Camptothecin-type pharmaceuticals and their antibody conjugates

Abstract

We provide camptothecin-based pharmaceuticals and their antibody conjugates. [Solution] A compound of the following formula I and its antibody complex are provided. JPEG2026086826000042.jpg62170 (In formula I, R1 and R2 are independently a C1-C3 alkyl group, -H, -CF3, aryl group, heteroaryl group, etc.)

Description

[Technical Field]

[0001] This invention relates to camptothecin-based pharmaceuticals and antibody-drug conjugates used as antitumor agents. [Background technology]

[0002] Antibody-drug conjugates (ADCs), as novel targeted therapies, typically consist of three parts: an antibody or antibody-like ligand, a small molecule drug, and a linker that binds the ligand to the drug. Antibody-drug conjugates achieve their therapeutic objectives by utilizing the specific recognition of antibodies against antigens to deliver drug molecules near target cells and effectively release them. In August 2011, the U.S. Food and Drug Administration (FDA) approved Adecteis, a novel ADC for the treatment of Hodgkin lymphoma and relapsing large cell lymphoma (ALCL), developed by Seattle Genetics. TM The drug has been approved for market release. Its safety and efficacy have been clinically demonstrated.

[0003] Camptothecin-type drugs (irinotecan, exatecan, SN38, etc.) are known to exert their antitumor effects by inhibiting DNA topoisomerase I as small molecule compounds with antitumor properties. Many camptothecin-type drugs are widely used clinically, with the main indications being bone cancer, prostate cancer, breast cancer, and pancreatic cancer. Unlike irinotecan, which is currently used clinically, exatecan does not require enzyme activation. Furthermore, compared to SN-38, the pharmacodynamic component of irinotecan, and topothecan, which is used clinically, exatecan exhibits a stronger inhibitory effect on topoisomerase I and shows a stronger killing effect against various cancer cells in vitro. In particular, it is effective against cancer cells that show resistance to SN-38 through the expression of P-glycoprotein. Exatecan has not yet been successfully marketed as a monotherapy drug, which is presumably due to its narrow therapeutic concentration range caused by its high cellular activity.

[0004] The advantages of antibody-drug conjugates (ADCs) lie in their improved water solubility, enhanced targeting capabilities, the ability of antibodies to specifically bind to antigens, deliver the drug to the vicinity of target cells, and release the drug near the target cells, thereby effectively killing tumor cells while reducing toxicity and side effects. Camptothecin-based drugs have considerable potential for application in ADCs.

[0005] The problem that this invention aims to solve is to develop superior antitumor camptothecin compounds, improve the safety and efficacy of antitumor small molecule compounds in ADC drugs, and obtain antitumor drugs with excellent therapeutic effects.

[0006] Based on a comprehensive understanding of ADC-class pharmaceuticals, the inventors designed a series of active derivatives of antitumor camptothecin and experimentally demonstrated that these antitumor small molecule compounds exhibited higher antitumor activity in cell experiments. [Overview of the project]

[0007] The present invention aims to provide camptothecin derivatives and antibody-drug conjugates having superior antitumor effects.

[0008] Camptothecin compounds represented by formula I or pharmaceutically acceptable salts thereof. [ka] In formula I, R1 and R2 are each independently selected from the group consisting of C1-C3 alkyl groups, substituted alkyl groups, -H, -CF3, aryl groups, substituted aryl groups, and heteroaryl groups, or R1 and R2 together with the carbon atoms to which they are bonded constitute cyclobutane, cyclopentane, or cyclohexane, provided 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 to them constitute cyclobutane, cyclopentane, or cyclohexane. [ka] In structural formula (a), R2 is independently -(CH2)n 1 -CH3, -CF3, aryl group, heteroaryl group, or 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, aryl group, heteroaryl group, or substituted aryl group, provided that n 1 = 0, 1, or 2. In structural formula (c), R1 and R2, together with the carbon atoms bonded to them, constitute 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, aryl group, heteroaryl group, or substituted aryl group, provided that n 1 = 0, 1, or 2. [ka] The carbon bonded to R2 has two conformations: R-form and S-form. In structural formula (a-1), the carbon bonded to R2 is the R-isomer. In structural formula (a-2), the carbon bonded to R2 is the S-isomer.

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

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

[0013] In another aspect of the present invention, there is provided an antibody-drug conjugate represented by Formula II, which is configured to exert a drug effect by releasing a drug moiety D after reaching a target cell. [Chemical formula] In Formula II, Ab is an antibody, an antibody fragment or a protein, L is an arbitrary linker having one end bound to Ab and the other end bound to the drug moiety D, D is selected from the camptothecin compounds or pharmaceutically acceptable salts thereof according to any one of claims 1 to 6, and is bound to L via a hydroxyl group of D, m is selected from integers 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-, -(PEG)n2-, provided that n1 is selected from integers of 1 - 3 and n2 is selected from integers of 1 - 20.

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

[0016] Preferably, the antibody-drug conjugate or salt thereof is an antitumor or anticancer agent and is applied to the treatment of solid tumors and hematological malignancies, 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. [Modes for carrying out the invention]

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

[0018] The term "alkylene group" refers to a divalent linear saturated hydrocarbon group having 1 to 20 carbon atoms, including groups with 1 to 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2-CH2-), n-propylene, n-butylene, n-pentylene, and n-hexylene groups. Unless otherwise specified, the term "aryl group" refers to a polyvalent unsaturated, generally aromatic hydrocarbon group, including monocyclic, fused, or covalently bonded polycyclic (at most tricyclic) groups. The term "heteroaryl group" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, or S, wherein the N and S atoms may be optionally oxidized, and the N atom may optionally be quaternized. Heteroaryl groups can be bonded to other parts of the molecule via heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and diphenyl groups. Examples of heteroaryl groups include pyridyl, pyridadinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnoline, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisozolyl, isobenzofuranyl, isoindolyl, indadinyl, benzotriazinyl, and thienopyridine. This includes, but is not limited to, groups such as thienopyrimidinyl, pyridopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuran, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl. When described as "substitution," the above aromatic ring and heteroaromatic ring substituents are selected from the following acceptable substituents.

[0019] Unless otherwise specified, the substituent of the alkyl group may be a substituent selected from the group consisting of - halogen, - OR', - NR'R'', - SR', - SiR'R''R''', - OC(O)R', - C(O)R', - CO2R', - CONR'R'', - OC(O)NR'R'', - NR''C(O)R', - NR'-C(O)NR''R''', - NR''C(O)2R', - NH-C(NH2)=NH, - NR'C(NH2)=NH, - NH-C(NH2)=NR', - S(O)R', - S(O)2R', - S(O)2NR'R'', - NR'S(O)2R'', - CN and - NO2. The number of substituents is from 0 to (2m'+1), where m' is the total number of carbon atoms in this group. R', R'' and R''' are each independently hydrogen, unsubstituted C 1-8 alkyl group, unsubstituted aryl group, aryl group 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 alkyl group. When R' and R'' are bonded to the same nitrogen atom, they can form a 3-, 4-, 5-, 6- or 7-membered ring together with this nitrogen atom. For example, - NR'R'' includes 1-pyrrolidinyl group and 4-morpholinyl group.

[0020] The "derivative" of the compound described in this specification refers to a substance having a chemical structure similar to this compound, but containing at least one chemical group not present in this compound and / or lacking at least one chemical group present in this compound. The compound corresponding to the derivative is called the "parent" compound. Usually, a "derivative" can be produced from the parent compound by one or more chemical reaction steps.

[0021] L-ligand A ligand unit is a targeting agent that specifically binds to a target site. The ligand can specifically bind to a cellular component, or bind to a cellular component, or to another target molecule of interest. The target site or target is typically located on the surface of a cell. In some embodiments, the action of the ligand unit is to deliver the drug unit to a specific population of target cells that interact with the ligand unit. Ligands include, but are not limited to, proteins, polypeptides, peptides, and non-protein molecules such as sugars. Examples of suitable ligand units include antibodies, such as full-length (complete) antibodies, and their antigen-binding fragments. In embodiments where the ligand unit is a non-antibody targeting reagent, the ligand unit may be a peptide, polypeptide, or a 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, a linker is covalently bonded to the sulfur atom of the ligand. In some embodiments, the sulfur atom is the sulfur atom of a cysteine ​​residue, forming an interchain disulfide bond of the antibody. In another embodiment, the sulfur atom is the sulfur atom of a cysteine ​​residue introduced into the ligand unit, forming an interchain disulfide bond of the antibody. In yet another embodiment, 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 yet another embodiment, the sulfur atom bound to the linker is selected from a cysteine ​​residue that forms an interchain disulfide bond of the antibody, or a cysteine ​​residue introduced into the ligand unit (e.g., by site-directed mutagenesis or chemical reaction). In some embodiments, the EU index in the Kabat (Kabat EA et al., (1991)) "Sequences of proteins of Immunological Interest" (Sequences of proteins of Immunological Interest), fifth edition, NIH publication 91-3242) numbering system is followed.

[0022] In this specification, “antibody” or “antibody unit” includes any part of an antibody structure within the scope to which it belongs. This unit can bind to, reactively associate with, or compound with a receptor, an antigen, or other receptor units of a targeted cell population. The antibody may be any protein or protein molecule that can bind to, compound with, or react with a portion of a cell population that is being treated or biologically modified.

[0023] In the present invention, it is preferable that the antibody constituting the antibody-drug conjugate has its intrinsic wild-state antigen-binding ability. Therefore, it is preferable that the antibody of the present invention binds specifically to the antigen. Such antigens include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules related to 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). Tumor-associated factors may also be cluster differentiation factors (e.g., CD proteins).

[0024] The antibodies used in the antibody-drug conjugates described in this invention 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 manufactured according to antibody manufacturing methods and information known in the art. To develop effective cellular-level targets usable for the diagnosis and treatment of cancer, researchers are looking for 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 unexpressed on the surface of one or more non-cancer cells. Typically, such tumor-associated polypeptides are overexpressed on the surface of cancer cells more than on the surface of non-cancer cells. Such tumor-associated factors have been shown to significantly improve the specific targeting characteristics of antibody-based cancer therapy.

[0025] Tumor-associated antigens include, but are not limited to, the tumor-associated antigens (1)-(36) listed below. For convenience, antigen-associated information well known in the art will be referred to by name, alternative name, or gene bank 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 sequences identified in the references, or possess biological properties and characteristics that are in complete agreement with the sequences of tumor-associated antigens described in the references.

[0026] The term "suppression" or "suppression of" refers to reducing or completely blocking a detectable amount.

[0027] The term "cancer" refers to a physiological condition or disease characterized by uncontrolled cell proliferation. "Tumor" includes cancer cells.

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

[0029] As used herein, "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 complex). This compound may contain at least one amino group or carboxyl group, which can form an addition salt with the corresponding acid or base. Exemplary salts include, but are not limited to, sulfates, trifluoroacetates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonate tartrates, ascorbic acid, salicylates, formates, benzoates, glutamates, methanesulfons, sulfinates, benzenesulfons, p-toluenesulfons, potassium salts, sodium salts, etc. Furthermore, the structure of a pharmaceutically acceptable salt may have multiple charged atoms. Examples of pharmaceutically acceptable salts that contain multiple charged atoms include those containing multiple counterions. For example, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

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

[0031] In antibody-drug conjugates containing a non-cleavable linker, the drug release mechanism involves the conjugate binding to an antigen and being taken up by a cell. Afterward, the antibody is enzymatically digested in lysosomes, releasing an active molecule consisting of a small-molecule drug, a linker, and antibody amino acid residues. While this structural change of the drug molecule does not reduce its cytotoxicity, the active molecule (amino acid residues) is charged, preventing the drug from entering adjacent cells. Therefore, such active drugs cannot kill tumor cells (antigen-negative cells) that do not express the adjacent target antigen (bystander effect) (Ducry et al., 2010, Bioconjugate Chem. 21:5-13).

[0032] Cleavable linkers can be cleaved within target cells to release active drugs (small molecule drugs). Cleavable linkers can be divided into two types: chemically unstable linkers and enzymatically unstable linkers.

[0033] Chemically unstable linkers can be selectively cleaved depending on differences in plasma and cytoplasmic properties. Such properties include pH levels and glutathione concentrations.

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

[0035] Glutathione-sensitive linkers are also called disulfide linkers. Drug release is due to the concentration difference between high concentrations of glutathione (millimole level) in basal cells and low concentrations of glutathione (micromolar level) in the blood. This is particularly pronounced in tumor cells. In tumor cells, the low oxygen content increases the activity of reductases, which in turn increases the concentration of glutathione. Disulfide bonds are thermodynamically stable and therefore highly stable in plasma.

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

[0037] A suicide linker is generally either interlocked between a cleavable linker and the 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 and releases the active drug bound to it. Common suicide linkers include p-aminobenzyl alcohols (PABs) and β-glucuronides, among others.

[0038] The present invention will be further described below with reference to specific examples. These examples are for illustrative purposes only and do not limit the scope of the present invention. In the following examples, test methods for which specific conditions are not explicitly stated shall adopt general conditions or conditions recommended by the manufacturer. Unless otherwise specified, all percentages, proportions, ratios or parts are given by weight.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those well known to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred methods and materials described herein are illustrative only.

[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, and the reaction was quenched with water. The mixture was extracted with dichloromethane (10 mL x 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 obtain 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] In a 500 mL single-necked flask, the compounds 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 of dry tetrahydrofuran, and 67 mL of toluene were added and mixed uniformly. The mixture was heated to 85 °C under a nitrogen atmosphere and reacted for 2.5 hours. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 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 one-neck flask and mixed uniformly. After cooling to 0°C, benzyl L-lactate (1.2 g, 7.0 mmol, 5 eq) was slowly added, and the mixture was then heated to room temperature to allow the reaction to proceed. After confirming the completion of the reaction by TLC, saturated NaHCO3 solution was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse-phase column chromatography to obtain 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 mixed uniformly. After cooling to 0°C, DBU (137 mg, 0.9 mmol, 1.1 eq) was slowly added, and the mixture was heated to room temperature to allow the reaction to proceed. After confirming the completion of the reaction by TLC, the mixture was concentrated to obtain the crude product of Compound 6 (550 mg). This product was used directly in the next reaction without purification.

[0044] Example 5: Synthesis of Compound 7 [ka] In a 25 mL single-neck flask, 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 and stirred at room temperature for 5 minutes. Then, crude compound 6 (550 mg) was added and the mixture was reacted at room temperature. After confirming the completion of the reaction by HPLC, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse-phase column chromatography 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 the hydrogenation reaction was carried out at room temperature. After confirming the completion of the reaction by HPLC, water was added and the mixture was filtered. The filtrate was concentrated to obtain the crude product of compound 8 (52 mg). This was used directly in the next reaction without 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. The mixture was allowed to react at room temperature, and after confirming the completion of the reaction by HPLC, it was purified by preparative HPLC and lyophilized to obtain 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 LDMF were added to a 25 mL one-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC and lyophilized to obtain 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, and the reaction was quenched with water. The mixture was extracted with dichloromethane (10 mL x 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 obtain 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. Benzyl bromide (5.0 g, 29.2 mmol, 1.2 eq) was added dropwise under an ice bath and a nitrogen atmosphere. The mixture was then heated to room temperature and allowed to react for 5 hours. After confirming the completion of the reaction 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 obtain 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)2 (1.44 g, 7.86 mmol, 2.0 eq), and 25 mL of Tol were added to a 50 mL single-neck flask. The mixture was then homogenized under a nitrogen atmosphere and stirred, followed by heating to 100 °C and reaction for 5.5 hours. After confirming clear product spots by TLC, the mixture was filtered, and the filtrate was concentrated to obtain a yellow oily substance (4.0 g). The crude product was purified by column chromatography to obtain 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 and mixed uniformly. After cooling to 0°C, DBU (335 mg, 2.2 mmol, 1.2 eq) was slowly added under a nitrogen atmosphere, and the reaction was continued at 0°C for 30 minutes. After confirming the completion of the reaction of the starting materials by TLC, the reaction mixture was used directly for the next reaction.

[0052] Example 13: Synthesis of Compound 17 [ka] In a 50 mL single-neck flask, 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. DIEA was added dropwise under an ice bath, and the mixture was continued to react under a nitrogen atmosphere for 10 minutes. Under an ice bath, the reaction solution of compound 16 was slowly added dropwise, and the mixture was heated to room temperature and reacted for 1.5 hours. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 17 (0.91 g, 71%) was obtained.

[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 of LDMF were added to a 25 mL single-neck flask, and the hydrogenation reaction was carried out at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was filtered, and the filtrate was used directly for the next reaction.

[0054] Example 15: Synthesis of Compound 19 [ka] The reaction solution of compound 18 was filtered into a 25 mL one-neck flask. Under ice bath conditions, SMCC (80 mg, 0.24 mmol, 2.0 eq) and DIEA (62 mg, 0.48 mmol, 4.0 eq) were added in that order, followed by addition under a nitrogen atmosphere. The mixture was then heated to room temperature and reacted for 1 hour. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, freeze-dried, and compound 19 (66 mg, 78%) was obtained. MS: [MH] 709.2.

[0055] Example 16: Synthesis of compounds 20 and 21 [ka] Compound 19 (10 mg, 14 µl, 1.0 eq), Compound 1 (9 mg, 21 µl, 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 µl, 2.0 eq) was added under an ice bath. After adding the mixture under a nitrogen atmosphere, the temperature was raised to room temperature and the reaction was allowed to proceed for 1 hour. After confirming that the reaction of starting compound 19 was complete by HPLC, the reaction mixture was purified by preparative HPLC to obtain 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 solution of compound 18 (0.15 mmol, 1.0 eq) was filtered into a 25 mL one-neck flask. Under ice bath conditions, MC (93 mg, 0.3 mmol, 2.0 eq) and DIEA (78 mg, 0.6 mmol, 4.0 eq) were added in that order, followed by addition under a nitrogen atmosphere. The mixture was then heated to room temperature and reacted for 1 hour. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 22 (90 mg, 86%) was obtained. MS: [MH] 683.2.

[0057] Example 18: Synthesis of compounds 23 and 24 [ka] Compound 22 (15 mg, 21.9 ml, 1.0 eq), Compound 1 (14.3 mg, 32.8 ml, 1.5 eq), and PyBop (22.8 mg, 43.8 mmol, 2.0 eq) were dissolved in dry DMF (0.8 mL). DIEA (7.3 μL, 43.8 ml, 2.0 eq) was added under an ice bath, followed by addition under a nitrogen atmosphere. The mixture was then heated to room temperature and reacted for 1 hour. After confirming that the reaction of starting compound 22 was complete by HPLC, the reaction solution was purified by preparative HPLC to obtain 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 of LDMF were added to a 5 mL single-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 25 (15.0 mg, 32.6%) was obtained. 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] In a 5 mL single-neck flask, 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 and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 26 (7.2 mg, 20.6%) was obtained. 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 one-neck flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 27 (10.0 mg, 20.8%) was obtained. 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] In a 5 mL single-neck flask, 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 and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 28 (12.2 mg, 23.3%) was obtained. 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 one-necked flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 29 (13.5 mg, 19.4%) was obtained. 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 compound was purified by preparative HPLC, lyophilized, and compound 30 (8.2 mg, 11.7%) was obtained. 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 one-necked flask and reacted at room temperature. After confirming the completion of the reaction by HPLC, the compound was purified by preparative HPLC, lyophilized, and compound 31 (16.3 mg, 20.1%) was obtained. 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: Cell activity test of camptothecin drug The cytotoxic activity of the drug camptothecin was measured using the following experiment. Camptothecin was added to culture media containing human tumor cells expressing A431, Fadu, Bxpc-3 (EGFR-positive cells) and U87-MG, SW620 (negative control cells), respectively. After culturing the cells for 72 hours, cell viability was measured. In vitro experiments using cells are used to measure cell viability, cytotoxicity, and programmed cell death induced by the camptothecin of the present invention.

[0066] The in vitro efficacy of camptothecin was measured by cell proliferation tests. CellTiter 96® AqueousOne Solution Cell Proliferation Assay is a commercially available product (Promega Corp., Madison, WI). CellTiter 96® Aqueous One Solution Cell Proliferation Assay (a) is a detection reagent for measuring the number of viable cells in cell proliferation and cytotoxicity experiments by colorimetric method. This reagent contains a novel tetrazole compound [3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, intramolecular salt; MTS] and an electron coupling agent (phenazine ethosulfate; PES). Because PES has enhanced chemical stability, it 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, where the electron coupling agent PMS used in CellTiter 96® AQueous Assay is supplied separately from the MTS solution. MTS (Owen's reagent) is bioreduced by cells to a colored formazan product that can be directly dissolved in the culture medium (Figure 1). Such conversion is likely to be completed under the action of NADPH or NADH produced by dehydrogenases in metabolically active cells. For detection, a small amount of CellTiter 96® AQueous One Solution Reagent is added directly to the culture medium in the culture plate wells, incubated for 1-4 hours, and the absorbance value at 490 nm is 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 can be dissolved in tissue culture medium, the CellTiter 96® AQueous One Solution Assay has fewer operating steps compared to the MTT or INT methods.

[0069] In this invention, A431, Fadu, Bxpc-3 (EGFR-positive expressing cells) and U87-MG, SW620 (negative control cells) were used as a research system for in vitro drug efficacy detection. Cells were inoculated into a 96-well plate at an appropriate cell density, and camptothecin was administered after 24 hours. After 24 hours, the camptothecin was diluted with detection medium (starting at 1 μM, 5-fold dilution, 9 concentrations, with detection medium added to the 10th column as a blank control). The diluted camptothecin was added to the corresponding cell wells, and the wells were shaken for 3 minutes at a shaking speed of 550 rpm / min using a microwell plate oscillator (model: MX100-4A). After shaking, the wells were incubated in a CO2 incubator for 3 days. After 3 days, 20 μl of MTS (Promega, G3581) was added to each well and reacted for 2 hours, and the readings were obtained at 490 nM using a microplate reader (Molecular Device, model: SpectraMAX190). The inhibitory effect of camptothecin on cell proliferation was evaluated by detecting the activity of dehydrogenases within mitochondria.

[0070] [Table 1]

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

[0072] Example 27: General coupling method for preparing ADCs Antibody molecule C, with a monomer ratio exceeding 95% after pre-purification using an ultrafiltration centrifuge, was replaced with phosphate buffer at a concentration of 10 mg / ml. TCEP was added in an amount 20 times the number of moles of antibody molecules, and the mixture was reacted at room temperature for 4 hours to cleave the disulfide bonds between antibody chains. The payload was added in an amount 20 times the number of moles of antibody molecules, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was replaced with PBS using an ultrafiltration centrifuge with a cutoff molecular weight of 30 kDa to remove the uncoupled payload. The ADC sample after the liquid 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 cell activity of camptothecin drugs, this invention uses A431, Fadu, Bxpc-3 (antigen-positive expressing cells), and SW620 (antigen-negative control cells) as research systems for in vitro drug efficacy detection. Cells were inoculated into 96-well plates at appropriate cell densities, and the ADC drug was administered after 24 hours. After 24 hours, the ADC drug was diluted with detection medium (starting at 1 μM, 5-fold dilution, 9 concentrations, with detection medium added to the 10th column as a blank control). The diluted ADC drug was added to the corresponding cell wells, and the wells were shaken for 3 minutes at a shaking speed of 550 rpm / min using a microwell plate oscillator (model: MX100-4A). After shaking, the wells were incubated in a CO2 incubator for 3 days. After 3 days, 20 μl of MTS (Promega, G3581) was added to each well and reacted for 2 hours, and the readings were obtained at 490 nM using a microplate reader (Molecular Device, model: SpectraMAX190). The inhibitory effect of ADC drugs on cell proliferation was evaluated by detecting the activity of dehydrogenases within mitochondria.

[0075] [Table 3]

[0076] As is clear from the above ADC cell activity tests, the camptothecin drug described in the present invention, after being coupled to an antibody by linker L, exhibits good antitumor activity in many antigen-positive tumor cell lines and has great clinical value.

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

[0078] [Table 4] [Table 5]

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

Claims

1. A camptothecin compound represented by formula I or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In formula I, R １ and R ２ are each independently selected from the group consisting of C １ -C ３ alkyl group, substituted alkyl group, -H, -CF ３ , aryl group, substituted aryl group and heteroaryl group, or R １ and R ２ together with the carbon atoms to which they are attached form cyclobutane, cyclopentane or cyclohexane, provided that R １ and R ２ are not simultaneously hydrogen.)

2. R １ is hydrogen, R ２ is C １ -C ３ Alkyl alkyl group, -CF ３ , an aryl group, a substituted aryl group or a heteroaryl group, or R １ R ２ is C １ -C ３ Alkyl alkyl group, -CF ３ , an aryl group, a heteroaryl group or a substituted aryl group, or R １ and R ２ These, together with the carbon atoms bonded to them, constitute cyclobutane, cyclopentane, or cyclohexane. 【Chemistry 2】 In structural formula (a), R ２ (CH ２ )n １ -CH ３ , -CF ３ , an aryl group, a heteroaryl group, or a substituted aryl group, provided that n １ = 0, 1, or 2, In structural formula (b), R １ and R ２ (CH ２ )n １ -CH ３ , -CF ３ , an aryl group, a heteroaryl group, or a substituted aryl group, provided that n １ = 0, 1, or 2, In structural formula (c), R １ and R ２ Together with the carbon atoms bonded to them, they constitute cyclobutane, cyclopentane, or cyclohexane, provided that n ２ A camptothecin compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the coefficient is 1, 2, or 3.

3. R １ is hydrogen, R ２ (CH ２ )n １ -CH ３ , -CF ３ , an aryl group, a heteroaryl group, or a substituted aryl group, provided that n １ = 0, 1, or 2, 【Transformation 3】 R ２ The carbon bonded to it has two conformations: R-form and S-form. In structural formula (a-1), R ２ The carbon bonded to it is the R-isomer. In structural formula (a-2), R ２ The camptothecin compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the carbon bonded to the carbon is the S-isomer.

4. The camptothecin compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the substituent on the aryl group is selected from the group consisting of halogen, hydrocarbyl group, alkoxy group, hydroxyl group, nitro group, amino group and cyano group. 【Request Item 5】 【Chemistry 4】 A camptothecin compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

6. An antitumor agent comprising a camptothecin compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, An antitumor agent for the treatment of solid tumors or hematological malignancies, 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.

7. An antibody-drug conjugate represented by formula II, configured to exert its therapeutic effect by releasing drug portion D after reaching target cells. 【Transformation 5】 In formula II, Ab is an antibody, antibody fragment, or protein. L is an arbitrary linker in which one end is connected to Ab and the other end is connected to drug portion D. D is selected from the camptothecin compounds described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and is bonded to L via the hydroxyl group of D. m is chosen from integers between 1 and 20.

8. Linker L is -O-, -N(R)n １ -ien-CH ２ -, -CH(R)n １ -, amide bond, ester bond, -S-, -(PEG)n ２ - Selected from the group consisting of, where n １ n is chosen from integers 1-3. ２ The antibody-drug conjugate according to claim 7, wherein is selected from an integer between 1 and 20.

9. The antibody-drug conjugate according to claim 7 or 8, wherein the antibody portion of the antibody-drug conjugate is specifically bound to target cells of cancer or autoimmune disease.

10. A pharmaceutical composition comprising an antibody-drug conjugate according to any one of claims 7 to 9, A pharmaceutical composition for treating solid tumors or hematological malignancies, 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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