Camptothecin-based drugs and their antibody conjugates

Abstract

To provide a camptothecin drug and its antibody conjugate.SOLUTION: The present invention provides a compound of the formula I (where, R1 and R2 are independently selected from the group consisting of a C1-C3 alkyl group, a substituted alkyl group, -H, -CF3, an aryl group, a substituted aryl group and a heteroaryl group, or R1 and R2 form a ring structure together with carbon atoms bound to them, provided that R1 and R2 are not both hydrogen at the same time) and an antibody-drug conjugate of the formula II (where, Ab represents an antibody, an antibody fragment or a protein, L represents a linker, and D represents the compound of formula I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to camptothecin-class drugs used as antitumor drugs and antibody-drug conjugates thereof. [Background technology]

[0002] Antibody-drug conjugates (ADCs) are new targeted drugs that generally consist of three parts: an antibody or antibody-like ligand, a small molecule drug, and a linker that connects the ligand and drug. Antibody-drug conjugates utilize the specific recognition of antibodies against antigens to deliver drug molecules to the vicinity of target cells and effectively release the drug molecules, thereby achieving the therapeutic goal. In August 2011, the U.S. Food and Drug Administration (FDA) approved Adecteis, a new ADC drug for the treatment of Hodgkin lymphoma and recurrent degenerative large cell lymphoma (ALCL), developed by Seattle Genetics. TM The safety and effectiveness of this drug have been clinically proven.

[0003] Camptothecin-class drugs (irinotecan, exatecan, SN38, etc.) are small molecule compounds with antitumor properties known to exert antitumor effects by inhibiting DNA topoisomerase I. Many camptothecin-class drugs are widely used clinically, primarily for the treatment of bone cancer, prostate cancer, breast cancer, and pancreatic cancer. Unlike the currently used irinotecan, exatecan does not require enzyme activation. Furthermore, compared to SN-38, the pharmacodynamic equivalent of irinotecan, and the currently used topotecan, exatecan exhibits stronger inhibitory effects against topoisomerase I and exhibits more potent killing effects against various cancer cells in vitro. It is particularly effective against cancer cells that exhibit resistance to SN-38 through the expression of P-glycoprotein. Exatecan has not yet been successfully marketed as a standalone chemotherapy drug, presumably due to its narrow therapeutic window resulting from its high cellular activity.

[0004] The advantages of antibody-drug conjugates (ADCs) are their improved water solubility and targeting, allowing the antibody to specifically bind to the antigen, delivering the drug to the surrounding area of ​​the target cell, and releasing the drug near the target cell, thereby effectively killing tumor cells and reducing toxicity and side effects. Camptothecin-based drugs have considerable application prospects in ADCs.

[0005] The problem to be solved by the present invention is to develop a more excellent antitumor camptothecin compound, improve the safety and efficacy of antitumor small molecular weight compounds in ADC drugs, and obtain an antitumor drug with excellent therapeutic effect.

[0006] Based on a comprehensive understanding of ADC-type drugs, the inventors designed a series of active derivatives of antitumor camptothecin, and demonstrated through experiments that the antitumor small molecule compounds showed higher antitumor activity in cell experiments. Summary of the Invention

[0007] An object of the present invention is to provide camptothecin derivatives and antibody-drug conjugates thereof that have superior antitumor effects.

[0008] A camptothecin-class compound represented by formula I or a pharmaceutically acceptable salt thereof. [ka] In Formula I, R1 and R2 are each independently selected from the group consisting of a C1-C3 alkyl group, a substituted alkyl group, -H, -CF3, an aryl group, a substituted aryl group, and a heteroaryl group, or R1 and R2 together with the carbon atoms attached thereto form a cyclobutane, cyclopentane, or cyclohexane, with the proviso that R1 and R2 are not both hydrogen atoms.

[0009] Preferably, R1 is hydrogen and R2 is a C1-C3 alkyl group, -CF3, aryl group, substituted aryl group, or heteroaryl group, or R1 and R2 are a C1-C3 alkyl group, -CF3, aryl group, heteroaryl group, or substituted aryl group, or R1 and R2 together with the carbon atoms bonded thereto form cyclobutane, cyclopentane, or cyclohexane; [ka] In structural formula (a), R2 is independently -(CH2)n 1 -CH3, -CF3, an aryl group, a heteroaryl group, or a substituted aryl group, provided that n 1 = 0, 1 or 2, In structural formula (b), R1 and R2 are independently -(CH2)n 1 -CH3, -CF3, an aryl group, a heteroaryl group, or a substituted aryl group, provided that n 1 = 0, 1 or 2, In structural formula (c), R1 and R2 together with the carbon atoms bonded thereto form cyclobutane, cyclopentane, or cyclohexane, provided that n 2 =1, 2 or 3.

[0010] More preferably, R1 is hydrogen and R2 is independently -(CH2)n 1 -CH3, -CF3, an aryl group, a heteroaryl group, or a substituted aryl group, provided that n 1 = 0, 1 or 2, [ka] The carbon bonded to R2 has two conformations: R and S. In structural formula (a-1), the carbon bonded to R2 is in the R configuration, In structural formula (a-2), the carbon bonded to R2 is in the S configuration.

[0011] Preferably, the camptothecin compound or a pharmaceutically acceptable salt thereof is [ka] is selected from the group consisting of:

[0012] Preferably, the camptothecin compound or a pharmaceutically acceptable salt thereof is an antitumor drug and is applied to the treatment of solid tumors or hematological tumors, including lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, lung cancer, or esophageal cancer.

[0013] In another aspect of the present invention, there is provided an antibody-drug conjugate of Formula II that is configured to exert its therapeutic effect by releasing drug moiety D after reaching target cells. [ka] In Formula II, Ab is an antibody, antibody fragment, or protein; L is an optional linker that is attached at one end to an Ab and at the other end to a drug moiety, D; D is selected from the camptothecin-class compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and is bonded to L via the hydroxyl group of D; m is selected from an integer of 1-20.

[0014] Preferably, the linker L of the antibody-drug conjugate is selected from the group consisting of -O-, -N(R)n1-, -CH2-, -CH(R)n1-, an amide bond, an ester bond, -S-, and -(PEG)n2-, wherein n1 is selected from an integer of 1 to 3, and n2 is selected from an integer of 1 to 20.

[0015] In another aspect of the present invention, there is provided a method for treating a patient in need of treatment. The method comprises administering to the patient any one of the antibody-drug conjugates described above. The patient is suffering from a tumor, an autoimmune disease, or an infectious disease. The antibody of the antibody-drug conjugate specifically binds to target cells of the cancer or autoimmune disease.

[0016] Preferably, the antibody-drug conjugate or a salt thereof is an antitumor or anticancer drug, and is applicable to the treatment of solid tumors and hematological tumors, including lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer. DETAILED DESCRIPTION OF THE INVENTION

[0017] Abbreviations and Definitions Unless otherwise specified, the following terms and phrases used herein have the following meanings: When a trade name is used herein, the trade name includes the formulation of the product, the generic drug, and the active ingredient of the drug, unless the context dictates otherwise.

[0018] The term "alkylene group" refers to a divalent, linear, saturated hydrocarbon group having 1-20 carbon atoms, including groups of 1 to 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CH-CH-), n-propylene, n-butylene, n-pentylene, and n-hexylene. Unless otherwise specified, the term "aryl group" refers to a polyunsaturated, generally aromatic hydrocarbon group, including monocyclic, fused-ring, or covalently linked polycyclic (at most three-ring) groups. The term "heteroaryl group" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, or S, where the N and S atoms are optionally oxidized and the N atom is optionally quaternized. A heteroaryl group can be attached to the rest of the molecule through a heteroatom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and diphenyl groups. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnoline, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisozolyl, isobenzofuranyl, isoindolyl, indazinyl, benzotriazinyl, and thienopyridyl. Examples of aromatic and heteroaromatic ring systems include, but are not limited to, thienopyrimidinyl, pyridopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuran, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl. When described as "substituted," substituents on the above aromatic and heteroaromatic ring systems are selected from the following acceptable substituents.

[0019] Unless otherwise specified, alkyl group substituents may be selected from the group consisting of -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 ranges from 0 to (2m'+1), where m' is the total number of carbon atoms in the group. R', R'', and R''' are each independently hydrogen, unsubstituted C(NH) 1-8 Alkyl 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 represents an alkyl group. When R' and R" are attached to the same nitrogen atom, they can form a 3-, 4-, 5-, 6-, or 7-membered ring together with the nitrogen atom. For example, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl groups.

[0020] A "derivative" of a compound described herein refers to a substance that has a similar chemical structure to the compound, but contains at least one chemical group not present in the compound and / or lacks at least one chemical group present in the compound. The compound corresponding to the derivative is called the "parent" compound. Typically, a "derivative" can be produced from the parent compound by one or more chemical reaction steps.

[0021] L-ligand The Ligand unit is a targeting agent that specifically binds to a targeting moiety. The Ligand can specifically bind to a cellular component, or bind to a cellular component, or bind to other target molecules of interest. The targeting moiety or target is typically located on the surface of a cell. 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. Examples of suitable Ligand units include antibodies, such as full-length (complete) antibodies, and antigen-binding fragments thereof. In embodiments where the Ligand unit is a non-antibody targeting reagent, the Ligand unit may be a peptide, polypeptide, or non-protein molecule. Examples of such targeting reagents include interferons, lymphokines, hormones, growth factors and colony-stimulating factors, vitamins, nutrient transport molecules, or any other cell-binding molecule or substance. In some embodiments, the linker is covalently bonded to the 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 introduced into the Ligand unit and forms an interchain disulfide bond of the antibody. In another aspect, the sulfur atom is the sulfur atom of a cysteine ​​residue introduced into the Ligand unit (e.g., by site-directed mutagenesis or chemical reaction). In another aspect, the sulfur atom attached to the Linker is selected from cysteine ​​residues that form interchain disulfide bonds of the antibody or cysteine ​​residues introduced into the Ligand unit (e.g., by site-directed mutagenesis or chemical reaction). In some embodiments, the numbering system is according to the EU index in Kabat (Kabat EA et al., (1991)) "Sequences of proteins of Immunological Interest" (Sequences of proteins of Immunological Interest), fifth edition, NIH publication 91-3242).

[0022] As used herein, the term "antibody" or "antibody unit" includes within its scope any portion of an antibody structure that is capable of binding to, reactively associating with, or complexing with a receptor, antigen, or other receptor unit on the targeted cell population. An antibody may be any protein or proteinaceous molecule that is capable of binding to, complexing with, or reacting with a portion of a cell population to be treated or biologically modified.

[0023] In the present invention, the antibody constituting the antibody-drug conjugate preferably retains its inherent antigen-binding ability in its native state. Therefore, the antibody of the present invention preferably specifically binds to an antigen. Examples of such antigens include 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 (e.g., molecules known or predicted to have functionality), lymphokines, cytokines, molecules involved in cell cycle regulation, molecules involved in angiogenesis, and angiogenesis-related molecules (e.g., molecules known or predicted to have functionality). The tumor-associated factor may be a cluster differentiation factor (e.g., CD protein).

[0024] Antibodies used in the antibody-drug conjugates described herein include, but are not limited to, antibodies against cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are known in the art and can be produced according to antibody production methods and information known in the art. To develop effective cellular targets that can be used for cancer diagnosis and treatment, researchers are seeking transmembrane or other tumor-associated peptides. These targets can be specifically expressed on the surface of one or more cancer cells, while being poorly or completely expressed on the surface of one or more non-cancer cells. Typically, such tumor-associated polypeptides are overexpressed on the surface of cancer cells compared to non-cancer cells. It has been shown that such tumor-associated factors can significantly improve the specific targeting properties of antibody-based cancer therapy.

[0025] Tumor-associated antigens include, but are not limited to, tumor-associated antigens (1)-(36) shown below. For convenience, antigen-related information well known in the art is provided by name, other name, and GenBank accession number. Nucleic acid and protein sequences corresponding to tumor-associated antigens can be found in public databases such as GenBank. Tumor-associated antigens targeted by antibodies include all amino acid sequence variants and homologs, and have at least 70%, 80%, 85%, 90%, or 95% identity with the sequences identified in the references, or have biological properties and characteristics that are identical to the sequences of the tumor-associated antigens described in the cited literature.

[0026] The terms "inhibit" or "inhibition of" refer to reducing the detectable amount or preventing it completely.

[0027] The term "cancer" refers to a physiological condition or disease characterized by unregulated cell growth. A "tumor" includes cancer cells.

[0028] The term "autoimmune disease" refers to a disease or disorder that originates from an individual's own tissues or proteins.

[0029] As used herein, a "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound (e.g., a drug, a drug-linker, or a ligand-linker-drug conjugate). The compound may contain at least one amino or carboxyl group, thereby allowing it to form an addition salt with a corresponding acid or base. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, salicylate, formate, benzoate, glutamate, methanesulfonate, sulfinate, benzenesulfonate, p-toluenesulfonate, potassium salt, sodium salt, and the like. Additionally, pharmaceutically acceptable salts have multiple charged atoms in their structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt include multiple counterions, e.g., a pharmaceutically acceptable salt has one or more charged atoms and / or one or more counterions.

[0030] Herein, depending on the intracellular drug release mechanism, the "linker" or "linker of an antibody-drug conjugate" can be divided into two types: non-cleavable linkers and cleavable linkers.

[0031] In antibody-drug conjugates containing non-cleavable linkers, the drug release mechanism is that after the conjugate binds to an antigen and is taken up by cells, the antibody is enzymatically digested in the lysosome, releasing the active molecule consisting of the small molecule drug, the linker, and the antibody amino acid residues. This structural change in the drug molecule does not reduce its cytotoxicity, but because the active molecule (amino acid residues) is charged, the drug cannot enter neighboring cells. Therefore, such active drugs cannot kill neighboring tumor cells that do not express the target antigen (antigen-negative cells) (the bystander effect) (Ducry et al., 2010, Bioconjugate Chem. 21:5-13).

[0032] The cleavable linker can be cleaved in the target cell to release the active drug (small molecule drug body). Cleavable linkers can be divided into two types: chemically labile linkers and enzymatically labile linkers.

[0033] Chemically labile linkers can be selectively cleaved due to differences in plasma and cytoplasmic properties, such as pH value, glutathione concentration, and the like.

[0034] pH-sensitive linkers are called acid-cleavable linkers. Such linkers are relatively stable in the neutral environment of blood (pH 7.3-7.5) but are hydrolyzed in the weakly acidic environment of endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0). First-generation antibody-drug conjugates often use such linkers (e.g., hydrazones, carbonates, acetals, and ketals). Because the plasma stability of acid-cleavable linkers is insufficient, antibody-drug conjugates containing such linkers typically have relatively short half-lives (2-3 days). This relatively short half-life limits the application of pH-sensitive linkers in next-generation antibody-drug conjugates to some extent.

[0035] Glutathione-sensitive linkers are also called disulfide bond linkers. Drug release is due to the concentration difference between the high concentration of glutathione (millimolar) in basal cells and the low concentration of glutathione (micromolar) in blood. This is particularly evident in tumor cells, where low oxygen content increases the activity of reductase enzymes, which in turn increases the concentration of glutathione. Disulfide bonds are thermodynamically stable, making them highly stable in plasma.

[0036] Enzymatically labile linkers (e.g., peptide linkers) allow for better control of drug release. Peptide linkers can be effectively cleaved by lysosomal proteases, such as cathepsin B or plasmin (the content of such enzymes is increased in some tumor tissues). Such peptide linkers are thought to be highly stable in the plasma circulation. This is because proteases are usually inactivated by inappropriate extracellular pH values ​​and serum protease inhibitors. Due to their high plasma stability, favorable intracellular cleavage selectivity, and efficacy, enzymatically labile linkers are widely used as cleavable linkers in antibody-drug conjugates. Typical enzymatically labile linkers include Val-Cit (vc), Phe-Lys, etc.

[0037] A suicide linker is generally interposed between a cleavable linker and an active drug, or is part of the cleavable linker itself. The mechanism of action of a suicide linker is that after the cleavable linker is cleaved under appropriate conditions, the suicide linker spontaneously rearranges its structure to release the active drug bound to it. Common suicide linkers include p-aminobenzyl alcohols (PAB) and β-glucuronides.

[0038] The present invention will be further described below with reference to specific examples. These examples are merely for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention. In the following examples, test methods for which specific conditions are not clearly indicated will adopt general conditions or conditions recommended by manufacturers. Unless otherwise specified, all percentages, ratios, proportions, or parts are by weight.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred implementation methods and materials described herein are merely exemplary.

[0040] Example 1: Synthesis of Compound 2 [ka] Compound 1 (exatecan mesylate, purchased) (40 mg, 75.3 mmol, 1.0 eq) and L-lactic acid (10 mg, 113.0 mmol, 1.5 eq) were dissolved in 5 mL of dry DMF, and PyBop (58.8 mg, 113.0 mmol, 1.5 eq) and DIEA (15.7 μL, 113.0 mmol, 1.5 eq) were added. After stirring at room temperature for 3 hours, the reaction was confirmed to be complete by TLC. Water was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 2 (30.9 mg, 81.1%). LC-MS:[M+H]+:508.2.1H NMR(400Mz,CDCl3 / CD3OD):0.91-0.94(3H,m),1.32-1.39(3H,m),1.71-1.83(2H,m),2.31(3H,s),2.78-3.02(2H,m),3.16-3.26(2H,m), 4.27-4.35(1H,m),4.81-4.92(1H,m),5.15-5.24(2H,m),5.49-5.76(2H,m),7.52(1H,d,J=12.0Hz),7.58(1H,s),7.75(1H,d,J=12.0Hz).

[0041] Example 2: Synthesis of Compound 4 [ka] A 500 mL single-neck flask was charged with the compound 3N-fluorenylmethoxycarbonyl-glycyl-glycine (10 g, 28.2 mmol, 1.0 eq), lead tetraacetate (17.5 g, 55.3 mmol, 1.4 eq), 200 mL dry tetrahydrofuran, and 67 mL toluene, stirred uniformly, heated to 85 °C under a nitrogen atmosphere, and reacted for 2.5 h. After confirming the completion of the reaction by TLC, 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 4 (8.7 g, 83.7%).

[0042] Example 3: Synthesis of Compound 5 [ka] Compound 3 (500 mg, 1.4 mmol, 1.0 eq), p-toluenesulfonic acid monohydrate (26 mg, 0.1 mmol, 0.1 eq), and 10 mL of THF were added to a 25 mL single-neck flask, stirred uniformly, cooled to 0 °C, and then L-benzyl lactate (1.2 g, 7.0 mmol, 5 eq) was slowly added. The mixture was then warmed to room temperature and reacted. After confirming the completion of the reaction by TLC, saturated NaHCO3 solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a reverse-phase column to give compound 5 (400 mg, 60.3%). 1H NMR(400Mz,CDCl3):1.39(3H,d,J=6.8Hz),3.78(2H,t,J=4.0Hz),4.17-4.27(2H,m),4.42(2H,d,J=4.0Hz),4.72-4.85(2H,m),5.11-5 .58(2H,m),5.43(1H,s),7.06(1H,t,J=8.0Hz),7.25-7.33(6H,m),7.38(2H,t,J=8.0Hz),7.57(2H,d,J=8.0Hz),7.75(2H,d,J=8.0Hz).

[0043] Example 4: Synthesis of Compound 6 [ka] Compound 5 (400 mg, 0.8 mmol, 1.0 eq) and 10 mL of DMF were added to a 25 mL single-neck flask and stirred uniformly. The mixture was then cooled to 0°C, and DBU (137 mg, 0.9 mmol, 1.1 eq) was slowly added. The mixture was then warmed to room temperature and reacted. After confirming the completion of the reaction by TLC, the mixture was concentrated to give crude compound 6 (550 mg). This was used in the next reaction without further purification.

[0044] Example 5: Synthesis of Compound 7 [ka] Z-Gly-Gly-Phe-OH (372 mg, 0.9 mmol, 1.1 eq), PyBOP (852 mg, 1.6 mmol, 2.0 eq), and 3 mL of DMF were added to a 25 mL single-neck flask and stirred at room temperature for 5 minutes. Then, crude compound 6 (550 mg) was added and reacted at room temperature. After completion of the reaction was confirmed by HPLC, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a reverse-phase column to obtain compound 7 (326 mg, 59.2%).

[0045] Example 6: Synthesis of Compound 8 [ka] Compound 7 (50 mg, 1.0 eq, 0.08 mmol), 5% Pd / C (50 mg), and 3 ml of DMF were added to a 25 ml single-neck flask and hydrogenated at room temperature. After confirming the completion of the reaction by HPLC, water was added, filtered, and the filtrate was concentrated to obtain crude compound 8 (52 mg). This was used in the next reaction without further purification.

[0046] Example 7: Synthesis of Compound 9 [ka] Compound 8 (52 mg), SMCC (23 mg, 0.07 mmol, 1.0 eq), DIEA (22.2 mg, 0.24 mmol, 2.5 eq), and 3 mL of DMF were added to a 25 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the reaction mixture was purified by preparative HPLC and lyophilized to give compound 9 (9.0 mg, 18.1%). MS: [MH] 655.1.

[0047] Example 8: Synthesis of Compound 11 [ka] Compound 9 (9.0 mg, 0.014 mmol, 1.0 eq), exatecan mesylate (6.6 mg, 0.014 mmol, 1.0 eq), PyBOP (14.3 mg, 0.028 mmol, 2.0 eq), DIEA (6.2 mg, 0.048 mmol, 3.5 eq), and 0.5 mL DMF were added to a 25 mL single-neck flask and reacted at room temperature. After confirming completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to give compound 11 (7.0 mg, 48.3%). TOF: [M+Na]+ 1096.42.

[0048] Example 9: Synthesis of Compounds 12 and 13 [ka] Compound 1 (exatecan mesylate) (40 mg, 75.3 mmol, 1.0 eq) and trifluorolactic acid (16.3 mg, 113.0 mmol, 1.5 eq) were dissolved in 5 mL of dry DMF, and PyBop (58.8 mg, 113.0 mmol, 1.5 eq) and DIEA (15.7 μL, 113.0 mmol, 1.5 eq) were added. After stirring at room temperature for 3 hours, the reaction was confirmed to be complete by TLC. Water was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 12 (13.5 mg, 32%). LC-MS:[M+H]+:562.2.1H NMR(400Mz,CDCl3 / CD3OD):0.91-0.95(3H,m),1.78-1.84(2H,m),2.34(3H,s),3.04-3.14(2H,m),3.27-3.32(2H,m),4 .42-4.47(1H,m),5.08-5.20(3H,m),5.41-5.58(2H,m),7.23-7.25(1H,m),7.52-7.55(1H,m);Compound 13(15.5mg,36.7%). LC-MS:[M+H]+:562.2.1H NMR(400Mz,CDCl3 / CD3OD):0.90-1.00(3H,m),1.74-1.89(2H,m),2.34(3H,s),3.01-3.09(2H,m),3.32-3. 38(2H,m),4.65-4.71(1H,m),4.89-4.96(1H,m),5.17-5.30(2H,m),5.55-5.65(2H,m),7.53-7.61(2H,m).

[0049] Example 10: Synthesis of Compound 14 [ka] Trifluorolactic acid (3.5 g, 24.3 mmol, 1.0 eq) and K2CO3 (5.0 g, 36.5 mmol, 1.5 eq) were dissolved in 35 mL of dry DMF, and benzyl bromide (5.0 g, 29.2 mmol, 1.2 eq) was added dropwise in an ice bath under a nitrogen atmosphere. The mixture was then warmed to room temperature and reacted for 5 hours. After completion of the reaction was confirmed by TLC, water was added to quench the reaction, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 14 (3.14 g, 55%). 1H NMR (400Mz, DMSO): 4.91-4.94 (1H, m), 5.25 (2H, s), 7.17-7.19 (1H, d), 7.39 (5H, s).

[0050] Example 11: Synthesis of Compound 15 [ka] Compound 4 (1.45 g, 3.9 mmol, 1.0 eq), compound 14 (1.84 g, 7.8 mmol, 2.0 eq), Zn(OAc) (1.44 g, 7.86 mmol, 2.0 eq), and 25 mL of Tol were added to a 50 mL single-neck flask and stirred uniformly under a nitrogen atmosphere. The mixture was then heated to 100 °C and reacted for 5.5 h. After confirming the presence of a clear product spot by TLC, the mixture was filtered and the filtrate was concentrated to give a yellow oil (4.0 g). The crude product was purified by column chromatography to give compound 15 (0.99 g, 46%). 1H NMR(400Mz,CDCl3):3.68-3.83(2H,m),4.20-4.23(1H,m),4.49(2H,d,J=8.0Hz),4.73-4.78(1H,m),4.89-5.00(2H,m),5.1 9(1H,s),5.25(2H,s),7.11(1H,s,),7.29-7.35(7H,m),7.43(2H,t,J=8.0Hz),7.59(2H,d,J=8.0Hz),7.79(2H,d,J=8.0Hz).

[0051] Example 12: Synthesis of Compound 16 [ka] Compound 15 (990 mg, 1.8 mmol, 1.0 eq) and 10 mL of DMF were added to a 25 mL single-neck flask, stirred uniformly, and then cooled to 0° C. DBU (335 mg, 2.2 mmol, 1.2 eq) was slowly added under a nitrogen atmosphere, and the reaction was continued for 30 minutes at 0° C. After confirming the completion of the reaction of the raw materials by TLC, the reaction solution was directly used in the next reaction.

[0052] Example 13: Synthesis of Compound 17 [ka] Z-Gly-Gly-Phe-OH (909 mg, 2.2 mmol, 1.2 eq), PyBOP (1.4 g, 2.7 mmol, 1.5 eq), and 10 mL of DMF were added to a 50 mL single-neck flask, and DIEA was added dropwise in an ice bath. The reaction was continued for 10 minutes under a nitrogen atmosphere. The reaction solution of compound 16 was slowly added to the reaction solution in an ice bath, and after the dropwise addition, the mixture was warmed to room temperature and reacted for 1.5 hours. After the completion of the reaction was confirmed by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 17 (0.91 g, 71%).

[0053] Example 14: Synthesis of Compound 18 [ka] Compound 17 (85 mg, 1.0 eq, 0.12 mmol), 5% Pd / C (85 mg), and 6 mL DMF were added to a 25 mL single-neck flask and hydrogenated at room temperature for 1 hour. After confirming the completion of the reaction with the raw materials by HPLC, the reaction mixture was filtered, and the filtrate was used directly in the next reaction.

[0054] Example 15: Synthesis of Compound 19 [ka] The reaction mixture containing compound 18 was filtered into a 25 mL single-neck flask, and SMCC (80 mg, 0.24 mmol, 2.0 eq) and DIEA (62 mg, 0.48 mmol, 4.0 eq) were added in this order under an ice bath. The mixture was then heated to room temperature and reacted for 1 hour. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to give compound 19 (66 mg, 78%). MS: [MH] 709.2.

[0055] Example 16: Synthesis of Compounds 20 and 21 [ka] Compound 19 (10 mg, 14 μmol, 1.0 eq), compound 1 (9 mg, 21 μmol, 1.5 eq), and PyBop (14.6 mg, 28 mmol, 2.0 eq) were dissolved in dry DMF (0.5 mL), and DIEA (5 μL, 28 μmol, 2.0 eq) was added under an ice bath and a nitrogen atmosphere. The mixture was then warmed to room temperature and reacted for 1 hour. After confirming the completion of the reaction of starting compound 19 by HPLC, the reaction mixture was purified by preparative HPLC to give compound 20 (2.77 mg, 17.5%) (LC-MS: [M+H]: 1128.0) and compound 21 (3.92 mg, 24.8%) (LC-MS: [M+H]: 1128.0), respectively.

[0056] Example 17: Synthesis of Compound 22 [ka] The reaction mixture (0.15 mmol, 1.0 eq) of compound 18 was filtered into a 25 mL single-neck flask, and MC (93 mg, 0.3 mmol, 2.0 eq) and DIEA (78 mg, 0.6 mmol, 4.0 eq) were added in that order under an ice bath. The mixture was then heated to room temperature and reacted for 1 hour. After completion of the reaction was confirmed by HPLC, the mixture was purified by preparative HPLC and lyophilized to give compound 22 (90 mg, 86%). MS: [MH] 683.2.

[0057] Example 18: Synthesis of Compounds 23 and 24 [ka] Compound 22 (15 mg, 21.9 μmol, 1.0 eq), compound 1 (14.3 mg, 32.8 μmol, 1.5 eq), and PyBop (22.8 mg, 43.8 mmol, 2.0 eq) were dissolved in dry DMF (0.8 mL), and DIEA (7.3 μL, 43.8 μmol, 2.0 eq) was added in an ice bath. After adding DIEA under a nitrogen atmosphere, the mixture was warmed to room temperature and reacted for 1 hour. After confirming the completion of the reaction of starting compound 22 by HPLC, the reaction mixture was purified directly by preparative HPLC to give compound 23 (6.01 mg, 25%) (LC-MS: [M + H] + : 1102.0) and compound 24 (5.57 mg, 23.2%) (LC-MS: [M + H] + : 1102.0).

[0058] Example 19: Synthesis of Compound 25 [ka] Mandelic acid (42 mg, 0.09 mmol, 1.1 eq), exatecan (35 mg, 0.08 mmol, 1.0 eq), PyBOP (84 mg, 0.16 mmol, 2.0 eq), DIEA (36.4 mg, 0.28 mmol, 3.5 eq) and 1 mL DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 25 (15.0 mg, 32.6%). 1H NMR(CDCl3,400Mz)δ7.70(d,1H,J=8.0Hz),7.64(s,1H),5.64-5.75(m,2 H),5.48-5.38(m,1H),5.29-5.21(m,1H),5.19-5.11(m,1H),3.37-3.11( m,2H),2.55-2.38(m,4H),2.32-2.15(m,2H),2.08-1.99(m,1H),1.94-1. 85(m,4H),1.33-1.24(m,4H),1.05(t,3H,J=7.2Hz);LC-MS:[M+H]548.4.

[0059] Example 20: Synthesis of Compound 26 [ka] D-Lactic acid (11.2 mg, 0.08 mmol, 1.1 eq), exatecan (30.0 mg, 0.07 mmol, 1.0 eq), PyBOP (119.5 mg, 0.14 mmol, 2.0 eq), DIEA (31.2 mg, 0.25 mmol, 3.5 eq), and 1 mL of DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 26 (7.2 mg, 20.6%). 1H NMR(CDCl3,400Mz)δ7.75(d,1H,J=10.4Hz),7.70(s,1H),5.75-5.63(m,2 H),5.46-5.38(m,1H),5.30-5.16(m,2H),4.50-4.40(m,1H),3.34-3.13( m,2H),2.50-2.36(m,3H),2.34-2.21(m,1H),2.05-2.02(s,1H),1.96-1. 84(m,2H),1.35-1.23(m,3H),1.06(t,3H,J=4.0Hz);LC-MS:[M+H]508.3.

[0060] Example 21: Synthesis of Compound 27 [ka] 2-Methyllactic acid (10.5 mg, 0.10 mmol, 1.1 eq), exatecan (40 mg, 0.09 mmol, 1.0 eq), PyBOP (95.6 mg, 0.18 mmol, 2.0 eq), DIEA (41.4 mg, 0.32 mmol, 3.5 eq), and 1 mL of DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 27 (10.0 mg, 20.8%). 1H NMR(CDCl3,400Mz)δ7.68(d,1H,J=24Hz),7.63(s,1H),5.77-5.59(m,2H),5.48-5.39(m,1H),5.30-5.22(m,1H),5.19-5.11(m,1H), 3.33-3.10(m,2H),2.24(s,3H),1.71-1.63(m,2H),1.58-1.52(m,2H),1.40-1.20(m,6H),1.05(t,3H,J=7.2Hz);LC-MS:[M+H]522.2.

[0061] Example 22: Synthesis of Compound 28 [ka] R)-(-)-Mandelic acid (15.2 mg, 0.10 mmol, 1.1 eq), exatecan (40 mg, 0.09 mmol, 1.0 eq), PyBOP (95.6 mg, 0.18 mmol, 2.0 eq), DIEA (41.4 mg, 0.32 mmol, 3.5 eq), and 1 mL of DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 28 (12.2 mg, 23.3%). 1H NMR(CDCl3,400Mz)δ7.76(d,1H,J=8.0Hz),7.69(s,1H),7.53-7.35(m,5H),5.77-5.70(m,1H),5.65-5.55(m,1H),5.34-5.20(m,4H),3. 32-3.31(m,2H),2.47-2.40(m,3H),2.30-2.27(m,1H),2.05-2.02(s,1H),1.93-1.89(m,3H),1.07(t,3H,J=8.0Hz);LC-MS:[M+H]570.2.

[0062] Example 23: Synthesis of Compound 29 [ka] 3,5-Difluoromandelic acid (23.7 mg, 0.13 mmol, 1.1 eq), exatecan (50 mg, 0.11 mmol, 1.0 eq), PyBOP (119.5 mg, 0.23 mmol, 2.0 eq), DIEA (37.1 mg, 0.29 mmol, 2.5 eq) and 1 mL of DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 29 (13.5 mg, 19.4%). 1H NMR(DMSO,400Mz)δ8.76(d,1H,J=8.4Hz),7.81(d,1H,J=10.8Hz),7.31(s,1H),7.27-7.07(m,4H),5.54-5.47(m,1H),5.43(s,2H),5.2 0-5.03(m,4H),3.20-3.09(m,2H),2.43-2.38(m,3H),2.17-2.09(m,1H),1.96-1.79(m,3H),0.88(t,3H,J=7.2Hz);LC-MS:[M+H]606.2.

[0063] Example 24: Synthesis of Compound 30 [ka] 3,5-Difluoromandelic acid (22.5 mg, 0.13 mmol, 1.1 eq), exatecan (50 mg, 0.11 mmol, 1.0 eq), PyBOP (119.5 mg, 0.23 mmol, 2.0 eq), DIEA (37.1 mg, 0.29 mmol, 2.5 eq), and 1 mL of DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 30 (8.2 mg, 11.7%). NMR(DMSO,400Mz)δ8.60(d,1H,J=8.4Hz),7.79(d,1H,J=11.2Hz),7.31(s,1H),7.0 2-6.90(m,2H),6.90-6.72(m,1H),6.05-5.93(m,2H),5.52-5.40(m,2H),5.19-5.09 (m,1H),5.09-4.92(m,2H),2.98-2.85(m,2H),2.22-2.14(m,3H),1.94-1.83(m,1H ),1.75-1.59(m,1H),1.53-1.45(m,2H),0.66(t,3H,J=7.2Hz);LC-MS:[M+H]614.2.

[0064] Example 25: Synthesis of Compound 31 [ka] S-2-hydroxybutyric acid (16.3 mg, 0.16 mmol, 1.1 eq), exatecan (68.0 mg, 0.16 mmol, 1.0 eq), HATU (59.4 mg, 0.16 mmol, 1.0 eq), DIEA (50.5 mg, 0.39 mmol, 2.5 eq), and 1 mL of DMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the mixture was purified by preparative HPLC and lyophilized to obtain compound 31 (16.3 mg, 20.1%). 1H NMR(DMSO,400Mz)δ8.36(d,1H,J=8.8Hz),7.79(d,1H,J=11.2Hz),7.31(s,1 H),6.53(s,1H),5.60-5.52(m,1H),5.46-5.40(m,3H),5.24-5.17(m,2H),3. 23-3.09(m,2H),2.45-2.38(m,3H),2.28-2.08(m,2H),1.94-1.80(m,2H),1 .79-1.66(m,1H),1.66-1.55(m,1H),1.05-0.84(m,6H);LC-MS:[M+H]522.3.

[0065] Example 26: Cellular activity test of camptothecin drugs The following experiment was carried out to determine the cytotoxic activity of camptothecin drugs. Camptothecin drugs were added to culture media containing human tumor cells expressing A431, Fadu, and Bxpc-3 (EGFR-positive cells), and U87-MG and SW620 (negative control cells). After culturing the cells for 72 hours, cell viability was measured. In vitro experiments using cells were used to measure cell viability, cytotoxicity, and programmed cell death induced by the camptothecin drugs of the present invention.

[0066] The in vitro efficacy of camptothecin drugs was measured using a cell proliferation assay. CellTiter 96® Aqueous One Solution Cell Proliferation Assay is a commercially available product (Promega Corp., Madison, WI). The CellTiter 96® AQueous One Solution Cell Proliferation Assay(a) is a detection reagent for colorimetrically measuring viable cell counts in cell proliferation and cytotoxicity experiments. This reagent contains a novel tetrazole compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling agent (phenazine ethosulfate; PES). Due to its enhanced chemical stability, PES can be mixed with MTS to form a stable solution. This convenient "single-solution" mode is an improvement over the first-generation CellTiter 96® AQueous Assay, in which the electron coupling agent PMS used in the CellTiter 96® AQueous Assay is provided separately from the MTS solution. MTS (Owen's reagent) is bioreduced by cells to a colored formazan product, which can be directly dissolved in the culture medium (Figure 1). This conversion is likely accomplished under the action of NADPH or NADH produced by dehydrogenases in metabolically active cells. At the time of detection, a small amount of CellTiter 96® AQueous One Solution Reagent is added directly to the medium of a culture plate well, incubated for 1–4 hours, and absorbance values ​​at 490 nm are read using a microplate reader.

[0067] [ka]

[0068] The amount of formazan product detected at 490 nm is directly proportional to the number of viable cells in culture. Because the formazan product of MTS is soluble in tissue culture medium, the CellTiter 96® AQueous One Solution Assay requires fewer manipulation steps than the MTT or INT methods.

[0069] In this study, A431, Fadu, and Bxpc-3 (EGFR-positive cells) and U87-MG and SW620 (negative control cells) were used as a research system for in vitro drug efficacy detection. Cells were seeded at appropriate densities in 96-well plates, and camptothecin was administered 24 hours later. After 24 hours, camptothecin was diluted with detection medium (starting at 1 μM, followed by 5-fold dilutions, nine concentrations, with detection medium added to column 10 as a blank control). The diluted camptothecin was added to the corresponding cell wells and shaken at 550 rpm / min for 3 minutes using a microwell plate oscillator (model number: MX100-4A). After shaking, the plates were placed in a CO2 incubator and incubated for 3 days. After 3 days, 20 μl of MTS (Promega, G3581) was added to each well and incubated for 2 hours. The readings were then taken at 490 nM using a microplate reader (Molecular Device, model number: SpectraMAX190). The inhibitory effect of camptothecin drug on cell proliferation was evaluated by detecting the activity of dehydrogenase in mitochondria.

[0070] [Table 1]

[0071] SN38 is a typical highly active camptothecin drug and has been clinically proven in the IMMU-132 ADC. The present inventors have demonstrated through cellular activity experiments that the camptothecin derivatives described in the present invention exhibit cellular activity equivalent to or greater than that of SN38 in representative tumor cells, including Fadu, BXPC-3, A431, U87-MG, and SW620.

[0072] Example 27: General coupling method for preparing ADCs Antibody molecule C, which had a monomer ratio exceeding 95% after pre-purification using an ultrafiltration centrifuge tube, was exchanged into phosphate buffer at a concentration of 10 mg / ml. TCEP was added in an amount 20 times the moles of the antibody molecule, and the reaction was allowed to proceed at room temperature for 4 hours to cleave the disulfide bonds between the antibody chains. Payload was added in an amount 20 times the moles of the antibody molecule, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction, the mixture was exchanged into PBS using an ultrafiltration centrifuge tube with a 30 kDa molecular weight cutoff, and uncoupled payload was removed. The ADC sample after the exchange was filtered through a 0.22 μm sterile filter and stored. Coupling compounds 11, 20, 21, 23, and 24 were coupled to antibody molecule C using the general coupling method described in Example 27.

[0073] [Table 2]

[0074] Example 28: ADC antitumor cell activity test Similar to the method for testing the cellular activity of camptothecin drugs, in this study, A431, Fadu, Bxpc-3 (antigen-positive expressing cells), and SW620 (antigen-negative control cells) were used as the in vitro drug efficacy testing system. Cells were seeded at appropriate densities into 96-well plates, and 24 hours later, the ADC drug was administered. After 24 hours, the ADC drug was diluted with detection medium (starting at 1 μM, followed by 5-fold dilutions, nine concentrations, with detection medium added to column 10 as a blank control). The diluted ADC drug was added to the corresponding cell wells and shaken at 550 rpm / min using a microwell plate oscillator (model number: MX100-4A) for 3 minutes. After shaking, the cells were placed in a CO2 incubator and incubated for 3 days. After 3 days, 20 μl of MTS (Promega, G3581) was added to each well, and the incubation time was 2 hours. The readings were then taken at 490 nM using a microplate reader (Molecular Device, model number: SpectraMAX190). The inhibitory effect of ADC drugs on cell proliferation was evaluated by detecting the activity of dehydrogenase in mitochondria.

[0075] [Table 3]

[0076] As is clear from the above ADC cellular activity tests, the camptothecin drugs described in the present invention, after being coupled to antibodies via linker L, exhibit good antitumor activity in many antigen-positive tumor cell lines, and have great clinical value.

[0077] Example 29: In vivo efficacy testing of ADCs In the present invention, an A431 tumor-bearing mouse model was constructed to evaluate the in vivo efficacy of ADC. 6 A431 cells were injected subcutaneously into the right flank of 4-6 week-old BALB / c nude mice, and the average size of the mouse tumors was 140-150 mm. 3 When the tumors reached a growth stage, they were randomly divided into groups of 5 mice per group and intravenously administered a blank control (buffer blank) and antibody-drug conjugate C-11 at a dose of 10 mg / kg on days 0, 7, 14, and 21, respectively. Tumor volume measurements are shown as the mean tumor volume at the time of measurement ± SE. Changes in mouse weight were recorded to observe the early toxicity of the ADC drug in vivo.

[0078] [Table 4] [Table 5]

[0079] The above-described in vivo efficacy test of the ADC in mice demonstrated that the camptothecin drug described in the present invention, after being coupled to an antibody via linker L, exhibited clear antitumor activity in tumor-bearing mice, with the mean tumor volume being significantly smaller than that of the blank control. The mouse weight did not change significantly during the administration period, and no mice died within the group. Therefore, the camptothecin drug described in the present invention has good safety.

Claims

1. A camptothecin-class compound represented by formula I or a pharmaceutically acceptable salt thereof. 【Chemistry 1】

2. An antitumor drug comprising the camptothecin-class compound or a pharmaceutically acceptable salt thereof according to claim 1, An anti-tumor drug for treating solid or hematological tumors, including lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, lung cancer or esophageal cancer.

3. An antibody-drug conjugate of formula II, which is configured to exert its therapeutic effect by releasing the drug moiety D after reaching the target cell. 【Chemistry 2】 In Formula II, Ab is an antibody, antibody fragment, or protein; L is an optional linker attached at one end to Ab and at the other end to a drug moiety, D; D is selected from the camptothecin-class compounds or pharmaceutically acceptable salts thereof according to claim 1, and is bonded to L via the hydroxyl group of D; m is an integer selected from 1 to 20.

4. The antibody-drug conjugate of claim 3 , wherein the antibody portion of the antibody-drug conjugate specifically binds to a target cell of cancer or an autoimmune disease.

5. A pharmaceutical composition comprising the antibody-drug conjugate of claim 3 or 4, A pharmaceutical composition for treating solid tumors or hematological tumors, including lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

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