Novel camptothecin derivative and antibody-drug conjugate comprising same

Abstract

The invention relates to a novel camptothecin derivative which has a structure shown in a chemical formula 1 and has more preferable properties in the aspects of curative effect, toxicity, selectivity, action time, administration mode, treatment mode, stability and / or producibility and the like compared with an existing camptothecin derivative. The present invention relates to a pharmaceutical composition comprising: (i) a Bcl family protein, including a drug-resistant protein Survivin, and / or (ii) an effect of an efflux pump, which can maximize the effect of main drug target modulation by means of an additional mechanism of action: (i) a Bcl family protein, including the drug-resistant protein Survivin, and / or (ii) an effect of an efflux pump; the invention also relates to a carrier-drug conjugate containing the camptothecin derivative. The novel camptothecin derivative and the carrier-drug conjugate comprising the same according to the present invention have excellent anti-tumor efficacy and safety, and thus can be used for the treatment of various cancers.

Description

Technical Field

[0001] This invention relates to a novel camptothecin derivative with excellent anticancer efficacy and safety, as well as a carrier-drug conjugate containing the same, and its pharmaceutical uses. Background Technology

[0002] Inhibitors of isomerase type I (TOPISomerase I), which are involved in DNA replication and recombination, are drugs with proven anticancer mechanisms of action and efficacy and safety. They have been clinically demonstrated to have excellent anticancer effects in various refractory solid tumors such as colorectal cancer, lung cancer, breast cancer, and ovarian cancer.

[0003] Camptothecin (CPT) and its derivatives are known as representative type I topoisomerase inhibitors. However, camptothecin has the problems of low water solubility and high toxicity.

[0004] To address these issues, research has been conducted on camptothecin derivatives with lower toxicity and higher water solubility. Among them, drugs such as irinotecan and topotecan have been approved for the treatment of colorectal cancer, ovarian cancer, and lung cancer and are currently on the market.

[0005] To date, various camptothecin derivatives are still under development. Among them, SN-38 is a potent topoisomerase I inhibitor with an IC50 value in the nanomolar range in multiple cell lines. It is the active form of irinotecan, a prodrug used to treat colorectal cancer, and has also shown activity in lung cancer, breast cancer, and brain cancer. Trop-2-SN-38 antibody-drug conjugates (ADCs) have shown efficacy in various cancer types, including triple-negative breast cancer (TNBC), bladder cancer, and gastric cancer; however, resistance to SN-38 remains a challenge.

[0006] Furthermore, Daiichi Sankyo utilized DXd in the development of Enhertu, a derivative of essanotecan, which exhibits approximately 10 times the activity of SN-38 in cancer cells. DXd possesses good solubility, relatively high safety, and a strong bystander-killing effect, thus offering advantages in treating heterogeneous tumors; however, it suffers from a short half-life, which can reduce off-target effects.

[0007] To date, when developed camptothecin-based drugs are used as payloads for antibody-drug conjugates (ADCs), they exhibit lower cytotoxicity compared to ADCs containing traditional ultra-toxic payloads such as mMAE or mMAF. However, safety concerns remain, and there is also the issue of drug resistance resulting from overexpression of drugs such as ABCG2 Drug Efflux Pump, which can lead to a decline in anticancer efficacy.

[0008] Therefore, there is an urgent need for a camptothecin derivative that not only has higher cytotoxicity and excellent safety, but also significantly reduces drug resistance that leads to decreased anticancer efficacy, especially a camptothecin derivative suitable as an effective payload, and a carrier-drug conjugate containing it. Summary of the Invention

[0009] The technical problem that the invention aims to solve

[0010] Against the above-mentioned technical background, the purpose of this invention is to provide a novel camptothecin derivative that has a strong inhibitory effect on type I topoisomerase, exhibits high cytotoxicity, and has excellent safety.

[0011] Furthermore, the present invention aims to provide a carrier-drug conjugate comprising a camptothecin derivative according to the present invention, and a pharmaceutical composition comprising a camptothecin derivative according to the present invention or a carrier-drug conjugate comprising thereto.

[0012] Furthermore, the present invention aims to provide a method for treating cancer using camptothecin derivatives or carrier-drug conjugates containing the camptothecin according to the present invention.

[0013] means for solving problems

[0014] To address the aforementioned issues, a first aspect of the present invention provides a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

[0015] A second aspect of the invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising a compound represented by Formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

[0016] For compounds represented by Chemical Formula 1 according to the present invention, even if simple functional groups such as C1-3 alkyl, hydroxyl, halogen, and amino are added, or existing hydroxyl, ethyl, and oxo groups are replaced or removed with other groups, as long as they exhibit the same effect as the carrier-drug conjugate of the present invention, they obviously fall within the equivalent scope of the present invention.

[0017] The present invention will now be described in more detail.

[0018] This invention provides a novel camptothecin derivative having the structure shown in Formula 1.

[0019]

Chemical Formula 1

[0020] In the chemical formula 1, R is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, C2-C10 alkynyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C2-C10 heteroaryl, C1-C10 monoalkylamino or C1-C10 dialkylamino, nitro, and cyano.

[0021] As an example, in the chemical formula 1, R can be selected from the group consisting of the following.

[0022]

[0023] Specifically, the compound of chemical formula 1 may be a camptothecin derivative represented by chemical formulas 2 to 10 (referred to as compound 2 to compound 10 respectively), but is not limited thereto.

[0024]

Chemical Formula 2

[0025]

Chemical Formula 3

[0026] [Chemical Formula 4]

[0027] [Chemical Formula 5]

[0028]

Chemical Formula 6

[0029] [Chemical Formula 7]

[0030] [Chemical Formula 8]

[0031] [Chemical Formula 9]

[0032]

Chemical Formula 10

[0033] The camptothecin derivative of the present invention, represented by chemical formula 1 or its isomer, is a hydrophobic small molecule that can permeate the cell membrane. Therefore, it can be delivered to cancerous tissue through the EPR effect (enhanced permeability and retention effect), accumulate at a high concentration while penetrating deep into the cancerous tissue, and exert cytotoxicity inside the cell by crossing the cell membrane, causing cell death and being released. It can also continuously penetrate the cell membrane of surrounding cells to enter the cell and exert its effects.

[0034] In this specification, the camptothecin derivatives represented by compounds of Formula 1 or isomers thereof according to the present invention include not only the compounds of Formula 1 or isomers thereof, but also pharmaceutically acceptable salts thereof, solvates thereof, and prodrugs thereof.

[0035] In this specification, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as salts of inorganic ions including sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, and iron, as well as salts of inorganic acids such as hydrochlorides, phosphates, and sulfates. Furthermore, it includes salts of organic acids such as ascorbic acid salts, citrates, tartrates, lactates, maleates, malonates, fumarates, glycolates, succinates, propionates, acetates, orotates, and acetylsalicylates, as well as amino acid salts such as lysine, arginine, and guanidine salts. Additionally, it includes, but is not limited to, organic ionic salts that can be used in pharmaceutical reactions, purification, and separation processes, such as tetramethylammonium salts, tetraethylammonium salts, tetrapropylammonium salts, tetrabutylammonium salts, benzyltrimethylammonium salts, and benzyl chloride salts.

[0036] "Prodrug" has the meaning used in this technical field. For example, it is an inactive compound that is converted into an active drug state in vivo through drug metabolism. For example, it refers to a compound that has been chemically modified from a physiologically active substance or a therapeutically active organic compound and designed to release or release a parent compound in vivo under enzymatic or other conditions. A prodrug is converted into the target compound in vivo after administration. It also refers to the chemical modification of compounds that, while useful drugs, have unsuitable properties in terms of side effects, stability, solubility, absorption, duration of action, etc., to enable their clinical use.

[0037] "Solvate" means a compound represented by Formula 1 or an isomer thereof and a pharmaceutically acceptable salt thereof, additionally comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0038] In one embodiment, the present invention provides a carrier-drug conjugate comprising a compound represented by chemical formula 1 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvation thereof.

[0039] In this invention, "carrier" refers to a substance that has the ability to selectively and specifically deliver the camptothecin derivative according to the invention to a target site, such as cancer cells. It can be an antibody, peptide, liposome and / or aptamer, but is not limited thereto, and is preferably an antibody.

[0040] Aptamer-drug conjugates (ApDCs) are conjugates formed by replacing the antibody in an aptamer-based drug-conjugate (ADC). Aptamers are single-stranded nucleic acids with a three-dimensional structure. Aptamers are typically discovered through the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) process. SELEX is a technique that involves adding target protein molecules to a compound library to obtain functional nucleic acids that bind to them. Aptamers bind to targets very strongly and selectively, and are therefore also known as chemical antibodies. Aptamers are approximately 20 kDa in size and exhibit superior cell penetration and lower immunogenicity compared to antibodies.

[0041] Because aptamers can be obtained through chemical synthesis, the binding sites and quantities of the drug can be precisely designed during the preparation of aptamer-drug conjugates. Compared to ADCs, their production cost is lower. Aptamers are typically composed of natural nucleic acids, and therefore are degraded by nucleases in vivo, resulting in low in vivo stability. However, the ease with which aptamers can be chemically modified can overcome the stability limitations of modified aptamers.

[0042] Peptide-drug conjugates (PDCs) are conjugates formed by replacing antibodies with peptides in antibody-drug conjugates (ADCs). Peptides are composed of amino acids and have a molecular weight ranging from 500 to 5000 Da (Daltons). This is a very small size compared to antibodies with a molecular weight of 150 kDa (kilodaltons) or higher. Therefore, peptide-based PDCs have superior cell penetration ability compared to ADCs and a very low likelihood of immunogenicity. Furthermore, peptides can be obtained through chemical synthesis. Therefore, PDCs not only have very low production costs but also allow for precise control of the binding site and ratio between the peptide and the drug. Generally, peptides are easily degraded by proteases, resulting in a relatively short biological half-life. To overcome the limitations of peptide-based drug conjugates, strategies utilizing modified peptides, such as cyclic peptides and the introduction of non-natural amino acids, have been proposed.

[0043] Liposomes, while lacking the antibody backbone structure, possess the ability to recognize antigens like antibodies, thus serving as a type of artificial antibody. Liposomes specific to target proteins can be discovered using phage display technology.

[0044] Phage display is a technique for expressing desired proteins on the surface of bacteriophages. Liposomes have a molecular weight of approximately 30 kDa, about 20% that of antibodies. Therefore, they are considered to have relatively lower immunogenicity and improved cell penetration compared to antibodies. Furthermore, liposomes can modulate thermal and pH stability, thus potentially improving structural stability. Their production cost is also considered relatively low compared to antibodies. Due to these advantages, the development of liposome-drug conjugates (Repebody-DCs) is receiving increasing attention as a strategy to replace antibodies with liposomes.

[0045] In this invention, the target bound by the carrier, such as an antigen, can be exemplified, without limitation, as antigens such as Her2, FolR, and PSMA that are selectively distributed on the surface of cancer cells, and antigens such as Trop2 that are also distributed in small amounts in normal tissues but overexpressed in cancer cells.

[0046] Exemplary cancer cell target antigens may include 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, ADORA2A, AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOCl, AR, aromatase, ASPH, ATX, AX1, AXL, AZGP1 (zinc-a-glycoprotein), B4GALNT1, B7, B7.1, B7.2, B7-H1, B7-H3, B7-H4, B7-H6, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BCMA, BDNF. BLNK, BLR1 (MDR15), BIyS, BMP1, BMP2, BMP3B (GDFIO), BMP4, BMP6, BMP8, BMP10, BMPR1A, BMPR1B, BMPR2, BPAG1 (Netting Protein), BRCA1, C19orflO (IL27w), C3, C4A, C5, C5R1, CA6, CA9, CANT1, CAPRIN-1, CASP1, CASP4, CAV1, CCBP2 (D6 / JAB61), CCL1 (1-309), CCLI1 (Eosinophil Chemokines), CCL13 (MCP-4), CCL15 (MIP-Id), CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19 (MIP-3b) CCL2 (MCP-1), MCAF, CCL20 (MIP-3a), CCL21 (MEP-2), SLC, exodus-2, CCL22 (MDC / STC-I), CCL23 (MPIF-I), CCL24 (MPIF-2 / eosinophil chemokine-2), CCL25 (TECK), CCL26 (Eomycin-3), CCL27 (CTACK / ILC), CCL28, CCL3 (MIP-Ia), CCL4 (MIPIb), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1, CCNE1, CCNE2CCR1 (CKR1 / HM145), CCR2 (mcp-IRB / RA), CCR3 (CKR3 / CMKBR3), CCR4, CCR5 (CMKBR5 / ChemR13), CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6), CCR7 (CKR7 / EBI1), CCR8 또는CDw198(CMKBR8 / TERI / CKR-L1), CCR9(GPR-9-6), CCRL1(VSHK1), CCRL2(L-CCR), CD13,CD164, CD19, CDH6, CDIC, CD2, CD20, CD21, CD200, CD22, CD23, CD24, CD27,CD28, CD29, CD3, CD33, CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD40, CD40L,CD44, CD45RB, CD47, CD52, CD56, CD69, CD70, CD72, CD74, CD79A, CD79B, CD8,CD80, CD81, CD83, CD86, CD97, CD99, CD117, CD125, CD137, CD147, CD179b,CD223, CD279, CD152, CD274, CDH1 (E-cadherin), CDH1O, CDH12, CDH13, CDH18,CDH19, CDH2O, CDH3, CDH5, CDH7, CDH8, CDH9, CDH17, CDK2, CDK3, CDK4, CDK5,CDK6, CDK7, CDK9, CDKN1A (p21Wap1 / Cip1), CDKN1B (p27Kip1), CDKN1C, CDKN2A (p16INK4a), CDKN2B, CDKN2C, CDKN3, CEA, CEACAM5, CEACAM6, CEBPB, CERI, CFC1B, CHGA, CHGB, Chitinase, CHST1O, CIK, CKLFSF2, CKLFSF3, CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3, CLDN6, CLDN7 (tight junction protein-7), CLDN18, CLEC5A, CLEC6A, CLEC11A, CLEC14A, CLN3, CLU (clustering protein), CMKLR1,CMKOR1 (RDC1), CNR1, C-MET, COL18A1, COLIA1, COL4A3, COL6A1, CR2, Cripto, CRP, CSF1 (M-CSF), CSF2 (GM-CSF), CSF3 (GCSF), CTAG1B (NY-ESO-1), CTLA4, CTL8, CTNNB1CTNNB1 (β-catenin), CTSB (cathepsin B), CX3CL1 (SCYD1), CX3CR1 (V28), CXCL1 (GRO1), CXCL1O (IP-IO), CXCLI1 (1-TAC / IP-9), CXCL12 (SDF1), CXCL13, CXCL14, CXCL16, CXCL2 (GRO2), CXCL3 (GRO3) CXCL5 (ENA-78 / LIX), CXCL6 (GCP-2), CXCL9 (MIG), CXCR3 (GPR9 / CKR-L2), CXCR4, CXCR6 (TYMSTR / STRL33 / Bonzo), CYB5, CYC1,CYSLTR1, DAB2IP, DES, DKFZp451J0118, DLK1, DNCL1, DPP4, E2F1, Engel, Edge,Fennel, EFNA3, EFNB2, EGF, EGFR, ELAC2, ENG, Enola, ENO2, ENO3, EpCAM, EPHA1,EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2,EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN-A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 (HER-2), ERBB3, ERBB4, EREG, ERK8, estrogen receptor, Earl, ESR2, F3 (TF), FADD, FAP, farnesyltransferase, FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 (aFGF), FGF10, FGF11, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17FGF18, FGF19, FGF2(bFGF), FGF20,FGF21, FGF22, FGF23, FGF3(int-2), FGF4(HST), FGF5, FGF6(HST-2), FGF7(KGF),FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FIGF(VEGFD), FIL1(EPSILON), FBL1(ZETA), FLJ12584, FLJ25530, FLRT1(protein transcription factor), FLT1, FLT-3, FOLR1, FOS, FOSL1(FRA-1), FR-α, FY(DARC), GABRP(GABAa), GAGEB1, GAGEC1, GALNAC4S-6ST, GATA3,GD2, GD3, GDF5, GFI1, GFRA1, GGT1, GM-CSF, GNAS1, GNRH1, GPC1, GPC3, GPNB,GPR2(CCR10), GPR31, GPR44, GPR81(FKSG80), GRCC1O(C1O), GRP, GSN(Gelsolin),GSTP1, GUCY2C, HAVCR1, HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog,HER3, HGF, HIF1A, HIP1, CYC, HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74,HMOXI, HSP90, HUMCYT2A, ICEBERG, ICOSL, ID2, IFN-a, IFNA1, IFNA2, . IFNA4,IFNA5, EFNA6, BFNA7, IFNB1, IFNγ, IFNW1, IGBP1, IGF1, IGFIR, IGF2, IGFBP2,IGFBP3, IGFBP6, DL-1, ILIO, ILIORA, ILIORB, IL-1, IL1R1(CD121a), IL1R2(CD121b), IL-IRA, IL-2, IL2RA(CD25), IL2RB(CD122), IL2RG(CD132), IL-4, IL-4R(CD123), IL-5, IL5RA(CD125), IL3RB(CD131), IL-6, IL6RA,(CD126), IR6RB(CD130), IL-7,IL7RA (CD127), IL-8, CXCR1 (IL8RA), CXCR2, (IL8RB / CD128), IL-9, IL9R (CD129), IL-10, IL10RA (CD210), IL10RB (CDW210B), IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL13RA1, IL13RA2, IL14, IL15, IL15RA,IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19,ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, IL1R2,ILIRAP, ILIRAPLI, ILIRAPL2, ILIRL1, IL1RL2, ILIRN, IL2, IL20, IL20RA, IL21R,IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29,IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (glycoprotein 130), ILK, INHA,INHBA, INSL3, INSL4, IRAK1, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (α6 integrin), ITGAV, ITGB3, ITGB4 (β4 integrin), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KIT, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (keratin 19), KRT2A, KRTHB6 (hair-specific type II keratin), L1CAM, LAG3, LAMA5, LAMP1, LEP (leptin), Lewis Y antigen ("LeY"), LILRB1, Lingo-p75, Lingo-Troy, LGALS3BP, LRRC15, LPS,LTA (TNF-β), LTB, LTB4R (GPR16), LTB4R2, LTBR, ​​LY75, LYPD3, MACMARCKS, MAG or OMGP, MAGEA3, MAGEA6, MAP2K7 (c-Jun), MCP-1, MDK, MIB1, midkine, MIF, MISRII, MJP-2, mLSN, MK, MKI67 (Ki-67), mMP2, mMP9, MS4A1, MSMB, MT3 (metallothionein-UI), mTOR, MTSS1, MUC1 (mucin), MUC16, MYC, MYD88, NCK2, NCR3LG1, neurocan, NFKBI, NFKB2, NGFB (NGF), NGFR, NgR-Lingo, NgRNogo66 (Nogo) NgR-p75, NgR-Troy, NMEI (NM23A), NOTCH, NOTCH1, NOTCH3, NOX5, NPPB, NROB1, NROB2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, NY-ESO1, ODZI, OPRDI, P2RX7, PAP, PART1, PATE, PAWR, P-cadherin, PCA3, PCD1, PD-L1, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, L1-CAM, peg-pegylated asparaginase, PF4 (CXCL4), PGF, PGR, phosphacan, PIAS2, PI3 kinase, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-beta, PPBP (CXCL7), PPID, PR1, PRAME, PRKCQ, PRKD1, PRL, PROC, PROK2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTHR2, PTGS2 (COX-2), PTN, PVRIGRAC2 (P21Rac2), RANK, RANK ligand, RARB, RGS1, RGS13, RGS3, RNFI1O (ZNF144), Ron, ROBO2, ROR1, RXR, S100A2, SCGB 1D2 (lipophilic protein B), SCGB2A1 (mammin 2), SCGB2A2 (mammin 1), SCYE1 (endothelial monocyte-activating cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (Misoha), SERPINEI (PAI-I), SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLAMF7, SLC2A2, SLC33A1, SLC43A1, SLC44A4, SLC34A2 SLIT2, SPP1, SPRR1B (Spr1), ST6GAL1, ST8SIA1, STAB1, STATE, STEAP, STEAP2, TB4R2, TBX21, TCP1O, TDGF1, TEK, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, THIL, THBS1 (platelet-reactive protein-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNF-α, TNFAIP2 (B94), TNFAIP3 TNFRSFI1A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6(Fas),TNFRSF7, TNFRSF8, TNFRSF9, TNFSF1O(TRAIL), TNFRSF10A, TNFRSF10B, TNFRSF12A,TNFRSF17, TNFSF1 1(TRANCE), TNFSF12 (APO3L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (OX40 ligand), TNFSF5 (CD40 ligand), TNFSF6 (FasL),TNFSF7 (CD27 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB ligand), TOLLIP, Toll-like receptor, TOP2A (topoisomerase Iia), TP53, TPM1, TPM2, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1, TREM2, TROP2, TRPC6, TSLP, TWEAK, Tyrosinase, uPAR, VEGF, VEGFB, VEGFC, Vertican, VHL C5, VLA-4, WT1, Wnt-1, XCL1 (lymphocyte chemokine), XCL2 (SCM-Ib), XCRI (GPR5 / CCXCR1), YY1, ZFPM2, CLEC4C (BDCA-2, DLEC, CD303, CDH6, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (Dectin-1), CLEC11A, PDGFRa, SLAMF7, GP6 (GPVI), LILRA1 (CD85I), LILRA2 (CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), LILRB1, NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD30, CD300C, CD300E, CD300LB (CD300B), CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44), PILRB, SIGLEC1 (CD169, SN), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC9, SIGLEC10, SIGLEC11,SIGLEC12, SIGLEC14,SIGLEC15(CD33L3), SIGLEC16, SIRPA, SIRPB1(CD172B), TREM1(CD354), TREM2, KLRF1(NKp80), 17-1A, SLAM7, MSLN, CTAG1B / NY-ESO-1, MAGEA3 / A6, ATP5I(Q06185), OAT(P29758), AIFM1(Q9Z0X1), AOFA(Q64133), MTDC(P18155), CMC1(Q8BH59), PREP(Q8K411), YMEL1(O88967) LPPRC(Q6PB66), LONM(Q8CGK3), ACON(Q99KI0), ODO1(Q60597), IDHP(P54071), ALDH2(P47738), ATPB(P56480), AATM(P05202), TMM93(Q9CQW0), ERGI3(Q9CQE7), RTN4(Q99P72), CL041(Q8BQR4), ERLN2(Q8BFZ9), TERA(Q01853), DAD1(P61804) CALX(P35564), CALU(O35887), VAPA(Q9WV55), MOGS(Q80UM7), GANAB(Q8BHN3), ERO1A(Q8R180), UGGG1(Q6P5E4), P4HA1(Q60715), HYEP(Q9D379), CALR(P14211), AT2A2(O55143), PDIA4(P08003), PDIA1(P09103), PDIA3(P27773), PDIA6(Q922R8), CLH(Q68FD5), PPIB(P24369), TCPG(P80318), MOT4(P57787), NICA(P57716), BASI(P18572), VAPA(Q9WV55), ENV2(P11370), VAT1(Q62465), 4F2(P10852), ENOA(P17182), ILK(O55222), GPNMB(Q99P91), ENV1(P10404), ERO1A(Q8R180), CLH(Q68FD5), DSG1A(Q61495), AT1A1(Q8VDN2), HYOU1(Q9JKR6), TRAP1(Q9CQN1), GRP75(P38647), ENPL(P08113),CH60 (P63038), or CH10 (Q64433), but not limited to these.

[0047] Furthermore, the target antigen can be an antigen that is distributed in cancer cells at a rate more than 10 times higher than in normal cells.

[0048] In this invention, non-limiting examples of antibodies may include urrelumab, utomilumab, bebtelovimab, aducanumab, bapinezumab, crenezumab, donanemab, gantenerumab, lecanemab, solanezumab, nesvacumab, evinacumab, and enoblimab. oblituzumab, omeburtamab, belimumab, Ianalumab, tabalumab, bertilimumab, mogamulizumab, leronlimab, siplizumab, foralumab, muromonab-CD3, oteliximab, edaliximab Ibalizumab, Tregalizumab, Zanolimumab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab, Veltuzumab The following are listed: Epratuzumab, Basiliximab, Daclizumab, Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab, Mezagitamab, Bleeselumab, and Dacetuzumab.Iscalimab, Lucarumumab, Mitazalimab, Sotigalimab, Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab, Oreglusumab Oleclumab, Milatuzumab, Galiximab, Carotuximab, Adecatumumab, Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Lav Ravulizumab, Lacnotuzumab, Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab, Zalifrelimab, Cetuximab, Depatuxizumab, Futuximab, Imaginutuzumab gatuzumab, Matuzumab, Modotuximab, Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab, Zalutuzumab, Batoclinab, Nipocalimab, Rozanolixizumab, Burosumab, FarletuzumabDinutuximab, Naxitamab, Ragifilimab, Gimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertuzumab, Trastuzumab ), Datopotamab, Patritumab, Seribantumab, Duligotuzumab, Ficlatuzumab, Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotumab Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab, Bermekimab, Canakinumab, Gevokizumab, Briakinumab, Ustekinumab, Anrukinzumab, Cendakimab, Lebrikizumab, Tralokin (The following are listed as examples of specific anti-inflammatory drugs / anti-inflammatory drugs): umab, brodalumab, bimekizumab, ixekizumab, secukinumab, brazikumab, guselkumab, mirikizumab, risankizumab, tildrakizumab, nemolizumab, imsidolimab, and spesolimab.Pascolizumab, Dupilumab, Depemokimab, Mepolizumab, Reslizumab, Benralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Levilimab, Sarilumab Satralizumab, Tocilizumab, Abituzumab, Favezelimab, Fianlimab, Ieramilimab, Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab Tavolimab, Telazorlimab, Vonlerolizumab, Alirocumab, Bococizumab, Ebronucimab, Evolocumab, Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, and Camrelizumab (Ca mrelizumab, cimiplimab, geptanolimab, nivolumab, pembrolizumab, penpulimab, pitilizumab, prolgolimab, retifanlimab, sasanlimab, serplulimab, sintilimab, spartalizumabTislelizumab, Toripalimab, Ezabenlimab, Zimberelimab, Atezolizumab, Avelumab, Cosibelimab, Sugemalimab, Durvalumab, Envafolimab, Suvratoxumab, Denosumab, Zilove rtamab), Elotuzumab, Domvanalimab, Etigilimab, Ociperlimab, Tiragolumab, Vibostolimab, Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab, Golime Monoclonal antibodies (Golimumab), Infliximab, Certolizumab, Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab, Cabiralizumab, Bevacizumab, Brolucizumab, Ranibizumab, Olinvacimab, Icruc (e.g., umab), Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrindatamab, Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab)Glofitamab, Mosunetuzumab, Odronextamab, Flotetuzumab, Vibecotamab, Catumaxomab, Cibisatamab, Talquetamab, Ubamatamab, Emfizatamab, Blinatumomab, Amivantamab, Emexicam Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naptumomab, Belantamab, Pivekimab, Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibritumomab, Inot uzumab), epratuzumab, moxetumomab, brrentuximab, gemtuzumab, vadastuximab, lovotuzumab, polatuzumab, tusamitamab, telisotuzumab, rovalpituzumab, depatuxizumab, faretuzumab etuzumab, mirvetuximab, disitamab, anetumab, enfortumab, sacituzumab, vobarilizumab, cadonilimab, vudalimab, tebotelimab, ivonescimab, erfonrilimab, and ozoraralizumab.Faricimab, vanucizumab, or navicixizumab, etc., but not limited to these.

[0049] In the carrier-drug conjugate of the present invention, the carrier and the drug are preferably conjugated via a linker.

[0050] In this invention, the linker should remain stable in the bloodstream to prevent the drug from separating from carriers such as antibodies and to maintain its structure before reaching targets such as antigens, thereby minimizing damage to normal tissues. Ideally, antibody-drug conjugates remain stable during systemic circulation and are cleaved within target cells, releasing cytotoxic drugs appropriately and safely delivering the drug to the target, thus enabling antibody-drug conjugates to possess both therapeutic efficacy and safety.

[0051] According to the carrier-drug conjugate of the present invention, the carrier is coupled to a drug via a linker, wherein the drug is an active camptothecin derivative compound represented by chemical formula 1, preferably a compound represented by chemical formula 2 to chemical formula 10, but not limited thereto.

[0052] In the carrier-drug conjugate of the present invention, the active camptothecin derivative compound represented by chemical formula 1 is preferably a compound represented by chemical formula 2 to chemical formula 10, and can be connected to the linker at an appropriate site as long as its anticancer activity and other properties are not changed; accordingly, the present invention also provides a drug-linker formed by connecting the active camptothecin derivative compound to the linker.

[0053] Preferably, the drug-linker according to the invention may have a structure represented by chemical formulas 2a to 10a, but is not limited thereto. In chemical formulas 2a to 10a, L represents a linker.

[0054]

Chemical Formula 2a

[0055]

Chemical Formula 3a

[0056]

Chemical Formula 4a

[0057]

Chemical Formula 5a

[0058]

Chemical Formula 6a

[0059]

Chemical Formula 7a

[0060]

Chemical Formula 8a

[0061] [Chemical Formula 9a]

[0062] [Chemical Formula 10a]

[0063] In this invention, the linker can be in a form that can be cleaved in a specific intracellular environment and / or under specific conditions, that is, the drug can be released from the antibody by cleavage of the linker in the intracellular environment.

[0064] For example, the linker can be cleaved by cleavage factors in the intracellular environment (e.g., cleavage enzymes present in lysosomes or endosomes), and can be a peptide linker capable of being cleaved by intracellular peptidases or proteases (e.g., lysosomal or endosomal proteases). Typically, the peptide linker is at least 2 amino acids in length. The cleavage enzyme may include cathepsin B, cathepsin D, and plasmin, and releases the drug into the target cell by hydrolyzing the peptide. The peptide linker can be cleaved by the thiol-dependent protease cathepsin B, which is highly expressed in cancer tissues, for example, using linkers such as Gly-Gly-Phe-Gly (GGFG), Phe-Leu, or Gly-Phe-Leu-Gly, but is not limited thereto. Furthermore, the peptide linker can be, for example, a linker capable of being cleaved by intracellular proteases, such as the Val-Cit linker or the Phe-Lys linker.

[0065] In this invention, the cleavable linker can be pH-sensitive, meaning it is sensitive to hydrolysis at a specific pH value. Typically, a pH-sensitive linker indicates that it can undergo hydrolysis under acidic conditions. For example, the linker can be an acid-labile linker capable of hydrolysis in lysosomes, such as hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic amides, orthoesters, acetals, ketals, etc.

[0066] Furthermore, in this invention, the linkers can also be cleaved under reducing conditions; for example, disulfide linkers belong to this category. Various disulfide bonds can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene).

[0067] The linker may include a β-glucuronide linker, which can be recognized and hydrolyzed by β-glucuronidase, which is abundant in lysosomes or overexpressed in certain tumor cells. For example, the β-glucuronide linker disclosed in Korean Patent Publication No. 2015-0137015, such as a β-glucuronide linker containing a self-immolative group, can be used.

[0068] Furthermore, the linker can be, for example, a non-cleaving linker that releases the drug via an antibody hydrolysis step, for example, generating an amino acid-linker-drug complex. Such linkers can be thioether-based or maleimidocaproyl-based and are capable of maintaining stability in the bloodstream.

[0069] Preferably, the linker according to the invention may contain GGFG. According to one embodiment of the invention, a portion of at least one amino acid side chain constituting the linker may be replaced by a separable hydrophilic functional group under specific conditions; the hydrophilic functional group is preferably a monovalent hydrophilic functional group, such as a β-glucuronide or an ester or carbonate having 3 to 100 ethylene glycol repeating units of PEG (Polyethylene Glycol), but is not limited thereto.

[0070] More preferably, the connector may have a structure of chemical formula 11 or chemical formula 12, but is not limited thereto.

[0071]

[0072] In the chemical formula 12, n can be an integer from 3 to 10.

[0073] In this invention, when the carrier in the carrier-drug conjugate is an antibody, the drug and / or drug-linker of the compound of formulas 2 to 10, or of formulas 2a to 10a, can be randomly conjugated via lysine residues within the antibody, or via cysteine ​​residues exposed during the reduction of disulfide bonds. In some cases, the linker-drug can be conjugated via a genetically engineered tag, for example, by binding to lysine or cysteine ​​residues present in the peptide or protein.

[0074] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising a compound represented by chemical formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate comprising the same.

[0075] Furthermore, according to a specific embodiment of the present invention, a method for treating or preventing cancer is provided, comprising administering to a subject a therapeutically effective amount of a compound represented by Formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate comprising the same, according to the present invention. The subject may be a mammal, including humans.

[0076] In this invention, the cancer includes all cancers that can be treated by inhibiting topoisomerase I and / or inhibiting one or more cancer-associated survival genes selected from the group consisting of survivin, Mcl-1, XIAP and cIAP2, and can be solid tumors or hematologic malignancies. For example, the cancers mentioned can be selected from pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, etc. The cancer includes, but is not limited to, one or more of the following: visceral cancer, duodenal cancer, malignant soft tissue tumors, malignant bone tumors, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, nephroblastoma, breast cancer, triple-negative breast cancer (TNBC), sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematologic malignancies, and thymic cancer. Furthermore, the cancers mentioned include not only primary cancers but also metastatic cancers.

[0077] In this specification, "patient," "subject," and "object" refer to animals, such as mammals. In a particular embodiment, the patient is a human. In other embodiments, the patient is a non-human animal, such as a dog, cat, livestock (e.g., a horse, pig, or donkey), chimpanzee, or monkey.

[0078] In this invention, "therapeutic effective amount" refers to the amount of a compound represented by Formula 1, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate thereof, that is effective in the treatment or prevention of cancer. Specifically, "therapeutic effective amount" refers to an amount sufficient to treat the disease at a reasonable benefit / risk ratio suitable for medical treatment; the effective dose level can be determined based on individual type and severity, age, sex, disease type, drug activity, drug sensitivity, timing of administration, route of administration and excretion rate, duration of treatment, concurrent drugs, and other factors known in the art. The pharmaceutical compositions of this invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. They can be administered as a single dose or multiple doses. Taking all the above factors into account, it is important to obtain the maximum effect with the minimum dose without side effects; since the compounds of this invention represented by Formula 1, or their isomers thereof, and pharmaceutically acceptable salts thereof, or carrier-drug conjugates thereof exhibit dose-dependent effects, the dosage can be easily determined by those skilled in the art based on various factors such as the patient's condition, age, sex, and complications. Because the active ingredients of the pharmaceutical compositions of the present invention have excellent safety, they can also be used in doses exceeding the determined dosage range.

[0079] Furthermore, according to a specific embodiment of the present invention, the present invention provides the use of a compound or isomer thereof represented by any one of chemical formulas 1 to 10, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate thereof in the preparation of a medicament for the treatment or prevention of cancer.

[0080] Compounds or isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof, or carrier-drug conjugates thereof, used for the preparation of pharmaceutical preparations, represented by any of the formulas 1 to 10, may be mixed with pharmaceutically acceptable excipients, diluents, carriers, etc., and may be prepared together with other active preparations to form compound preparations, thereby enabling the active ingredients to produce synergistic effects.

[0081] The matters described in the uses, compositions and treatments of this invention are equally applicable without contradiction.

[0082] In this specification, the anticancer effect or therapeutic effect of an anticancer agent refers to its ability to reduce the severity of cancer, decrease tumor size, or delay or slow cancer progression during a patient's course of a specific cancer.

[0083] For example, the anticancer effect of an anticancer agent can be observed in vitro and / or in vivo by examining the cell viability (i.e., changes in cytotoxicity or cell number) of cancer cells after treatment with the agent. This can be indirectly confirmed, for example, by detecting drug response in cell lines or xenografts. Alternatively, the anticancer effect can be directly confirmed in cancer patients, yielding relevant data for database use. Furthermore, when designing dosing guidelines for anticancer agents, PK parameters and / or toxicity profiles from animal models can be considered simultaneously.

[0084] The anticancer effects of anticancer agents can be inferred from in vitro data, i.e., the maximum effect of the anticancer agent, such as IC50, IC60, IC70, IC80 and IC90; or from in vivo data, such as the highest blood concentration (Cmax) and / or the area under the blood concentration-time curve (AUC), in non-clinical animal models and clinical cancer patients.

[0085] The reactivity of anticancer agents refers to their clinical sensitivity in terms of anticancer efficacy.

[0086] When referring to the use of anticancer agents for treatment, "sensitivity" and "sensitiveness" are relative terms referring to the degree of effectiveness of a compound in alleviating or reducing the progression of the treated tumor or disease.

[0087] "Effective anticancer effect / response in patients" can be, for example, an inhibition of 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more in the patient response, which can be measured by any appropriate means, such as gene expression, cell count or analysis results.

[0088] In this specification, the dosage refers to the dose expected to produce a therapeutic effect. In this invention, the therapeutic effect can be an anticancer effect. The responsiveness (anticancer effect) of an anticancer agent, as the degree of response, can be the % maximum effect of the anticancer agent, such as IC50, IC60, IC70, IC80, and IC90, or a value indicating toxicity to normal cells (LC50).

[0089] For example, oral formulations can be prepared using various formulation techniques known in the art. For instance, they may include a biodegradable (hydrolyzable) polymer carrier for adhesion to the oral mucosa. They can be formulated to slowly erode over a predetermined period, during which drug delivery occurs substantially monolithically.

[0090] In oral dosage forms, drug delivery avoids the disadvantages of oral administration, such as slow absorption, degradation of the active ingredient in the fluids present in the gastrointestinal tract, and / or first-pass inactivation in the liver. For the biodegradable (hydrolyzable) polymer carrier, virtually any such carrier can be used, provided it does not impair the desired drug release characteristics, and the carrier should be compatible with any other components present in the oral dose unit. Typically, the polymer carrier comprises a hydrophilic (water-soluble and water-swellable) polymer capable of adhering to the moist surface of the oral mucosa. Examples of polymer carriers that may be used in this specification include acrylic polymers (e.g., carbomer). In some embodiments, non-limiting examples of other components that may be incorporated into the oral dosage form include disintegrants, diluents, binders, lubricants, flavoring agents, colorants, and preservatives. In some embodiments, for oral or sublingual administration, the dosage form may be a tablet, lozenge, or gel prepared using conventional methods.

[0091] In some embodiments, if the patient's condition improves, the compound may continue to be administered as determined by the physician; alternatively, the dosage of the administered drug may be temporarily reduced, or administration may be temporarily discontinued for a certain period (i.e., a "withdrawal period"). The length of the withdrawal period may vary between 2 and 1 year, and is only exemplified by including 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days. In some embodiments, the dose reduction during the discontinuation period is 10%–100%, which are examples only and include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0092] If the patient's condition improves, a maintenance dose may be given if necessary. Subsequently, the dose or frequency of administration, or both, may be reduced as a function of symptoms to a level that can maintain the improved disease, disorder, or pathological state. However, patients may require intermittent treatment for extended periods in the event of any recurrence of symptoms.

[0093] The specific dosage of the formulation corresponding to such dosage will vary depending on factors of the patient being treated, such as the specific compound, the severity of the disease, and individual characteristics (e.g., weight); however, it may be routinely determined, for example, according to methods known in the art, based on the dosage form, route of administration, and specific circumstances surrounding the patient. Generally, the dosage used in adult treatment is typically in the range of 0.02–5000 mg / day, or about 1–1500 mg / day.

[0094] In this specification, a single dose may be administered as a single dose or as a split dose, for example, divided into 2, 3, 4 or more sub-dose.

[0095] In some embodiments, the oral dosage form is a unit-dose form suitable for single-dose administration at a precise dose. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. In some embodiments, the unit dose is a packaged form comprising dose formulations separated from each other. Non-limiting examples include packaged tablets or capsules, and powders contained in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-resealable containers. Alternatively, multi-dose, resealable containers may be used, in which case preservatives are typically included in the composition.

[0096] In some embodiments, the non-enteric injectable formulation may be provided in unit dose form (non-limiting examples include ampoules) or in multi-dose containers and may contain additional preservatives.

[0097] Typically, it is prepared in a unit-dose injectable form with a pharmaceutically acceptable enteric carrier for enteric administration, i.e., bolus, intravenous injection, and intratumoral injection. It can optionally be in lyophilized or aqueous form, mixed with pharmaceutically acceptable diluents, carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.).

[0098] The effects of the invention

[0099] According to the present invention, the camptothecin derivative represented by chemical formula 1 has superior properties in terms of efficacy, toxicity, selectivity, duration of action, administration method, operability, stability and / or production feasibility compared to existing camptothecin derivatives, and has the following advantages: by (i) simultaneously inhibiting Bcl family proteins including the drug resistance protein Survivin and / or (ii) inhibiting the efflux pump, it has the advantage of maximizing the modulation efficacy of the main drug target.

[0100] Furthermore, the carrier-drug conjugate containing the camptothecin derivative represented by Formula 1 according to the present invention has the advantage of providing high safety while minimizing toxicity and exhibiting high therapeutic efficacy.

[0101] The present invention provides compounds of chemical formulas 2 to 10 as examples of compounds belonging to chemical formula 1, wherein the compounds of chemical formula 2, whether as a single compound or when prepared as an ADC, exhibit high toxicity and selectivity against cancer cells. Attached Figure Description

[0102] Figure 1 The diagram shows the structural formulas of various camptothecin-based anticancer agents (SN-38, Exatecan, Dxd, FL118).

[0103] Figure 2 To illustrate the in vitro cell viability analysis results of compound 2 in FaDu and NHEK cell lines.

[0104] Figure 3 The results show the in vitro cell viability analysis of compound 2 in the KPL-4 cell line.

[0105] Figure 4 The results show the in vitro cell viability analysis of compound 2 in the MDA-MB-453 cell line.

[0106] Figure 5 The results show the in vitro cell viability analysis of compound 2 in the MDA-MB-468 cell line.

[0107] Figure 6 The results are presented for the bystander killing effect analysis of compound 2-based ADCs in MDA-MB-468 and KPL-4 cell lines.

[0108] Figure 7 The results show the in vitro cell viability analysis of the compound 2-based ADC in the MDA-MB-453 cell line.

[0109] Figure 8 The results show the in vitro cell viability analysis of the compound 2-based ADC in the MDA-MB-468 cell line. Detailed Implementation

[0110] The present invention will be described in more detail below through embodiments. However, the following embodiments are only used to illustrate the technical features of the present invention and do not limit the scope of protection of the present invention.

[0111]

Example 1

[0112] Material preparation

[0113] The FaDu, A549, FaDu, NHEK, KPL-4, MDA-MB-453 and MDA-MB-468 cell lines used in this invention were purchased from ATCC; Trastuzumab was purchased from Wuxi Biologics; Enhertu was purchased from Daiichi-Sankyo; T-DM1 was purchased from Genentech; and Dxd was purchased from Symers.

[0114] Analysis conditions, etc.

[0115] Analytical conditions: U_AN_ACID, Instrument: Agilent Infinity II; Binary Pump: G7120A, Multisampler, Vial Temperature Control Module (VTC), Diode Array Detector (DAD): Agilent G7117B, 220-320nm, Photodiode Array Detector (PDA): 210-320nm, Mass Spectrometer Detector (MSD): Agilent G6135B, Electrospray Ionization (ESI), Positive / Negative Ion Mode 100-1000, Evaporative Light Scattering Detector (ELSD G7102A): Evaporation temperature 40℃, Nebulization temperature 40℃, Gas flow rate 1.6mL / min, Column: Waters XSelect CSH C18, 50x2.1mM, 2.5μM, Column temperature: 40℃, Flow rate: 0.6mL / min. Gradient: t0=5% B, t2min=98% B, t2.7min=98% B, Post-equilibrium time: 0.3 min, Mobile phase A: water containing 0.1% formic acid, Mobile phase B: acetonitrile containing 0.1% formic acid.

[0116] Acidic preparative LC (MPLC) (Luna)

[0117] Instrument type: Reveleris™ preparative medium-pressure liquid chromatography system (prep MPLC); Column: Phenomenex LUNA C18(3) (150 × 25 mm, 10 μm); Flow rate: 40 mL / min; Column temperature: room temperature; Mobile phase A: water containing 0.1% (v / v) formic acid, Mobile phase B: acetonitrile containing 0.1% (v / v) formic acid; Gradient; UV detection: 220, 254, 340 nm, evaporative light scattering detector (ELSD).

[0118] Acidic preparative medium-pressure liquid chromatography (MPLC) (Reprosil)

[0119] Instrument type: Reveleris™ preparative medium-pressure liquid chromatography system (prep MPLC); Column: Dr. Maisch Reprosil C18 (150 × 25 mm, 10 μm); Flow rate: 40 mL / min; Column temperature: room temperature; Mobile phase A: water containing 0.1% (v / v) formic acid, Mobile phase B: acetonitrile containing 0.1% (v / v) formic acid; Gradient; UV detection: 220, 254, 340 nm, evaporative light scattering detector (ELSD).

[0120] Synthesis of camptothecin derivatives

[0121] Example 1-1. Synthesis of the camptothecin derivative (compound 2) shown in chemical formula 2

[0122] (S)-3-hydroxybutyric acid (19 mg, 0.18 mmol) was dissolved in 1 mL of N,N-dimethylformamide, and HATU (69 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. 0.55 mL of this solution was added to a suspension obtained by dissolving (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione methanesulfonate (49 mg, 90 μmol) and DIPEA (39 μL, 0.23 mmol) in N,N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 30 minutes and then incubated overnight at -20 °C. The reaction mixture was purified by acidic preparative medium-pressure liquid chromatography (MPLC) (Luna 10–50), and the product fraction was collected and lyophilized to give a pale yellow solid. (Yield: 35 mg, 73%)

[0123] U_AN_ACID: m / z534.2[M+H]+

[0124] 1H NMR (400MHz, DMSO-d6) δ8.40 (d, J=8.7Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.29 (d, J=8.7Hz, 2H), 5.58-5.50 (m, 1H), 5.46-5.35 (m, 2H), 5.25-5.11 (m, 2H), 4.62 (d, J=4.4Hz, 1H), 4 .10-3.98 (m, 1H), 3.08-2.98 (m, 2H), 2.28 (dd, J=13.6, 7.4Hz, 1H), 2.18 (dd, J=13.6, 5.9Hz, 1H ), 2.14-1.99 (m, 2H), 1.92-1.77 (m, J=7.1Hz, 2H), 1.08 (d, J=6.2Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0125] Examples 1-2. Synthesis of the camptothecin derivative (compound 3) shown in formula 3

[0126] Dissolve (S)-3,3,3-trifluoro-2-hydroxypropionic acid (11.59 mg, 0.080 mmol) in N,N-dimethylformamide (2 mL), and add HATU (30.6 mg, 0.080 mmol).

[0127] After stirring the mixture for 3 minutes, (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione (30 mg, 0.067 mmol) and DIPEA (0.047 mL, 0.268 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was directly purified by acidic preparative medium-pressure liquid chromatography (MPLC) (Luna 10–50), and the product fraction was collected and lyophilized to give a grayish-white solid product. (Yield: 19 mg, 49%)

[0128] The compound (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizano[1,2-b]quinoline-11,14-dione can be obtained by the methods described in PCT / KR2023 / 009854, etc., but is not limited thereto.

[0129] U_AN_ACID: m / z574.2[M+H]+

[0130] 1H NMR (400MHz, DMSO-d6) δ8.95 (d, J=8.6Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 7.18 ( d, J=6.2Hz, 1H), 6.48 (s, 1H), 6.29 (d, J=7.1Hz, 2H), 5.61-5.52 (m, 1H), 5.46-5 .35 (m, 2H), 5.21 (d, J=19.2Hz, 1H), 5.06 (d, J=19.2Hz, 1H), 4.66-4.55 (m, 1H), 3.08-2.97 (m, 2H), 2.18-2.03 (m, 2H), 1.93-1.77 (m, 2H), 0.87 (t, J=7.3Hz, 3H).

[0131] Examples 1-3. Synthesis of camptothecin derivatives (compound 4) shown in formula 4

[0132] (R)-2-hydroxybutyric acid (20.9 mg, 0.201 mmol) was dissolved in 1 mL of DMF. HOSu (23.1 mg, 0.201 mmol) and EDC (38.6 mg, 0.201 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours.

[0133] Subsequently, 0.3 mL of activated acid solution was added to a suspension of (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizano[1,2-b]quinoline-11,14-dione (30 mg, 0.067 mmol) and triethylamine (0.019 mL, 0.134 mmol) dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 23 hours. The reaction mixture was directly purified by acidic preparative MPLC (Luna 10-50), and the product fraction was lyophilized to give a grayish-white solid. (Yield: 25 mg, 69%)

[0134] U_AN_ACID: m / z534.2[M+H]+

[0135] 1H NMR (400MHz, DMSO) δ8.39 (d, J=8.9Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.48 (s, 1H), 6.29 (d, J=3.6Hz, 2H), 5.57-5.50 (m, 1H), 5.48-5.44 (m, 1H), 5.41 (s, 2H) , 5.13 (s, 2H), 3.92-3.86 (m, 1H), 3.06-3.00 (m, 2H), 2.15-2.05 (m, 2H), 1.92- 1.74 (m, 3H), 1.71-1.62 (m, 1H), 0.93 (t, J=7.4Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0136] Examples 1-4. Synthesis of camptothecin derivatives (compound 5) shown in formula 5

[0137] (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione (30 mg, 0.067 mmol) and DIPEA (0.047 mL, 0.268 mmol) were added to dry dichloromethane (1 mL) to form a suspension, which was then cooled to 0 °C. Acryloyl chloride solution (5.44 μL, 0.067 mmol) was dissolved in 0.1 mL DCM and added dropwise. The reaction mixture was stirred at 0 °C, and after 30 minutes, 0.15 equivalents of acryloyl chloride were added as a DCM stock solution. After stirring for a total of 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO and purified by acidic preparative MPLC (Reprosil 10-50 method). The product fraction was collected and lyophilized to give a pale yellow, fluffy solid. (Yield: 22 mg, 65%)

[0138] U_AN_ACID: m / z502.2[M+H]+

[0139] 1H NMR (400MHz, DMSO-d6) δ8.71 (d, J=8.8Hz, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 6.4 9 (s, 1H), 6.30 (d, J=4.2Hz, 2H), 6.28-6.21 (m, 2H), 5.69 (dd, J=8.5, 3.7Hz, 1 H), 5.65-5.58 (m, 1H), 5.40 (s, 2H), 5.25-5.12 (m, 1H), 5.12-4.99 (m, 1H), 3. 10-3.02 (m, 2H), 2.16-2.06 (m, 2H), 1.92-1.78 (m, 2H), 0.86 (t, J=7.3Hz, 3H).

[0140] Examples 1-5. Synthesis of camptothecin derivatives (compound 6) shown in formula 6

[0141] (1S,4S)-4-hydroxycyclohexane-1-carboxylic acid (11 mg, 1 Eq, 78 μMol) was dissolved in N,N-dimethylformamide (1 mL). (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizano[1,2-b]quinoline-11,14-dione (35 mg, 8 μMol), DIPEA (41 μL, 0.23 mmol), and HATU (30 mg, 1 Eq, 78 μMol) were added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was purified by acidic preparative MPLC (Luna 5-40), and the product fraction was collected and lyophilized to give a bright yellow solid. (Yield: 28mg, 62%)

[0142] U_AN_ACID: m / z574.2[M+H]+

[0143] 1H NMR (400MHz, DMSO-d6) δ8.34 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.2 9 (d, J=6.4Hz, 2H), 5.57-5.48 (m, 1H), 5.46-5.35 (m, 2H), 5.19-5.10 (m, 1H), 5.09-4.99 (m , 1H), 4.34 (d, J=2.9Hz, 1H), 3.77 (s, 1H), 3.10-2.97 (m, 2H), 2.24-2.13 (m, 1H), 2.10-1.9 9 (m, 2H), 1.93-1.78 (m, 4H), 1.72-1.60 (m, 2H), 1.55-1.34 (m, 4H), 0.87 (t, J=7.3Hz, 3H).

[0144] Examples 1-6. Synthesis of camptothecin derivatives (compound 7) shown in formula 7

[0145] (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizano[1,2-b]quinoline-11,14-dione (50 mg, 0.11 mmol) was suspended in N,N-dimethylformamide (2.5 mL), and DIPEA (78 μL, 0.45 mmol), (1R,4R)-4-hydroxycyclohexane-1-carboxylic acid (16 mg, 0.11 mmol), and HATU (42 mg, 1 Eq, 0.11 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by acidic preparative MPLC (Luna 5-40), and the product fraction was collected and lyophilized. (Yield: 32mg, 48%)

[0146] U_AN_ACID: m / z574.2[M+H]+

[0147] 1H NMR (400MHz, DMSO-d6) δ8.39 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 6.50 (s, 1H), 6.29 (d, J=6.6Hz, 2H), 5.55-5.35 (m, 3H), 5.18-4.95 (m, 2 H), 4.56 (d, J=4.4Hz, 1H), 3.11-2.97 (m, 2H), 2.15-1.98 (m, 3H), 1.94-1 .71 (m, 6H), 1.54-1.39 (m, 2H), 1.16-1.00 (m, 2H), 0.87 (t, J=7.3Hz, 3H).

[0148] Examples 1-7. Synthesis of camptothecin derivatives (compound 8) shown in formula 8

[0149] (1S,3S)-3-hydroxycyclobutane-1-carboxylic acid (21 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (2 mL), and HATU (70 mg, 0.18 mmol) was added. The reaction mixture was stirred for 1 hour. 1 mL of this solution was added to a suspension of (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizano[1,2-b]quinoline-11,14-dione methanesulfonate (50 mg, 92 μMol) and DIPEA (32 μL, 0.18 mmol) dissolved in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours. Add 0.15 mL of active acid solution, and after 20 minutes, add DIPEA (16 μL, 92 μmol). Complete conversion is achieved after 20 minutes. The reaction mixture is then loaded into a syringe and filtered. Purification is performed by acidic preparative MPLC (Luna 5-40). The product fraction is collected and lyophilized to obtain a pale yellow, fluffy solid. (Yield: 30 mg, 60%)

[0150] U_AN_ACID: m / z546.2[M+H]+

[0151] 1H NMR (400MHz, DMSO-d6) δ8.39 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.4 8 (s, 1H), 6.29 (d, J=3.3Hz, 2H), 5.57-5.49 (m, 1H), 5.46-5.35 (m, 2H), 5.17- 4.99 (m, 3H), 3.99-3.88 (m, 1H), 3.04 (q, J=6.4Hz, 2H), 2.46-2.34 (m, 2H), 2. 32-2.24 (m, 1H), 2.13-2.00 (m, 4H), 1.92-1.79 (m, 2H), 0.87 (t, J=7.3Hz, 3H).

[0152] Examples 1-8. Synthesis of camptothecin derivatives (compound 9) shown in formula 9

[0153] (1R,3R)-3-hydroxycyclobutane-1-carboxylic acid (21 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (1 mL), and HATU (69 mg, 0.18 mmol) was added. The reaction mixture was stirred for 20 minutes. 0.55 mL of this solution was added to a suspension of (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizano[1,2-b]quinoline-11,14-dione methanesulfonate (49 mg, 90 μMol) and DIPEA (47 μL, 0.27 mmol) dissolved in N,N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by acidic preparative MPLC (Luna 10-50), and the product fraction was collected and lyophilized to give a yellow solid. (Yield: 29 mg, 59%)

[0154] U_AN_ACID: m / z546.2[M+H]+

[0155] 1H NMR (400MHz, DMSO-d6) δ8.36 (d, J=8.8Hz, 1H), 7.40 (s, 1H), 7.23 (s, 1H), 6.47 (s, 1H), 6.28 (d, J=4.3Hz, 2H), 5.58–5.49 (m, 1H), 5.46–5.34 (m, 2H), 5.26–4.8 2 (m, 3H), 4.41–4.30 (m, 1H), 3.11–2.95 (m, 2H), 2.95–2.84 (m, 1H), 2.47–2.34 (m, 2H), 2.13–1.95 (m, 4H), 1.92–1.76 (m, J=7.4Hz, 2H), 0.87 (t, J=7.3Hz, 3H).

[0156] Examples 1-9. Synthesis of camptothecin derivatives of formula 10 (compound 10)

[0157] (R)-3-hydroxybutyric acid (19 mg, 0.18 mmol) was dissolved in 1 mL of N,N-dimethylformamide, and HATU (69 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 20 minutes. 0.55 mL of this solution was added to a suspension containing (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxane[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione methanesulfonate (49 mg, 90 μMol) and DIPEA (47 μL, 0.27 mmol) dissolved in 2.5 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with 2 mL of DMSO and filtered through a nylon filter membrane. The filter membrane was washed twice with 4 mL of DMSO. All fractions were purified separately by acidic preparative MPLC (Luna 10-50), combined, and lyophilized to give a white solid. (Yield: 25 mg, 52%)

[0158] U_AN_ACID: 1H NMR (400MHz, DMSO-d6) δ8.41 (d, J=8.8Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.49 (s , 1H), 6.30 (d, J=6.1Hz, 2H), 5.59–5.47 (m, 1H), 5.41 (s, 2H), 5.26–5.05 (m, 2H), 4 .65 (d, J=4.7Hz, 1H), 4.11–3.98 (m, 1H), 3.08–2.96 (m, 2H), 2.32–2.17 (m, 2H), 2. 15–1.99 (m, 2H), 1.92–1.79 (m, 2H), 1.08 (d, J=6.2Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0159]

Example 2

[0160] Preparation of antibody-drug conjugates 221 The compound shown in Chemical Formula 2 of the present invention was conjugated with trastuzumab via the linker shown in Chemical Formula 11 above to prepare an antibody-drug conjugate containing the compound of the present invention, and its anticancer efficacy was tested.

[0161] The antibody-drug conjugate was prepared as follows.

[0162] Trastuzumab was desalted using a PD-10 column, and the buffer was replaced with reduction buffer (150 mM NaCl, 50 mM M istidine, pH 6.0). Then, 27.5 μM of the antibody was treated with 825 μM TCEP at 25 °C for 2 hours to reduce the disulfide bonds of the antibody.

[0163] Excess TCEP was then removed using a PD-10 desalting column. The drug-linker of formula 2a (165 μM) with the linker shown in formula 11 was then reacted with the reducing antibody (13.8 μM) at 25 °C for 1 hour in a reaction buffer containing 15% DMSO (25 mM Mistidine, pH 6.0) to carry out the coupling reaction.

[0164] At this point, the drug-to-antibody ratio (DAR) is approximately 8. After the conjugation reaction, excess drug-linker is removed by passing the product through a PD-10 desalting column to obtain the final antibody-drug conjugate.

[0165]

Example 3

[0166] The anticancer effect of compound 2 was confirmed.

[0167] 3-1. Evaluation of the cell viability of compound 2

[0168] In this embodiment, to confirm the anticancer efficacy of the compound of chemical formula 2 obtained according to Example 1-1 above, its effect in FaDu cells and NHEK (Normal Human Epidermal Keratinocytes) was confirmed.

[0169] In 96-well plates, 3000 FaDu and NHEK cell lines were seeded in each well and incubated at a constant temperature (37°C, 5% CO2). After 24 hours, 100 μL of the drug (9 concentrations, serially diluted 1 / 5 starting from 1000 nM) was added to the cells. At this point, the compound of chemical formula 2 of this invention was treated (control group treated Dxd). After 3 days of incubation at a constant temperature (37°C, 5% CO2), 100 μL of CellTiter-Glo reagent (using the CellTiter-Glo® Luminescent CellViability Assay kit (Promega, G7571)) was added to each well and pipetteted to mix. After incubation at room temperature (RT) for 10 minutes, luminescence was measured. The luminescence value at which the drug concentration was 0% was considered 100%, and the drug concentration corresponding to a luminescence value of 50% was the IC50 value.

[0170] like Figure 2 As shown, in the FaDu cell line, compound 2 of the present invention (compound of chemical formula 2) exhibits excellent cytotoxicity. Furthermore, compound 2 shows relatively low cytotoxicity in NHEK (Normal Human Epidermal Keratinocytes) cells, confirming its superior safety compared to Dxd.

[0171] 3-2. Evaluation of the cell viability of compound 2

[0172] Cancer cell lines KPL-4, MDA-MB-453, and MDA-MB-468 were inoculated using the same method as in Example 3-1 above and cultured at an incubator for 24 hours. Compound 2 (a compound of formula 2) was then treated. See [link to relevant documentation]. Figure 3 , Figure 4 and Figure 5 When compound 2 was evaluated for efficacy alone in various cancer cell lines, compound 2 showed cytotoxic efficacy similar to or better than DXd.

[0173] 3-3. Bystander Killing Effect of Compound 2-Based ADC

[0174] The ADC (compound 2-linker-trastuzumab) prepared according to Example 2 was confirmed. Figure 6 The bystander killing effect (marked as TRA-Compound 2).

[0175] Cancer cell lines KPL-4 and MDA-MB-468 were inoculated using the same method as in Example 3-1 above and cultured at an incubator. After 24 hours, the cells were treated with compound 2 (chemical formula 2). At this time, control groups were treated with untreated cells, trastuzumab, Enhertu, Kadcyla (T-DM1), isotype control - Dxd, and isotype control - compound 2, respectively. After 5 days of incubation at an incubator (37°C, 5% CO2), all cells were stained with anti-HER2 FITC antibody, diluted in buffer, and the total cell count was performed using flow cytometry (Beckman Coulter), and the number of cells expressing FITC fluorescence was determined.

[0176] See Figure 6 The study confirmed that compound 2-based ADCs exhibited a bystander-killing effect similar to Enhertu, but with superior efficacy compared to Kadcyla (T-DM1). Furthermore, it demonstrated superior cytotoxic efficacy compared to Enhertu in HER2-positive KPL-4 cell lines.

[0177] 3-4. Evaluation of the cell viability of compound 2-based ADCs

[0178] Cancer cell lines MDA-MB-453 and MDA-MB-468 were inoculated using the same method as in Example 3-1 above and cultured at an insulated temperature. After 24 hours, they were treated with compound 2-based ADCs. The efficacy of compound 2-based HER2-targeting ADCs, namely Tra-compound 2, was evaluated in various cancer cell lines with different HER2 expression levels. The results showed that it exhibited superior cytotoxic efficacy compared to Tra-DXd in HER2-positive cell lines. Furthermore, compound 2-based ADCs showed lower cytotoxicity in HER2-negative cell lines, confirming that it is safer than Dxd (see [reference]). Figure 7 and Figure 8 That is, it can be seen that the compound 2-based ADC prepared according to the present invention, even when using the same antibody, has better selectivity for cancer cells and exhibits higher toxicity compared to existing drugs (Dxd).

[0179] In summary, the compounds of Formula 1 according to the present invention not only exhibit toxicity to cancer cells on their own, but also show high toxicity to cancer cells in the form of an ADC bound to a linker-antibody. In particular, it has been confirmed that the compounds of Formula 2, when prepared as an ADC, exhibit significant toxicity to cancer cells compared to existing drugs, and demonstrate high selectivity for targeting cancer cells, making them potential candidates for use as excellent anticancer drugs.

[0180] The present invention has been described so far with a focus on preferred embodiments. Those skilled in the art will understand that the invention can be implemented in variations without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the invention is embodied in the claims rather than in the foregoing description, and all differences within the equivalent scope should be interpreted as included within the present invention.

Claims

1. A compound, its isomer, its pharmaceutically acceptable salt, or its solvate represented by Formula 1: [Chemical Formula 1]: ， in, In the chemical formula 1, R is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, C2-C10 alkynyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C2-C10 heteroaryl, C1-C10 monoalkylamino or C1-C10 dialkylamino, nitro, and cyano.

2. The compound represented by chemical formula 2 according to claim 1, or its isomers, pharmaceutically acceptable salts, or solvates thereof: [Chemical Formula 2]: 。 3. A carrier-drug conjugate comprising a compound of formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 1]: ， in, In the chemical formula 1, R is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, C2-C10 alkynyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C2-C10 heteroaryl, C1-C10 monoalkylamino or C1-C10 dialkylamino, nitro, and cyano.

4. The carrier-drug conjugate according to claim 3, wherein, The compound of chemical formula 1 is a compound represented by chemical formula 2: [Chemical Formula 2]: 。 5. The carrier-drug conjugate according to claim 3, characterized in that, The carrier is an antibody, peptide, liposome, or aptamer.

6. The carrier-drug conjugate according to claim 3, characterized in that, The carrier-drug conjugate is a form in which the carrier is conjugated to the drug via a linker.

7. The carrier-drug conjugate according to claim 6, characterized in that, The connector includes GGFG.

8. The carrier-drug conjugate according to claim 5, characterized in that, The carrier is an antibody, peptide, liposome, or aptamer that specifically binds to one or more substances selected from the group consisting of the following substances (antigens): 4-1BB, 5T4, integrin, activin, amyloid beta, angiopoietin (angiopoietin 1 or 2), angiopoietin-like protein 3, B-cell maturation antigen (BCMA), B-cell activating factor (BAFF), B7-H3, complement 5 (... 5), CCR4, CCR5, CCL11, CD2, CD3, CD4, CD6, CD11a, CD16A, CD19, CD20, CD22, CD25, CD27, CD28, CD30, CD32B, CD33, CD38, CD40, CD45, CD46, C D47, CD52, CD56, CD62, CD70, CD73, CD74, CD79b, CD80, CD105, CD123, CD154, CD166, CD262, CD278, CD319, CD326, Carcinoembryonic Antigen (Carcinoembryonic antigen, CEA), CGRP, Claudin-18, c-Met, CSF-1, CSF-1 receptor, CTLA4, DLL3, EGF receptor, hemophilia factor, Fc receptor, FGF23, folate receptor, GD2, glucocorticoid-induced TNF receptor (GITR), Glypican 3, GM-CSF, HER2, HER3, TROP2, hepatocyte growth factor (HGF), HGF), interferon receptor, interferon-γ, IgE, IGF-1 receptor, interleukin-1, interleukin-2 receptor, interleukin-4, interleukin-4 receptor, interleukin-5, interleukin-5 receptor, interleukin-6, interleukin-6 receptor, interleukin-8, interleukin-12 / 23, interleukin-13, interleukin-17A, interleukin-17 receptor A, interleukin-23, interleukin-31 receptor, interleukin-36 receptor, lymphocyte-activation gene 3 (LAG3), lysyl oxidase homolog 2,LOXL2), Mesothelin, Mucin-1, Mucin-16, Nectin-4, Nerve Growth Factor (NGF), OX40, Proprotein Convertase Subtilisin / Kexin type 9 (PCSK9), PD-1, PD-L1, Phospholipase C, RANKL (Receptor activator of nuclear factors kappa B ligand), Tyrosine-protein kinase transmembrane receptor (ROR1), Sialic acid-binding ig-like lectin 15 (Siglc-15), Transforming growth factor beta (TGFβ), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM) The following are listed: T cell immunoglobulin and mucin-domain containing-3 (T-3), tissue factor, tissue factor pathway inhibitor (TFPI), TROP-2, tumor necrosis factor (TNF), thymic stromallymphopoietin (TSLB), colony-stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF), VEGF receptor, and von Willebrand factor (vWF).

9. The carrier-drug conjugate according to claim 5, characterized in that, The carrier is an antibody.

10. The carrier-drug conjugate according to claim 9, characterized in that, The antibody is selected from one or more of the following groups of antibodies: urrelumab, utomilumab, bebtelovimab, aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, solanezumab, nesvacumab, and enoxaparin. Monoclonal antibodies (Enoblituzumab), Omburtamab, Belimumab, Ianalumab, Tabalumab, Bertilimumab, Mogamulizumab, Leronlimab, Siplizumab, Foralumab, Muromonab-CD3, Otelixizumab, Teplizumab Ibalizumab, Tregalizumab, Zanolimumab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab, Veltuzumab ab), Epratuzumab, Basiliximab, Daclizumab, Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab, Mezagitamab, Bleeselumab, DacetuzumabIscalimab, Lucarumumab, Mitazalimab, Sotigalimab, Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab, Oreglusumab Oleclumab, Milatuzumab, Galiximab, Carotuximab, Adecatumumab, Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Lav Ravulizumab, Lacnotuzumab, Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab, Zalifrelimab, Cetuximab, Depatuxizumab, Futuximab, Imaginutuzumab gatuzumab, Matuzumab, Modotuximab, Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab, Zalutuzumab, Batoclinab, Nipocalimab, Rozanolixizumab, Burosumab, FarletuzumabDinutuximab, Naxitamab, Ragifilimab, Gimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertuzumab, Trastuzumab ), Datopotamab, Patritumab, Seribantumab, Duligotuzumab, Ficlatuzumab, Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotumab Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab, Bermekimab, Canakinumab, Gevokizumab, Briakinumab, Ustekinumab, Anrukinzumab, Cendakimab, Lebrikizumab, Tralokin (The following are listed as examples of specific anti-inflammatory drugs / anti-inflammatory drugs): umab, brodalumab, bimekizumab, ixekizumab, secukinumab, brazikumab, guselkumab, mirikizumab, risankizumab, tildrakizumab, nemolizumab, imsidolimab, and spesolimab.Pascolizumab, Dupilumab, Depemokimab, Mepolizumab, Reslizumab, Benralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Levilimab, Sarilumab Satralizumab, Tocilizumab, Abituzumab, Favezelimab, Fianlimab, Ieramilimab, Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab Tavolimab, Telazorlimab, Vonlerolizumab, Alirocumab, Bococizumab, Ebronucimab, Evolocumab, Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, and Camrelizumab (Ca mrelizumab, cimiplimab, geptanolimab, nivolumab, pembrolizumab, penpulimab, pitilizumab, prolgolimab, retifanlimab, sasanlimab, serplulimab, sintilimab, spartalizumabTislelizumab, Toripalimab, Ezabenlimab, Zimberelimab, Atezolizumab, Avelumab, Cosibelimab, Sugemalimab, Durvalumab, Envafolimab, Suvratoxumab, Denosumab, Zilove rtamab), Elotuzumab, Domvanalimab, Etigilimab, Ociperlimab, Tiragolumab, Vibostolimab, Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab, Golime Monoclonal antibodies (Golimumab), Infliximab, Certolizumab, Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab, Cabiralizumab, Bevacizumab, Brolucizumab, Ranibizumab, Olinvacimab, Icruc (e.g., umab), Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrindatamab, Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab)Glofitamab, Mosunetuzumab, Odronextamab, Flotetuzumab, Vibecotamab, Catumaxomab, Cibisatamab, Talquetamab, Ubamatamab, Emfizatamab, Blinatumomab, Amivantamab, Emexicam Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naptumomab, Belantamab, Pivekimab, Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibritumomab, Inot uzumab), epratuzumab, moxetumomab, brrentuximab, gemtuzumab, vadastuximab, lovotuzumab, polatuzumab, tusamitamab, telisotuzumab, rovalpituzumab, depatuxizumab, faretuzumab etuzumab, mirvetuximab, disitamab, anetumab, enfortumab, sacituzumab, vobarilizumab, cadonilimab, vudalimab, tebotelimab, ivonescimab, erfonrilimab, and ozoraralizumab.Faricimab, Vanucizumab, and Navicixizumab.

11. A drug-linker comprising: Compounds of Formula 1, their derivatives, isomers, pharmaceutically acceptable salts, or solvates thereof; and transport carriers linked to said compound: [Chemical Formula 1]: ， In the chemical formula 1, R is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, C2-C10 alkynyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C2-C10 heteroaryl, C1-C10 monoalkylamino or C1-C10 dialkylamino, nitro, and cyano.

12. The drug-linker according to claim 11, characterized in that, The connector includes GGFG.

13. A pharmaceutical composition for cancer prevention or treatment, comprising: the camptothecin derivative according to claim 1, the carrier-drug conjugate according to claim 3, or the drug-linker according to claim 11.

14. The pharmaceutical composition according to claim 13, characterized in that, The cancers mentioned are selected from pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, and kidney cancer. The cancer includes one or more of the following: heart cancer, duodenal cancer, malignant soft tissue tumors, malignant bone tumors, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, nephroblastoma, breast cancer, triple-negative breast cancer (TNBC), sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematologic malignancies, and thymic cancer.

Images