. The DMF was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain intermediate 6-a, i.e., exatecan-N-bromoacetamide (90 mg, 86% yield). LCMS: (M+1) + 557.1 (calculated value: 556.39).

[0111] 1 ml of DMF was added to a 10 ml flask, followed by the addition of hydroxyamine hydrochloride (113 mg, 1.63 mmol), TEA (164 mg, 1.62 mmol), and compound 6-a (90 mg, 0.16 mmol) in that order. The mixture was stirred and reacted at room temperature for 1 hour, and the DMF was removed under reduced pressure. The mixture was then separated and purified by silica gel column chromatography to give compound 6, i.e., 2-hydroxyaminoacetylexatecan (90 mg, 86% yield). 1 H NMR(500MHz,DMSO-d6)δ10.86-10.38(m,1H),8.96(d,J=8.7Hz,1H),7.82(t,J=11.9 Hz,1H),7.32(s,1H),6.55(s,1H),5.77-5.54(m,1H),5.41(d,J=10.6Hz,2H),5.37- 5.16(m,2H),3.86(m,J=11.7,8.0Hz,2H),3.31-3.02(m,3H),2.40(d,J=14.0Hz,3H) ,2.29-2.07(m,2H),1.86(m,J=21.6,7.2Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+1) + 509.3 (calculated value: 508.18)

[0112] Example 7: 2-Methoxyaminoacetylexatecan (7) JPEG2025526504000048.jpg501701ml of DMF was added to a 10ml flask, followed by the addition of methoxyamine hydrochloride (126mg, 1.5mmol), TEA (182mg, 1.79mmol), and compound 6-a (100mg, 0.18mmol) in that order. The mixture was stirred and reacted at room temperature for 1 hour, and the DMF was removed under reduced pressure. The mixture was then separated and purified by silica gel column chromatography to obtain compound 6, i.e., 2-methoxyaminoacetylexatecan (80mg, 86% yield). 1 H NMR(500MHz,DMSO-d6)δ8.50-8.46(m,1H),7.80(d,J=10.8Hz,1H),7.30(d,J=1.9Hz,1 H),6.83(td,J=6.2,1.8Hz,1H),6.52(d,J=1.9Hz,1H),5.61-5.55(m,1H),5.42(s,2H) ,5.22(s,2H),4.01-3.87(m,1H),3.42(d,J=6.1Hz,3H),3.17(t,J=6.4Hz,2H),2.40(s ,3H),2.22-2.11(m,2H),1.86(dp,J=21.1,7.1Hz,2H),0.90-0.83(m,3H);LCMS:(M+1) + 523.20 (calculated value: 522.19)

[0113] Example 8: 2-Methylaminooxyacetylexatecan (8) To a mixture of 40 ml of water and 40 ml of THF, N-methylhydroxyamine hydrochloride (10 g, 119.7 mmol) was added and stirred until clear. Potassium carbonate (8.27 g, 60 mmol) was added, and 50 ml of a THF solution of Boc anhydride (28.75 g, 131.7 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The THF was removed under reduced pressure, and the mixture was extracted with DCM (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated to give compound 8-a, i.e., N-Boc-N-methylhydroxyamine (15 g, 88% yield). LCMS: (M+1) + 148.01 (calculated value: 147.17).

[0114] Compound 8-a (15 g, 101.9 mmol) was dissolved in 100 ml of isopropanol, and methyl bromoacetate (18.58 g, 121.4 mmol) and DIPEA (15.7 g, 121.7 mmol) were added to the mixture, which was heated to 85 ° C. under argon gas protection and reacted for 3 hours. The reaction mixture was concentrated, dissolved in 100 ml of EA, washed with saturated brine (30 ml × 3), dried over anhydrous sodium sulfate, and concentrated to give compound 8-b, i.e., N-Boc-N-methylaminooxyacetic acid methyl ester (18 g, 81.8% yield). LCMS: (M+1) + 220.21 (calculated value: 219.24).

[0115] Compound 8-b (18 g, 82 mmol) was dissolved in 180 ml of methanol, 82.2 ml of 1 M aqueous lithium hydroxide solution was added, and the mixture was stirred at room temperature to react. After the reaction, the reaction solution was concentrated to remove methanol, and 0.5 mmol / L aqueous hydrochloric acid was added to adjust the acidity to about pH = 3. The mixture was extracted with EA, the phases were separated, dried, filtered, and concentrated to give compound 8-c, N-Boc-N-methylaminooxyacetic acid (13.1 g, 77.3% yield). LCMS: (M+1) + 206.01 (calculated value: 205.21).

[0116] To 2 ml of DMF, exatecan methanesulfonate (100 mg, 0.19 mmol), DIPEA (48.58 mg, 0.37 mmol), compound 8-c (77.3 mg, 0.37 mmol), and HATU (118 mg, 0.31 mmol) were added in sequence, and the reaction mixture was stirred at room temperature for 6 hours to react. The DMF was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound 8-d, i.e., N-Boc-N-methylaminooxyacetylexatecan (68 mg, 75% yield). LCMS: (M+1) + 623.30 (calculated value: 622.65).

[0117] Compound 8-d (68 mg, 0.109 mmol) was dissolved in 2 ml of DCM, 1 ml of 4 M hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 30 minutes, reacted, and concentrated to give compound 8, i.e., 2-methylaminooxyacetylexatecan (61 mg, 100%). 1 H NMR(500MHz,DMSO-d6)δ8.93(d,J=8.5Hz,1H),7.79(d,J=10.5Hz,1H),7.30( s,1H),5.60(dt,J=8.3,4.1Hz,1H),5.42(s,2H),5.29(s,2H),4.73-4.64(m,2 H),3.18(s,2H),2.85(s,3H),2.39(s,3H),2.25(dt,J=8.8,4.6Hz,1H),2.19- 2.10(m,1H),1.85(dp,J=21.4,7.2Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+1) + 523.10 (calculated value: 522.19).

[0118] Example 9: 2-N-methyl-N-aminoacetylexatecan (9) JPEG2025526504000050.jpg391701 ml of DMF was added to a 10 ml flask, followed by the addition of 1-methyl-2-Boc hydrazine (36.41 mg, 0.25 mmol), TEA (54.6 mg, 0.54 mmol), and 6-a (100 mg, 0.18 mmol) in that order. The mixture was stirred at room temperature for 1 hour, the DMF was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to give compound 9-a, i.e., 2-N-methyl-N-Boc aminoacetylexatecan (72 mg, 63% yield). LCMS: (M+1) + 622.30 (calculated value: 621.21).

[0119] Compound 9-a (72 mg, 0.115 mmol) was dissolved in 2 ml of DCM, and 1 ml of 4 M hydrochloric acid in ethyl acetate was added. The reaction mixture was stirred at room temperature for 30 minutes to give compound 9, i.e., 2-N-methyl-N-aminoacetylexatecan (64 mg, 100% yield). 1H NMR(500MHz,DMSO-d6)δ8.53(d,J=8.9Hz,1H),8.33(s,1H),7.79(d,J=10.9Hz,1H),7.32-7.27( m,1H),6.53(d,J=1.6Hz,1H),5.60(dt,J=9.3,5.1Hz,1H),5.41(s,2H),5.29-5.15(m,2H),3.42 -3.40(m,2H),3.38-3.37(m,2H),3.37(s,3H),3.19(d,J=5.6Hz,1H),2.39(s,3H),2.15(q,J=6. 0Hz,2H),1.85(dp,J=21.7,7.0Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+H)+522.1(calculated value:521.18).

[0120] Example 10: 2-N-methyl-N-methylaminoacetylexatecan (10) JPEG2025526504000051.jpg551701 ml of DMF was added to a 10 ml flask, followed by the addition of 1,2-dimethylhydrazine dihydrochloride (71.72 mg, 0.54 mmol), TEA (91 mg, 0.89 mmol), and 6-a (100 mg, 0.18 mmol) in sequence. The mixture was stirred at room temperature for 1 hour to allow the reaction to proceed. After the reaction was completed, the DMF was removed under reduced pressure, and the mixture was separated and purified by silica gel column chromatography to obtain compound 10, i.e., 2-N-methyl-N-methylaminoacetylexatecan (85 mg, 88% yield). 1 H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.85(d,J=9.1Hz,1H),7.81(mJ=19.4,10.9Hz,1H),7.32 (d,J=11.1Hz,1H),6.54(s,1H),5.66-5.51(m,1H),5.49-5.38(m,2H),5.35-5.17(m,2H),3.73 -3.55(m,1H),3.19(m,J=19.8,15.3,9.5Hz,3H),2.73(s,3H),2.41(d,J=9.0Hz,3H),2.19(m,J =31.1,13.1,5.4Hz,2H),1.86(m,J=21.7,14.7,7.5Hz,2H),0.87(t,J=7.3Hz,3H);LCMS:(M+1) +536.20 (calculated value: 535.22).

[0121] Example 11: 2-N-methylhydroxyaminoacetylexatecan (11) JPEG2025526504000052.jpg501701ml of DMF was added to a 10ml flask, followed by the addition of N-methylhydroxyamine hydrochloride (30mg, 0.36mmol), TEA (58mg, 0.57mmol), and compound 6-a (100mg, 0.18mmol) in that order. The mixture was stirred at room temperature for 1 hour to allow the reaction to proceed, and the DMF was removed under reduced pressure. The mixture was then separated and purified by silica gel column chromatography to obtain compound 11, i.e., 2-N-methylhydroxyaminoacetylexatecan (70mg, 75% yield). 1 H NMR(500MHz,DMSO-d6)δ8.44(d,J=12.4Hz,1H),7.79(t,J=10.7Hz,1H),7.30(d,J= 4.9Hz,1H),6.63-6.41(m,1H),5.59(m,J=8.6,5.0Hz,1H),5.41(d,J=3.0Hz,2H),5. 32-5.12(m,2H),3.17(m,J=5.3Hz,2H),2.73(d,J=6.7Hz,3H),2.39(d,J=6.0Hz,3H) ,2.24-2.08(m,2H),1.85(m,J=21.3,7.1Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+H) + 523.20 (calculated value: 522.19).

[0122] Example 12: 2-Ethoxyaminoacetylexatecan (12) JPEG2025526504000053.jpg561701 ml of DMF was added to a 10 ml flask, followed by the addition of ethoxyhydroxyamine hydrochloride (126 mg, 1.29 mmol), TEA (182 mg, 1.8 mmol), and compound 6-a (100 mg, 0.18 mmol) in that order. The mixture was stirred at room temperature for 1 hour to allow the reaction to proceed, and the DMF was removed under reduced pressure. The mixture was then separated and purified by silica gel column chromatography to give compound 12, i.e., 2-ethoxyaminoacetylexatecan (81 mg, yield 83%). 1H NMR(500MHz,DMSO-d6)δ7.79(m,J=11.0,5.7Hz,1H),7.31(s,1H),5.63(m,J=9.2,5.4Hz ,1H),5.42(s,2H),5.31-5.16(m,2H),3.72-3.68(m,2H),3.45-3.42(m,2H),3.18(m,J= 17.3,9.0Hz,2H),2.40(d,J=6.4Hz,3H),2.27-2.10(m,2H),1.86(m,J=21.7,14.6,7.3H z,2H),1.24(m,J=7.1Hz,1H),1.00(m,J=6.9Hz,2H),0.87(m,J=6.8Hz,3H);LCMS:(M+1) + 537.10 (calculated value: 536.21).

[0123] Example 13: 3-aminooxetane-3-acetylexatecan (13) 3-Aminoxetane-3-carboxylic acid (0.5 g, 4.27 mmol) was added to a mixture of 10 mL of water and 10 mL of EtOH, and the mixture was stirred until clear. Sodium bicarbonate (0.72 g, 8.54 mmol) was added, and 5 mL of an EtOH solution of Boc anhydride (0.98 g, 4.48 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The ethanol was removed under reduced pressure, and the pH was adjusted to approximately 4 by adding hydrochloric acid dropwise. The product was extracted with DCM (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give compound 15-a, i.e., N-Boc-3-aminooxetane-3-carboxylic acid (0.8 g, 86% yield). LCMS: (M+1) + 118.01 (calculated value: 117.10).

[0124] To 1 ml of DMF, exatecan methanesulfonate (20 mg, 0.038 mmol), DIPEA (9.7 mg, 0.074 mmol), compound 13-a (16.5 mg, 0.075 mmol), and HATU (23.6 mg, 0.062 mmol) were added in sequence, and the reaction mixture was stirred at room temperature for 6 hours to allow the reaction to proceed. The DMF was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound 15-b, i.e., N-Boc-3-aminooxetane-3-acetylexatecan (15 mg, 65% yield). LCMS: (M+1) + 635.20 (calculated value: 634.66).

[0125] Compound 13-b (15 mg, 0.023 mmol) was dissolved in 2 ml of DCM, 1 ml of 4 M hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 30 minutes, reacted, and concentrated to give compound 13, i.e., 3-aminooxetane-3-acetylexatecan (61 mg, 100% yield). 1 H NMR(500MHz,DMSO-d6)δ8.55(m,2H),8.10(d,J=8.8Hz,1H),7.76(m,1H),7.30(d,J=7.1 Hz,1H),5.60-5.49(m,1H),5.42(m,2H),5.00-4.95(m,1H),4.88(d,J=6.2Hz,1H),4.57 (d,J=6.3Hz,1H),4.51(d,J=6.2Hz,1H),3.62(m,1H),3.46(m,1H),3.23(m,1H),3.16-3 .11(m,2H),2.38(m,3H),2.25-2.13(m,2H),1.92-1.78(m,2H),0.87(m,3H);LCMS:(M+1) + 535.31 (calculated value: 534.54).

[0126] Example 14: mc-Val-Cit-pab-formyl-2-N-methyl-N-aminoacetylexatecan (DC-1) JPEG2025526504000055.jpg391700.3 mL of NMP was added with compound 9 (14.14 mg, 0.027 mmol), DIPEA (17.52 mg, 0.135 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (7.33 mg, 0.054 mmol) in that order, and the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then added to 25 g of C18 preca The mixture was injected into a column (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water, 40 min), and lyophilized to give compound DC-1, i.e., mc-Val-Cit-pab-formyl-2-N-methyl-N-aminoacetylexatecan, as a yellow solid (15.2 mg, 50% yield). LCMS: (M+1) + 1121.09 (calculated value: 1120.21).

[0127] Example 15: mc-Val-Cit-pab-formyl-2-N-methyl-N-methylaminoacetylexatecan (DC-2) Compound 10 (14.52 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (7.33 mg, 0.054 mmol) were added sequentially to 0.3 mL of NMP, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then added to 25 g of C18 preca The mixture was injected into a column (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water, 40 min), and lyophilized to give compound DC-2, mc-Val-Cit-pab-formyl-2-N-methyl-N-methylaminoacetylexatecan, as a yellow solid (12.2 mg, 40%). LCMS: (M+1) + 1135.02 (calculated value: 1134.23).

[0128] Example 16: mc-Val-Cit-pab-formyl-exatecan-N-aminourea (DC-3) Compound 1 (13.38 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) were sequentially added to 0.3 mL of NMP and reacted at room temperature for 1 hour. The reaction mixture was then loaded onto a 25 g C18 precolumn (first equilibrated with acetonitrile and then with water, the aqueous phase containing 0.1% TFA). The mixture was eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water over 40 min) and lyophilized to give compound DC-3, a yellow solid (13 mg, 45%), i.e., mc-Val-Cit-pab-formyl-exatecan-N-aminourea. LCMS: (M+1)+1093.03 (calculated: 1092.15).

[0129] Example 17: mc-Val-Cit-pab-formyl-exatecan-N-methyl-N-aminourea (DC-4) JPEG2025526504000058.jpg451700.3 ml of NMP was added with compound 2 (13.7 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) in that order, and the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then added to 25 g of C18 The mixture was injected onto a precolumn (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 15% to 60% acetonitrile in water, 40 min), and lyophilized to give compound DC-4, i.e., mc-Val-Cit-pab-formyl-exatecan-N-methyl-N-aminourea, as a yellow solid (9 mg, 30%). LCMS: (M+1) 1107.11 (calculated: 1106.18).

[0130] Example 18: mc-Val-Cit-pab-formyl-exatecan-N',N-dimethylaminourea (DC-5) Compound 3 (14.11 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) were added sequentially to 0.3 mL of NMP, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then transferred to 25 g of C18 pregelatinized silica gel. The column was loaded (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA) and eluted by medium pressure reversed-phase C18 chromatography (gradient: 15% to 60% acetonitrile in water, 40 min), and lyophilized to give compound DC-5, i.e., mc-Val-Cit-pab-formyl-exatecan-N',N-dimethylaminourea, as a yellow solid (12.1 mg, 40%). LCMS: (M+1) + 1121.02 (calculated value: 1120.21).

[0131] Example 19: mc-Val-Cit-pab-formyl-2-aminooxyacetylexatecan (DC-6) JPEG2025526504000060.jpg381702 ml of DMF was added in turn to exatecan methanesulfonate (100 mg, 0.19 mmol), DIPEA (48.58 mg, 0.37 mmol), tert-butyloxycarbonylaminooxyacetic acid (45 mg, 0.23 mmol), and HATU (118 mg, 0.31 mmol), and the mixture was stirred at room temperature for 4 hours to allow the reaction to proceed. The DMF was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain the intermediate compound 2-Boc-aminooxyacetylexatecan (95 mg, 83% yield). 1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),8.73(d,J=8.6Hz,1H),7.75(d,J=10.8Hz,1H),7.28(d,J=2.1Hz,1H),6.52( d,J=1.5Hz,1H),5.62(dt,J=8.8,4.4Hz,1H),5.40(d,J=3.3Hz,2H),5.23(d,J=17.9Hz,1H),5.19-5.11(m,1H),4.3 2(d,J=15.8Hz,1H),4.23(d,J=15.9Hz,1H),3.23-3.15(m,2H),2.37(d,J=6.5Hz,3H),2.24(dq,J=14.1,4.9Hz,1H) ,2.17(tt,J=8.3,5.1Hz,1H),1.84(ddp,J=21.4,14.3,7.2Hz,2H),1.15(s,9H),0.85(t,J=7.2Hz,3H);LCMS:(M+1) + 609.30 (calculated value: 608.18).

[0132] Compound 2-Boc-aminooxyacetylexatecan (95 mg, 0.16 mmol) was dissolved in 1 ml of DCM, and 1 ml of 4 M hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 30 minutes, reacted, and concentrated to give compound 14, i.e., 2-aminooxyacetylexatecan (85 mg, 100% yield). 1 H NMR(500MHz,DMSO-d6)δ8.93(d,J=8.5Hz,1H),7.79(d,J=10.5Hz,1H),7.30( s,1H),5.60(dt,J=8.3,4.1Hz,1H),5.42(s,2H),5.29(s,2H),4.73-4.64(m,2 H),3.18(s,2H),2.85(s,3H),2.39(s,3H),2.25(dt,J=8.8,4.6Hz,1H),2.19- 2.10(m,1H),1.85(dp,J=21.4,7.2Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+1) + 509.20 (calculated value: 508.18).

[0133] Compound 14 (32.17 mg, 0.063 mmol), DIPEA (24.53 mg, 0.189 mmol), mc-Val-Cit-pab-PNP (70 mg, 0.095 mmol), and HOBt (8.55 mg, 0.063 mmol) were added sequentially to 0.7 mL of NMP and reacted at room temperature for 1 hour. The reaction mixture was then loaded onto a 25 g C18 precolumn (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water, 40 min), and lyophilized to give compound DC-6, a yellow solid (31.5 mg, 31% yield), i.e., mc-Val-Cit-pab-formyl-2-aminooxyacetylexatecan. LCMS: (M+1). + 1108.10 (calculated value: 1107.16).

[0134] Example 20: mc-Val-Cit-pab-formyl-N-methylaminooxyacetylexatecan (DC-7) Compound 8 (33.05 mg, 0.063 mmol), DIPEA (24.53 mg, 0.189 mmol), mc-Val-Cit-pab-PNP (70 mg, 0.095 mmol), and HOBt (8.55 mg, 0.063 mmol) were sequentially added to 0.7 mL of NMP and reacted at room temperature for 1 hour. The reaction mixture was then loaded onto a 25 g C18 precolumn (first equilibrated with acetonitrile and then with water, the aqueous phase containing 0.1% TFA). The mixture was eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water over 40 min) and lyophilized to give compound DC-7, a yellow solid (42 mg, 39%), i.e., mc-Val-Cit-pab-formyl-2-methylaminooxyacetylexatecan. LCMS:(M+1) + 1122.05 (calculated value: 1121.09).

[0135] Example 21: mc-Val-Cit-pab-formyl-exatecan-N'-aminooxamide (DC-8) JPEG2025526504000062.jpg391700.3 ml of NMP was added with compound 4 (14.14 mg, 0.027 mmol), DIPEA (17.52 mg, 0.135 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) in that order, and the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then added to 25 g of C1 The mixture was injected onto a 8 precolumn (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water, 40 min), and lyophilized to give compound DC-8, i.e., mc-Val-Cit-pab-formyl-exatecan-N'-aminooxamide, as a yellow solid (13 mg, 45%). LCMS: (M+1) + 1121.02 (calculated value: 1120.16).

[0136] Example 22: mc-Val-Cit-pab-formyl-exatecan N'-amino-N-methyloxamide (DC-9) JPEG2025526504000063.jpg411700.3 ml of NMP was added with compound 5 (14.52 mg, 0.027 mmol), DIPEA (17.52 mg, 0.135 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) in that order, and the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then transferred to 25 g of C18 proton exchange membrane. The resulting mixture was loaded onto a column (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 10% to 55% acetonitrile in water, 40 min), and lyophilized to give compound DC-9, mc-Val-Cit-pab-formyl-exatecan N'-amino-N-methyloxamide, as a yellow solid (13 mg, 45%). LCMS: (M+1) + 1135.10 (calculated value: 1134.19).

[0137] Example 23: mc-Val-Cit-pab-formyl-N-hydroxyaminoacetylexatecan (DC-10) Compound 6 (13.79 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) were sequentially added to 0.3 mL of NMP and reacted at room temperature for 1 hour. The reaction mixture was then loaded onto a 25 g C18 precolumn (first equilibrated with acetonitrile and then with water, the aqueous phase containing 0.1% TFA). The mixture was eluted by medium-pressure reverse-phase C18 chromatography (gradient: 5% to 50% acetonitrile in water over 40 min) and lyophilized to give compound DC-10, a yellow solid (13 mg, 45% yield), i.e., mc-Val-Cit-pab-formyl-N-hydroxyaminoacetylexatecan. LCMS:(M+1) + 1108.03 (calculated value: 1107.16).

[0138] Example 24: mc-Val-Cit-pab-formyl-N-methoxyaminoacetylexatecan (DC-11) Compound 7 (14.17 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) were added sequentially to 0.3 mL of NMP, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then transferred to 25 g of C18 proton exchange membranes. The resulting mixture was loaded onto a column (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 15% to 50% acetonitrile in water, 40 min), and lyophilized to give compound DC-11, i.e., mc-Val-Cit-pab-formyl-N-methoxyaminoacetylexatecan, as a yellow solid (13 mg, 45% yield). LCMS: (M+1) + 1122.06 (calculated value: 1121.19).

[0139] Example 25: mc-Val-Cit-pab-formyl-N-ethoxyaminoacetylexatecan (DC-12) Compound 12 (14.17 mg, 0.027 mmol), DIPEA (10.51 mg, 0.081 mmol), mc-Val-Cit-pab-PNP (20 mg, 0.027 mmol), and HOBt (3.66 mg, 0.027 mmol) were added sequentially to 0.3 mL of NMP, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then added to 25 g of C18 The mixture was injected onto a precolumn (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA), eluted by medium-pressure reverse-phase C18 chromatography (gradient: 15% to 50% acetonitrile in water, 40 min), and lyophilized to give compound DC-12, mc-Val-Cit-pab-formyl-N-ethoxyaminoacetylexatecan, as a yellow solid (13 mg, 45% yield). LCMS: (M+1) + 1136.02 (calculated value: 1135.20).

[0140] Example 26: mc-Gly-Gly-Phe-Gly-Methoxy-N-methylaminoacetylexatecan (DC-13) Fmoc-Gly-Gly-Phe-OH (10 g, 19.9 mmol) was added to 200 mL of DCM, HATU (11.43 g, 29.85 mmol), DIPEA (5.13 g, 39.8 mmol), and Gly-Gly-OtBu (4.11 g, 21.89 mmol). The mixture was allowed to react at room temperature for 15 hours, diluted with 200 mL of DCM, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to give DC-13-a (10.7 g, 79%) as a white solid, i.e., Fmoc-Gly-Gly-Phe-Gly-Gly-OtBu. LCMS: (M+1) + 672.5 (calculated value: 671.75).

[0141] DC-13-a (10.7 g, 15.9 mmol) was taken, and 110 mL of DCM and 50 mL of TFA were added, and the mixture was reacted at room temperature for 15 hours. The reaction mixture was concentrated, and 100 mL of EA was added. The mixture was filtered, and the filter cake was dried in an oven at 40° C. to obtain an off-white solid DC-13-b, i.e., Fmoc-Gly-Gly-Phe-Gly-Gly (8.8 g, 90%). LCMS: (M+1) + 616.10 (calculated value: 615.23).

[0142] DC-13-b (3 g, 4.8 mmol) was dissolved in 30 mL of DMF and stirred to dissolve. Then, copper acetate (1.46 mmol, 0.26 g), acetic acid (9.7 mmol, 0.58 g), and lead tetraacetate (5.3 mmol, 2.38 g) were added sequentially. The temperature was raised to 60 °C and the reaction was continued for 20 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give DC-13-c, i.e., Fmoc-Gly-Gly-Phe-Gly-N-hydroxymethyl acetate (1.81 g, 59%) as an off-white solid. LCMS: (M+1) + 630.10 (calculated value: 629.25).

[0143] DC-13-c (0.05 g, 0.076 mmol) was taken, 5 mL of THF was added, followed by compound 11 (0.04 g, 0.076 mmol) and PPTS (3.8 mg, 0.015 mmol). The mixture was refluxed at 60 ° C for 16 hours under argon gas protection, and purified by silica gel column chromatography to obtain DC-13-d (43 mg, 50%) as a white solid, i.e., Fmoc-Gly-Gly-Phe-Gly-methoxy-N-methylaminoacetylexatecan. LCMS: (M+1) + 1093.05 (calculated value: 1092.15).

[0144] DC-13-d (43 mg, 0.039 mmol) was dissolved in 0.5 ml of DMF, piperidine (33 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 1 hour to react. The reaction solution was concentrated to give DC-13-e, i.e., Gly-Gly-Phe-Gly-methoxy-N-methylaminoacetylexatecan (34 mg, 100%) as a yellowish brown solid. LCMS: (M+1) + 871.02 (calculated value: 869.91).

[0145] DC-13-e (34 mg, 0.039 mmol) was dissolved in 0.5 mL of anhydrous DMF, and 6-(maleimido)hexanoic acid succinimidyl ester (12 mg, 0.039 mmol) and DIPEA (5 mg, 0.039 mmol) were added sequentially. The mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was then loaded onto a 25 g C18 precolumn (first equilibrated with acetonitrile, then with water, the aqueous phase containing 0.1% TFA). The mixture was eluted by medium-pressure reverse-phase C18 chromatography (gradient: 15% to 50% acetonitrile in water, 40 min), and lyophilized to give compound DC-13, mc-Gly-Gly-Phe-Gly-methoxy-N-methylaminoacetylexatecan, as a yellow solid (12.4 mg, 30% yield). LCMS: (M+1). + 1064.05 (calculated value: 1063.11).

[0146] Example 27: 4-(Maleimidohexyloxy)benzaldehyde-aminooxyacetylexatecan oxime (DC-14) 6-Amino-1-hexanol (6.0 g, 51.20 mmol) and 60 mL of 48% aqueous HBr were added sequentially to a 100 mL single-neck flask and refluxed at 90 °C for 18 hours. The reaction mixture was then adjusted to pH 8-9 using solid sodium bicarbonate in an ice bath. Boc anhydride (11.2 g, 51.20 mmol) was added, the mixture was slowly warmed to room temperature, and the mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was extracted with EtOAc to obtain the desired product. The organic phase was washed three times with 5% aqueous NaCl, dried over anhydrous Na2SO4, and the dried organic phase was filtered and concentrated to give the off-white solid product, N-Boc-6-bromohexylamine (10.0 g, 71.4% yield). LCMS: (M+1) + 281.12 (calculated value: 280.21)

[0147] 50 mL of acetonitrile was added to a 100 mL single-neck flask, and N-Boc-6-bromohexylamine (5.0 g, 17.84 mmol), p-hydroxybenzaldehyde (2.2 g, 17.84 mmol), and anhydrous potassium carbonate (6.2 g, 44.61 mmol) were added sequentially. The mixture was refluxed at 60 °C for 18 hours with stirring. The reaction mixture was filtered, and 10.0 g of silica gel sand was added to the filtrate. Column chromatography was performed using PE and EA, and the mixture was concentrated to give an off-white solid product, i.e., 4-(N-Boc-hexyloxy)benzaldehyde (5.0 g, 87.7% yield). LCMS: (M+1) + 322.14 (calculated value: 321.42).

[0148] A 100 mL single-neck flask was charged with 3 mL of 1,4-dioxane, followed by the addition of 4-(N-Boc-hexyloxy)benzaldehyde (1.0 g, 4.52 mmol) and 3 mL of 4 mol / L HCl / 1,4-dioxane solution. The mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 9 using saturated aqueous sodium bicarbonate in an ice bath. N-methoxycarbonylmaleimide (700.90 mg, 4.52 mmol) was added, and the mixture was stirred in an ice bath for 2 hours. The solid was filtered, washed with 10 mL of purified water, and dried at 35 °C to give the off-white solid product L-20 (1.0 g, 73.5% yield). LCMS: (M+1) + 302.23 (calculated value: 301.34)

[0149] To 3 ml of methanol, L-20 (24.59 mg, 0.081 mmol), pyridine (14.2 mg, 0.179 mmol), anhydrous sodium sulfate (23.18 mg, 0.163 mmol), and finally compound 14 (83 mg, 0.163 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the product DC-14, i.e., 4-(maleimidohexyloxy)benzaldehyde-aminooxyacetylexatecan oxime (36 mg, 56% yield), was obtained by LCMS: (M+1). + 792.11 (calculated value: 791.30).

[0150] Example 28: 4-(Maleimidoethyloxyethoxy)benzaldehyde-aminooxyacetylexatecan oxime (DC-15) Diglycolamine (6.0 g, 57.07 mmol) and 60 mL of 48% HBr aqueous solution were added sequentially to a 100 mL single-neck flask and refluxed at 90 °C for 18 hours. The reaction mixture was then adjusted to pH 8-9 using solid sodium bicarbonate in an ice bath. Boc anhydride (12.46 g, 57.07 mmol) was added, the mixture was slowly warmed to room temperature, and the mixture was stirred overnight. The reaction mixture was filtered and extracted with EtOAc to obtain the desired product. The organic phase was washed three times with 5% aqueous NaCl, dried over anhydrous Na2SO4, and the dried organic phase was filtered and concentrated to give an off-white solid product, i.e., N-Boc-bromoethoxyethylamine (10.8 g, 70.6% yield). LCMS: (M+1) + 269.02 (calculated value: 268.15)

[0151] 50 mL of acetonitrile was added to a 100 mL single-neck flask, and N-Boc-bromoethoxyethylamine (5.0 g, 18.65 mmol), p-hydroxybenzaldehyde (2.28 g, 18.65 mmol), and anhydrous potassium carbonate (6.44 g, 46.62 mmol) were added sequentially. The mixture was refluxed at 60 °C for 18 hours with stirring. The reaction mixture was filtered, and 10.0 g of silica gel sand was added to the filtrate. Column chromatography was performed using PE and EA, and the mixture was concentrated to give the off-white solid product, 4-(N-Boc-aminoethoxyethoxy)benzaldehyde (5.3 g, 91.8% yield). LCMS: (M+1) + 310.24 (calculated value: 309.36)

[0152] A 100 ml single-neck flask was charged with 3 ml of 1,4-dioxane, 4-(N-Boc-aminoethoxyethoxy)benzaldehyde (0.6 g, 1.94 mmol), and 3 ml of 4 mol / L HCl / 1,4-dioxane solution. The mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 9 using saturated aqueous sodium bicarbonate in an ice bath. N-methoxycarbonylmaleimide (300.83 mg, 1.94 mmol) was added, and the mixture was stirred in an ice bath for 2 hours. The solid was filtered, washed with 10 ml of purified water, and dried at 35 °C to obtain an off-white solid product L-021 (500 mg, 89% yield). LCMS: (M+1) + 290.13 (calculated value: 289.29)

[0153] To 3 ml of methanol, L-021 (23.61 mg, 0.082 mmol), pyridine (14.2 mg, 0.179 mmol), anhydrous sodium sulfate (23.18 mg, 0.163 mmol), and finally compound 14 (83 mg, 0.163 mmol) were added, and the mixture was stirred at room temperature for 1 hour to react. After the reaction was completed, the mixture was subjected to 1 g of silica gel column chromatography to obtain product DC-15, i.e., 4-(maleimidoethyloxyethoxy)benzaldehyde-aminooxyacetylexatecan oxime (42 mg, 66% yield). LCMS: (M+1) + 780.12 (calculated value: 779.26)

[0154] Example 29: HS627-Succinimido-N-hexanoyl-Val-Cit-pab-formyl-exatecan-N-aminourea (ADC-3a) JPEG2025526504000070.jpg51170HS627 antibody (20.0 mg / mL, 10 mg, 0.066 mmol) was taken and the pH was adjusted to 7.2 using 1 M Na2HPO4 solution, followed by the addition of 0.1 M ethylenediaminetetraacetic acid disodium solution (25 μL) and the prepared TCEP-HCl (tris(2-carboxyethyl)phosphine hydrochloride) solution (10 mM, 0.04 ml). The mixture was allowed to react at room temperature (25°C) on a rotating turntable for 90 minutes.

[0155] DC-3 (0.9 mg, 0.8 mmol) was dissolved in 0.09 ml of DMA, added to the above solution, and mixed well. The mixture was then reacted on a rotating turntable at room temperature for 2 hours. After the reaction was completed, the buffer was replaced with 20 mM histidine acetate buffer, pH 6.0, 120 mM sucrose, and 0.2 g / L polysorbate 20 using a NAP-5 gel column (Cytiva) to obtain ADC-3a (1.8 mg / ml, 3 ml).

[0156] UV-HPLC calculated mean value: n=7.40

[0157] Example 30: HS627-Succinimido-N-hexanoyl-Val-Cit-pab-formyl-2-aminooxyacetylexatecan (ADC-6a) JPEG2025526504000071.jpg51170HS627 antibody (20.0 mg / mL, 10 mg, 0.066 mmol) was taken and the pH was adjusted to 7.2 using 1 M Na2HPO4 solution, followed by the addition of 0.1 M ethylenediaminetetraacetic acid disodium solution (25 μL) and the prepared TCEP-HCl (tris(2-carboxyethyl)phosphine hydrochloride) solution (10 mM, 0.04 ml). The mixture was allowed to react at room temperature (25°C) on a rotating turntable for 90 minutes.

[0158] DC-6 (0.9 mg, 0.8 mmol) was dissolved in 0.09 ml of DMA, added to the above solution, and mixed well. The mixture was then reacted on a rotating turntable at room temperature for 2 hours. After the reaction was completed, the buffer was replaced with 20 mM histidine acetate buffer, pH 6.0, 120 mM sucrose, and 0.2 g / L polysorbate 20 using a NAP-5 gel column (Cytiva) to obtain ADC-6a (3.2 mg / ml, 2 ml).

[0159] UV-HPLC calculated mean value: n=7.70

[0160] Example 31: HS627-Succinimido-N-hexanoyl-Val-Cit-pab-formyl-N-methylaminooxyacetylexatecan (ADC-7a) JPEG2025526504000072.jpg51170HS627 antibody (20.0 mg / mL, 10 mg, 0.066 mmol) was taken and the pH was adjusted to 7.2 using 1 M Na2HPO4 solution, followed by the addition of 0.1 M ethylenediaminetetraacetic acid disodium solution (25 μL) and the prepared TCEP-HCl (tris(2-carboxyethyl)phosphine hydrochloride) solution (10 mM, 0.04 ml). The mixture was allowed to react at room temperature (25°C) on a rotating turntable for 90 minutes.

[0161] DC-7 (0.9 mg, 0.8 mmol) was dissolved in 0.09 ml of DMA, added to the above solution, and mixed well. The mixture was then reacted on a rotating turntable at room temperature for 2 hours. After the reaction was completed, the buffer was replaced with 20 mM histidine acetate buffer, pH 6.0, 120 mM sucrose, and 0.2 g / L polysorbate 20, using a NAP-5 gel column (Cytiva) to obtain ADC-7a (3.1 mg / ml, 2 ml).

[0162] UV-HPLC calculated mean value: n = 7.30

[0163] Example 32: HS627-Succinimido-4-(N-hexyloxy)benzaldehyde oxime oxoacetylexatecan (ADC-14a) JPEG2025526504000073.jpg50170HS627 antibody (20.0 mg / mL, 10 mg, 0.066 mmol) was taken and the pH was adjusted to 7.2 using 1 M Na2HPO4 solution, followed by the addition of 0.1 M ethylenediaminetetraacetic acid disodium solution (25 μL) and the prepared TCEP-HCl (tris(2-carboxyethyl)phosphine hydrochloride) solution (10 mM, 0.04 ml). The mixture was allowed to react at room temperature (25°C) on a rotating turntable for 90 minutes.

[0164] DC-14 (0.63 mg, 0.8 mmol) was dissolved in 0.063 ml of DMA, added to the above solution, and mixed well. The mixture was then reacted on a rotary turntable at room temperature for 2 hours. After the reaction was completed, the buffer was replaced with 20 mM histidine acetate buffer, pH 6.0, 120 mM sucrose, and 0.2 g / L polysorbate 20 using a NAP-5 gel column (Cytiva) to obtain ADC-14a (2.9 mg / ml, 2 ml).

[0165] UV-HPLC calculated mean value: n=4.3.

[0166] Example 33: HS627-Succinimido-4-(N-ethoxyethoxy)benzaldehyde oxime oxoacetylexatecan (ADC-15a) JPEG2025526504000074.jpg55170HS627 antibody (20.0 mg / mL, 10 mg, 0.066 mmol) was taken and the pH was adjusted to 7.2 using 1 M Na2HPO4 solution, followed by the addition of 0.1 M ethylenediaminetetraacetic acid disodium solution (25 μL) and the prepared TCEP-HCl (tris(2-carboxyethyl)phosphine hydrochloride) solution (10 mM, 0.04 ml). The mixture was allowed to react at room temperature (25°C) on a rotating turntable for 90 minutes.

[0167] DC-15 (0.62 mg, 0.8 mmol) was dissolved in 0.062 ml of DMA, added to the above solution, mixed well, and reacted for 2 hours at room temperature on a rotary turntable. After the reaction was completed, the buffer was replaced with 20 mM histidine acetate buffer, pH 6.0, 120 mM sucrose, and 0.2 g / L polysorbate 20 using a NAP-5 gel column (Cytiva) to obtain ADC-15a (3.2 mg / ml, 2 ml).

[0168] UV-HPLC calculated mean value: n=7.6.

[0169] Example 1: Inhibition of tumor cell proliferation activity In vitro inhibitory activity test method for compounds (low molecular weight toxins) Human esophageal cancer cells OE33 and human breast cancer cells SK-BR-3 were cultured in RPMI1640 (Cellmax) containing 10% fetal bovine serum (Cellmax). Exponentially growing tumor cells were cultured at a density of 1 × 10 5 The small molecule compounds were diluted to 10,000 nM, 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.13 nM in medium. 2 μL of the diluted compounds were added per well to the 96-well cell culture plate. Three replicate wells were set up for each concentration. 2 μL of the diluted solution was added per well to the negative and blank controls. After addition, the plate was returned to the incubator at 37°C and 5% CO2 for 72 hours. After incubation, the plate was removed, the medium was aspirated, and 100 μL of medium containing 10% CCK-8 was added per well. The plate was then incubated at 37°C for 3 hours. After incubation, the culture plate was removed and placed on an ELISA plate in a dark place, and the absorbance was measured using a reference wavelength of 630 nm and a measurement wavelength of 450 nm. 50 IC values were calculated from absorbance values using a four-parameter regression in GraphPad (Tables 1-3). The DNA topoisomerase I inhibitor Dxd was used as a positive control. 50 For values, "++++" is IC 50 <10 nM, "+++" indicates IC 50 indicates that the IC is between 10 and 100 nM, and "++" indicates that the IC 50 indicates that the IC is between 100 and 500 nM, and "+" indicates that the IC 50 Indicates >500 μM.

[0170] In vitro inhibitory activity testing method for ADCs The human esophageal cancer cells OE33, lung cancer cells NCI-H1975, and breast cancer cells MDA-MB-231 used in the activity measurements were cultured in RPMI1640 (Cellmax), RPMI1640 (Cellmax), and DMEM (Cellmax) medium containing 10% fetal bovine serum until the exponential growth phase. After trypsin digestion, the supernatant was discarded by centrifugation, and the cells were resuspended in 3 × 10 medium. 4 cells / mL, 0.5 × 10 4 cells / mL, 1.5 × 10 4 The ADCs were diluted to 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, and 0.026 nM in medium. 100 μL of the diluted ADCs were added to each well of a 96-well cell culture plate. Each well contained three replicate wells. For the negative and blank controls, 100 μL of medium was added per well. After the addition, the plate was returned to the incubator at 37°C and 5% CO2 for 6 days. After incubation, the plate was removed from the culture medium, aspirated, and 100 μL of medium containing 10% CCK-8 was added per well. The plate was then incubated at 37°C for 3 hours. After incubation, the culture plate was removed and placed on an ELISA plate in a dark place, and the absorbance was measured using a reference wavelength of 630 nm and a measurement wavelength of 450 nm. 50 The IC was calculated from the absorbance values using a four-parameter regression in GraphPad (Tables 1 and 3). The ADC drug DS-8201a was used as a positive control. 50 For values, "++++" is IC 50 <10 nM, and "++++" indicates IC 50 indicates that the IC is between 10 and 100 nM, and "++" indicates that the IC 50 indicates that the IC is between 100 and 500 nM, and "+" indicates that the IC 50 Indicates >500 μM.

[0171] The structural formula of the positive control compound DXD is as follows: JPEG2025526504000075.jpg67170JPEG2025526504000076.jpg64170JPEG2025526504000077.jpg37170JPEG2025526504000078.jpg55170

[0172] All of the compounds in the examples provided by the present invention have good inhibitory effects on the proliferation of cancer cells such as esophageal cancer cells and breast cancer cells 3, and most of the compounds, such as compounds 2, 3, 7, 8, 9, and 13, have IC 50 The value is 10 nM or less, and it has significant anti-cancer activity.

[0173] The compounds of the examples of the present invention were used to construct antibody-drug conjugates, and the resulting conjugates had significant inhibitory activity against esophageal cancer cells, lung cancer cells, and breast cancer cells. The exemplary conjugates ADC-3a, ADC-6a, and ADC-7a all had significant inhibitory activity against the above cells, with the inhibitory activity of ADC-7a all being even lower than 10 nM.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, During the ceremony, R is -Z-R １ wherein Z is a single bond or C═O; R １ is -(CH ２ ) ｎ NR ａ R ｂ , -CH ２ OR ａ , -NOR ａ , -(CH ２ ) ｎ ONR ａ R ｂ or -R ３ and n is selected from 0, 1, 2, or 3; R ａ , R ｂ are each independently hydrogen, a hydroxy group, an amino group, or C １ ~C ６ Alkyl group, C １ ~C ６ Alkylamino group, amino C １ ~C ６ Alkyl group or C １ ~C ６ alkoxy groups, R ３ is selected from a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group containing an N, O, or S heteroatom; R ３ optionally further comprises R ｃ is replaced by R ｃ is hydrogen, a hydroxy group, an amino group, C １ ~C ６ Alkyl group, C １ ~C ６ alkylamino group, or C １ ~C ６ alkoxy groups, However, -Z-R １ is -NH ２ , -CH ２ OH, -CH ２ NH ２ or -CH ２ OCH ２ NH ２ or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, provided that the compound is not:

2. R １ is -NR ａ R ｂ , -CH ２ NR ａ R ｂ , -CH ２ OR ａ , -NOR ａ , -(CH ２ ) ｎ ONR ａ R ｂ or -R ３ is selected from Preferably, R １ is -NR ａ R ｂ , —C(O)NR ａ R ｂ , -CH ２ NR ａ R ｂ , -CH ２ ONR ａ R ｂ or -R ３ is selected from Preferably, R ａ , R ｂ are each independently hydrogen, a hydroxy group, an amino group, or C １ ~C ６ Alkyl group, C １ ~C ６ Alkylamino group or C １ ~C ６ alkoxy groups, Preferably, R ａ , R ｂ are each independently selected from hydrogen, a hydroxy group, an amino group, a methyl group, a methylamino group, or a methoxy group; R ３ is selected from 3-6 membered heterocycloalkyl groups containing N, O or S heteroatoms, R ３ optionally further comprises R ｃ is replaced by R ｃ is hydrogen, a hydroxy group, an amino group, C １ ~C ６ Alkyl group, C １ ~C ６ alkylamino group, or C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein the aryl group is selected from the group consisting of aryl, aryl alkoxy ...

3. R １ is -NHNH ２ , -N(CH ３ ) NH ２ , -N(CH ３ ) NHCH ３ , -C(O)NHNH ２ , -C(O)N(CH ３ ) NH ２ , -CH ２ NHOH, -CH ２ NHOCH ３ , -CH ２ ONH ２ , -CH ２ ONHCH ３ , -CH ２ NCH ３ NH ２ , -CH ２ N (CH ３ ) NHCH ３ , -CH ２ N (CH ３ ) OH, —CH ２ NHOCH ２ CH ３ 3. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein the hydroxyl group is selected from the group consisting of hydroxyl, hydroxybenzoate ...

4. The compound of formula (I) is a compound represented by formula (Ia), (Ib), (Ic) or (Id), In formula (Ia), R １ is defined as in the compounds of formula (I), Preferably, R １ is -NHNH ２ or -N(CH ３ ) NH ２ and In formula (Ib), R ２ is -NHOH, -ONH ２ , -NHO(C １ ~C ３ alkyl group), -ONH(C １ ~C ３ alkyl group), -N(C １ ~C ３ alkylamino group), -N(C １ ~C ３ alkyl group)NH(C １ ~C ３ alkyl group), -N(C １ ~C ３ alkyl group) OH or -NHO(C １ ~C ３ alkyl group), Preferably, R ２ is -NHOH, -NHOCH ３ , -ONH ２ , -ONHCH ３ , -NCH ３ NH ２ , -N(CH ３ ) NHCH ３ , -N(CH ３ ) OH or —NHOCH ２ CH ３ is selected from In formula (Ic), R ａ , R ｂ is defined as in the compounds of formula (I), except that R ａ , R ｂ is not H at the same time, Preferably, R ａ , R ｂ are each independently hydrogen, an amino group, or C １ ~C ３ Alkyl group, C １ ~C ３ alkylamino groups, Preferably, —NR ａ R ｂ is -NHNH ２ , -N(CH ３ ) NH ２ or -N(CH ３ ) NHCH ３ is selected from In formula (Id), X is CH ２ , NH, O or S, preferably X is CH ２ or O, more preferably X is O, R ｃ is hydrogen, a hydroxy group, an amino group, C １ ~C ６ Alkyl group, C １ ~C ６ Alkylamino group or C １ ~C ６ alkoxy groups, Preferably, R ｃ is selected from a hydroxy group or an amino group; 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

5. The following compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof:

6. The following reaction pathway: Reaction Pathway 1: reacting exatecan with N,N'-carbonyldiimidazole, followed by reaction with hydrazine or a substituted hydrazine to obtain the corresponding N-aminourea exatecan derivative; Reaction Pathway 2: reacting a substituted hydrazine with oxalyl chloride, followed by reaction with exatecan to obtain the corresponding oxamide hydrazide exatecan derivative; Reaction Scheme 3: reacting exatecan with bromoacetic acid to obtain bromoacetylexatecan, and condensing bromoacetylexatecan with an amine compound to obtain the corresponding amide exatecan derivative; Reaction Scheme 4: directly reacting exatecan with a carboxylic acid compound to obtain the corresponding amide exatecan derivative; A method for preparing the compound according to any one of claims 1 to 5, selected from:

7. A drug-linker compound represented by formula (II) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein R is defined as in the compound of formula (I), L is -L １ -Q-L ２ and R is partially L １ is connected to Here, L １ is selected from the group represented by the formula: Here, the positions indicated by the symbols below are linked to the R group, The positions indicated by the symbols below are linked to the Q group: L ２ is selected from the group represented by the formula: Q is Val-Cit, Val-Ala, Ala-Ala-Asn, Gly-Gly-Phe-Gly, Gly-Lys, Gly-Gly-lys, (CH ２ ) ｍ１ O (CH ２ ) ｍ２ , or (CH ２ ) ｍ３ wherein m1 and m2 are each independently selected from an integer of 1 to 4, m1 is preferably 2, m2 is preferably 2, m3 is preferably 6, and preferably Q is selected from Val-Cit, Gly-Gly-Phe-Gly, (CH ２ ) ２ O (CH ２ ) ２ , or (CH ２ ) ６ is selected from Preferably, L １ is a group represented by the formula or a group represented by the formula: Preferably, L ２ is a group represented by the formula or a group represented by the formula: A drug-linker compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

8. A drug-antibody conjugate compound represented by formula (III), or a pharmaceutically acceptable salt thereof: wherein R is defined as in formula (I) or a compound thereof, and L is defined as in formula (II) or a compound thereof; Ab is a tumor-associated antigen antibody, n is selected from an integer from 1 to 8, Preferably, the tumor-associated antigen is selected from Her2, Trop2, 5T4, ROR1, or B7-H3; Preferably, the drug-antibody conjugate compound of formula (III) is selected from the following compounds: Preferably, the drug-antibody conjugate compound of formula (III) is selected from the following compounds: A drug-antibody conjugate compound or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, the drug-linker compound according to claim 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, or the antibody-drug conjugate according to claim 8, and a pharmaceutically acceptable adjuvant.

10. Use of the compound according to any one of claims 1 to 5, the drug-linker compound according to claim 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, or the antibody-drug conjugate according to claim 8, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating cancer, Preferably, the cancer is gastric cancer, esophageal cancer, breast cancer and lung adenocarcinoma.

11. A method for treating cancer, comprising the step of administering to a patient in need thereof the compound according to any one of claims 1 to 5, the drug-linker compound according to claim 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, or the antibody-drug conjugate according to claim 8, or the pharmaceutical composition according to claim 9.

Images