Novel camptothecin derivative and carrier-drug conjugate comprising same

Abstract

The present invention relates to a novel camptothecin derivative having the structure of chemical formula 1, and a carrier-drug conjugate comprising same, the derivative possessing properties preferable to those of a conventional camptothecin derivative in terms of efficacy, toxicity, selectivity, duration of action, administration, handling, stability, and / or manufacturability and having the advantage of maximizing the efficacy of the main drug target modulation through additional mechanisms of (i) inhibiting, simultaneously, the Bcl family such as a resistance protein Survivin and / or (ii) inhibiting efflux pump activity. The novel camptothecin derivative and carrier-drug conjugate, according to the present invention, exhibit excellent anticancer efficacy and safety, and thus can be applied to treatment of various cancers.

Description

Novel camptothecin derivatives and antibody-drug conjugates containing the same

[0001] The present invention relates to a novel camptothecin derivative having excellent anticancer efficacy and safety, a carrier-drug conjugate comprising the same, and pharmaceutical uses thereof.

[0002] Inhibitors of topoisomerase I, an isomerizing enzyme involved in DNA replication and recombination, are drugs with proven efficacy and safety and anticancer mechanisms. In clinical trials, their excellent anticancer efficacy has been proven in various intractable solid cancers, including colon cancer, lung cancer, breast cancer, and ovarian cancer.

[0003] Camptothecin (CPT) and its derivatives are known as representative type 1 topoisomerase inhibitors, but camptothecin has the problem of low water solubility and high toxicity.

[0004] To address these issues, research has been conducted on camptothecin derivatives with low toxicity and high water solubility, and drugs such as irinotecan and topotecan have been approved for use in the treatment of colon cancer, ovarian cancer, and lung cancer and are currently on the market.

[0005] Various camptothecin derivatives are being developed to date, and SN-38 has an IC in the nanomolar range in several cell lines. 50 It is a potent topoisomerase-I inhibitor with a value of 100%, and is the active form of irinotecan, a prodrug used in the treatment of colorectal cancer, and is also active in lung, breast, and brain cancers. Trop-2-SN-38 antibody-drug conjugates (ADCs) are currently effective in a number of cancers, including TNBC, bladder cancer, and gastric cancer, but resistance to SN-38 still remains an issue.

[0006] Additionally, Daiichi Sankyo used DXd, a derivative of exatecan, a cytotoxic drug that is approximately 10 times more active against cancer cells than SN-38, in the development of Enhertu. DXd has good solubility, is relatively safe, and has a high cytotoxic effect on surrounding cells, making it advantageous for treating heterogeneous tumors. However, it has a short half-life, which can reduce off-target effects.

[0007] When camptothecin-based drugs developed to date are used as payloads in ADCs, they have lower cytotoxicity compared to ADCs with existing ultra-toxic payloads such as MMAE or MMAF, but still present safety issues. In addition, they have the problem of reduced anticancer efficacy due to resistance caused by overexpression of ABCG2 Drug Efflux Pump, etc.

[0008] Therefore, there is an urgent need for camptothecin derivatives that exhibit higher cytotoxicity while maintaining excellent safety and significantly reducing resistance that leads to decreased anticancer efficacy, particularly camptothecin derivatives suitable as payloads, and carrier-drug conjugates comprising the same.

[0009] Under this technical background, the present invention aims to provide a novel camptothecin derivative that exhibits a strong type 1 topoisomerase inhibitory effect, exhibits high cytotoxicity, and has excellent safety.

[0010] In addition, 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 the same.

[0011] Furthermore, the present invention aims to provide a method for treating cancer using a camptothecin derivative according to the present invention or a carrier-drug conjugate comprising the same.

[0012] To solve the above problem, the 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.

[0013] A second aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by Chemical Formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

[0014] C in the compound of chemical formula 1 according to the present invention 1-3 It is clear that even if a simple functional group such as an alkyl, hydroxy, halogen, or amine group is added, or an existing hydroxy, ethyl, or oxo functional group is replaced or removed with another functional group, it is included in the scope of equivalents of the present invention as long as it exhibits an effect equivalent to that of the immunoconjugate of the present invention.

[0015]

[0016] Hereinafter, the present invention will be described in more detail.

[0017] The present invention provides a novel camptothecin derivative having a structure represented by chemical formula 1.

[0018] [Chemical Formula 1]

[0019]

[0020] In the above 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, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted C2-C10 heteroaryl group, a C1-C10 mono- or dialkylamino, nitro, and cyano group.

[0021] For example, in the above chemical formula 1, R can be selected from the group consisting of:

[0022]

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

[0024] [Chemical Formula 2]

[0025]

[0026] [Chemical Formula 3]

[0027]

[0028] [Chemical Formula 4]

[0029]

[0030] [Chemical Formula 5]

[0031]

[0032] [Chemical Formula 6]

[0033]

[0034] [Chemical Formula 7]

[0035]

[0036] [Chemical Formula 8]

[0037]

[0038] [Chemical Formula 9]

[0039]

[0040] [Chemical Formula 10]

[0041]

[0042]

[0043] The camptothecin derivative represented by the chemical formula 1 or an isomer thereof according to the present invention is a hydrophobic small molecule that can penetrate cell membranes, and thus can be delivered to cancer tissues by the EPR effect (enhanced permeability and retention effect) and accumulate at a high concentration while penetrating deep into the cancer tissues, and after penetrating the cell membrane and exerting cytotoxicity inside the cells to cause cell death, it is released and can continuously move into the surrounding cells by penetrating the cell membrane and acting inside the cells.

[0044]

[0045] In the present specification, the camptothecin derivative represented by the compound of formula 1 or an isomer thereof according to the present invention includes not only the compound of formula 1 or an isomer thereof, but also a pharmaceutically acceptable salt thereof, a solvate thereof, and a prodrug thereof.

[0046] In this specification, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, and include, for example, salts of inorganic ions including sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, and iron, and salts of inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid, and salts of organic acids such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotate acid, and acetylsalicylic acid, and salts of amino acids such as lysine, arginine, and guanidine. In addition, there are salts of organic ions such as tetramethyl ammonium, tetraethyl ammonium, tetrapropyl ammonium, tetrabutyl ammonium, benzyl trimethyl ammonium, and benzethonium that can be used in pharmaceutical reactions, purification, and separation processes, but are not limited thereto.

[0047] The term "prodrug" has the meaning used in the relevant technical field. For example, it refers to a drug that is converted from an inactive compound to an active form through drug metabolism in the body. For example, it refers to a compound that is chemically modified from a physiologically active substance or therapeutically active organic compound and designed to liberate or release the parent compound in the body under enzymatic or other conditions. A prodrug is converted into the desired compound in the body after administration. Chemical modifications are applied to drugs that, despite being useful, have unsuitable properties such as side effects, stability, solubility, absorbability, and duration of action, making them clinically viable.

[0048] "Solvate" means a compound represented by formula 1 or an isomer thereof and a pharmaceutically acceptable salt thereof, further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0049]

[0050] In one aspect, the present invention provides a carrier-drug conjugate comprising a compound represented by the chemical formula 1 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0051] In the present invention, a "carrier" means a substance having the ability to selectively and specifically deliver a camptothecin derivative according to the present invention to a target site, for example, a cancer cell, and may be, but is not limited to, an antibody, a peptide, a lipobody, and / or an aptamer, and is preferably an antibody.

[0052]

[0053] Aptamer-drug conjugates (ApDCs) replace antibodies in ADCs with aptamers. Aptamers are single-stranded nucleic acids with a three-dimensional structure. Aptamers are typically discovered through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process, a technique that involves adding a target protein molecule to a compound library to obtain functional nucleic acids that bind to it. Aptamers can bind to their targets very potently and selectively, and are therefore also called chemical antibodies. Aptamers are approximately 20 kDa in size and are known to have superior cell penetration and lower immunogenicity compared to antibodies.

[0054] Aptamers can be chemically synthesized, allowing precise design of the conjugation location and number of drug molecules when manufacturing aptamer-drug conjugates. Compared to ADCs, production costs are lower. Aptamers are typically composed of natural nucleic acids, which are degraded by nucleases in the body, reducing their stability in the body. However, the ease of chemical modification of aptamers can be exploited to overcome the stability limitations of modified aptamers.

[0055]

[0056] Peptide-drug conjugates (PDCs) are a form of ADC that replaces antibodies with peptides. Peptides are composed of amino acids and range in size from 500 to 5,000 Da (Daltons), which is very small compared to antibodies, which typically weigh over 150 kDa (kilodaltons). Therefore, peptide-based PDCs have superior cell penetration capabilities compared to ADCs and a very low risk of immunogenicity. Furthermore, peptides can be chemically synthesized. This not only reduces production costs but also allows for precise control of the conjugation location and ratio of peptide and drug. Peptides are generally easily degraded by proteases, resulting in short biological half-lives. To overcome these limitations of peptide-based drug conjugates, strategies utilizing modified peptides, such as cyclic peptides and the introduction of unnatural amino acids, are being proposed.

[0057]

[0058] Repebodies are a type of artificial antigen that, although lacking an antibody backbone, possess the ability to recognize antigens like antibodies. Repebodies specific for target proteins can be identified using phage display technology.

[0059] Phage display is a technology that expresses a desired protein on the surface of bacteriophage. Repebodies are approximately 30 kDa in size, approximately 20% that of antibodies. Therefore, they are known to have relatively low immunogenicity and enhanced cell penetration compared to antibodies. Furthermore, Repebodies are expected to enhance structural stability by controlling thermal and pH stability. Their production costs are also considered relatively low compared to antibodies. Due to these advantages, interest is growing in the development of Repebodies-drug conjugates (Repebody-DC) as a strategy to replace antibodies with Repebodies.

[0060]

[0061] In the present invention, examples of targets to which the carrier binds, for example, antigens, include, but are not limited to, antigens selectively distributed on the surface of cancer cells, such as Her2, FolR, and PSMA, and antigens overexpressed in cancer cells that are also distributed in small numbers in normal tissues, such as Trop2.

[0062] 예시적인 암 세포 표적 항원은 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, 아로마타제 (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 (플렉틴), BRCA1, C19orflO (IL27w), C3, C4A, C5, C5R1, CA6, CA9, CANT1, CAPRIN-1, CASP1, CASP4, CAV1, CCBP2 (D6 / JAB61), CCL1 (1-309), CCLI1 (에오탁신), 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 / 에오탁신-2), CCL25 (TECK), CCL26(에오탁신-3), CCL27 (CTACK / ILC), CCL28, CCL3 (MIP-Ia), CCL4 (MIPIb), CCL5(RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1,CCNE1, CCNE2, CCR1 (CKR1 / HM145), CCR2 (mcp-IRB / RA), CCR3 (CKR3 / CMKBR3), CCR4, CCR5(CMKBR5 / ChemR13), CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6), CCR7 (CKR7 / EBI1), CCR8 또는 CDw198 (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-카드헤린), 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, 키티나제 (Chitinase), CHST1O, CIK, CKLFSF2, CKLFSF3, CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3, CLDN6, CLDN7 (클라우딘-7), CLDN18, CLEC5A, CLEC6A,<h2 style=";text-align:left;direction:ltr">CLEC11A, CLEC14A, CLN3, CLU (클러스테린), 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, CTNNB1 (b-카테닌), CTSB (카텝신 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, ESR2, Earl, ESR2, F3 (TF), FADD, FAP, FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF,FGF1 (aFGF), FGF10, FGF1 1, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, 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 (fibronectin), FLT1, FLT-3, FOLR1, FOS, FOSL1(FRA-1), FR-alpha, 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, histamine and histamine receptor, HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74, HMOXI, HSP90, HUMCYT2A, ICEBERG, ICOSL, ID2,IFN-a,IFNA1,IFNA2,IFNA4,IFNA5,EFNA6,BFNA7,IFNB1,IFNgamma,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, IL20, IL20RA. IL21R, IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (당단백자 130), ILK, INHA, INHBA, INSL3, INSL4. IRAK1, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (α6 인하그린), ITGAV, ITGB3, ITGB4 (β4 인하그린), 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 (신라틴 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-b), 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 (metallothionectin-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-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, PVRIG, RAC2 (P21Rac2), RANK, RANK ligand, RARB, RGS1, RGS13, RGS3, RNFI1O (ZNF144), Ron, ROBO2, ROR1, RXR, S100A2, SCGB 1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SCYE1 (endothelial monocyte-activating cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (MASPIN), 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 (thrombospondin-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNF-a, 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, versican, VHL C5, VLA-4, WT1, Wnt-1, XCL1 (lymphotactin), 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,<h2 style=";text-align:left;direction:ltr">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 is not limited thereto.

[0063] Additionally, the target antigen may be an antigen that is distributed more than 10 times more abundantly in cancer cells than in normal cells.

[0064]

[0065] Non-limiting examples of antibodies in the present invention include Urelumab, Utomilumab, Bebtelovimab, Aducanumab, Bapinezumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, Solanezumab, Nesvacumab, Evinacumab, Enoblituzumab, Omburtamab, Belimumab, Ianalumab, Tabalumab, Bertilimumab, Mogamulizumab, Leronlimab (Leronlimab), Siplizumab, Foralumab, Muromonab-CD3, Otelixizumab, Teplizumab, Ibalizumab, Tregalizumab, Zanolimumab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab, Veltuzumab, Epratuzumab Basiliximab, Daclizumab, Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab,Mezagitamab, Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Sotigalimab, Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab, Oleclumab, Milatuzumab, Galiximab, Carotuximab, Adecatumumab Adecatumumab, Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Ravulizumab, Lacnotuzumab, Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab, Zalifrelimab, Cetuximab, Depatuxizumab (Depatuxizumab), Futuximab, Imgatuzumab, Matuzumab, Modotuximab, Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab,Zalutumumab, Batoclimab, Nipocalimab, Rozanolixizumab, Burosumab, Farletuzumab, Dinutuximab, Naxitamab, Ragifilimab, Gimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertuzumab, Trastuzumab, Datopotamab Patritumab, Seribantumab, Duligotuzumab, Ficlatuzumab, Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab, Bermekimab, Canakinumab, Gevokizumab, Briakinumab, Ustekinumab Anrukinzumab, Cendakimab, Lebrikizumab, Tralokinumab, Brodalumab, Bimekizumab, Ixekizumab,Secukinumab, Brazikumab, Guselkumab, Mirikizumab, Risankizumab, Tildrakizumab, Nemolizumab, Imsidolimab, Spesolimab, Pascolizumab, Dupilumab, Defemokimab, Mepolizumab, Reslizumab, Benralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Revilimab Levilimab, Sarilumab, Satralizumab, Tocilizumab, Abituzumab, Fabezelimab, Fianlimab, Ieramilimab, Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab, Tavolimab, Telazorlimab, Vonlerolizumab, Alirocumab, Bococizumab, Ebronuximab (Ebronucimab), Evolocumab, Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, Camrelizumab,Cemiplimab, Geptanolimab, Nivolumab, Pembrolizumab, Penpulimab, Pidilizumab, Prolgolimab, Retifanlimab, Sasanlimab, Serplulimab, Sintilimab, Spartalizumab, Tislelizumab, Toripalimab, Ezabenlimab, Zimberelimab, Atezolizumab, Avelumab, Cosibelimab, Sugemalimab (Sugemalimab), Durvalumab, Envafolimab, Subratoxumab, Denosumab, Zilovertamab, Elotuzumab, Domvanalimab, Etigilimab, Ociferlimab, Tiragolumab, Vibostolimab, Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab, Golimumab, Infliximab, Certolizumab (Certolizumab), Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab, Cabiralizumab, Bevacizumab, Brolucizumab,Ranibizumab, Olinvacimab, Icrucumab, Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrindatamab, Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab, Glofitamab, Mosunetuzumab, Odronextamab, Flotetuzumab, Bivecotamab (Vibecotamab), Catumaxomab, Cibisatamab, Talquetamab, Ubamatamab, Emfizatamab, Blinatumomab, Amivantamab, Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naptumomab, Belantamab, Pivekimab, Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibritumomab, Inotuzumab (Inotuzumab), Epratuzumab, Moxetumomab, Brentuximab, Gemtuzumab, Vadastuximab, Lorvotuzumab, Polatuzumab,Tusamitamab, Telisotuzumab, Rovalpituzumab, Depatuxizumab, Farletuzumab, Mirvetuximab, Disitamab, Anetumab, Enfortumab, Sacituzumab, Vobarilizumab, Cadonilimab, Vudalimab, Tebotelimab, Ivonescimab, Erfonrilimab, Ozoralizumab, Faricimab, Vanucizumab (Vanucizumab) or navicixizumab, but is not limited thereto.

[0066]

[0067] In the carrier-drug conjugate according to the present invention, it is preferable that the carrier and the drug are conjugated via a linker.

[0068] In the present invention, the linker should be stable in the bloodstream to prevent the drug from being separated from a carrier such as an antibody and maintain its structure until it reaches a target such as an antigen, thereby minimizing damage to normal tissues. Ideally, the linker should be stable when the antibody-drug conjugate is circulated throughout the body, but should be cleaved in the target cell to appropriately release the cytotoxic drug, thereby safely delivering the drug to the target, so that the antibody-drug conjugate has both efficacy and safety.

[0069]

[0070] The carrier-drug conjugate according to the present invention may be characterized in that the carrier is in a form in which the drug, i.e., a compound which is an active camptothecin derivative represented by Chemical Formula 1, preferably a compound represented by Chemical Formula 2 to Chemical Formula 10, is conjugated via a linker, but is not limited thereto.

[0071] In the carrier-drug conjugate according to the present invention, the compound which is an active camptothecin derivative represented by the chemical formula 1, preferably a compound of chemical formula 2 to 10, can be linked to a linker at an appropriate site as long as its properties such as anticancer activity do not change, and accordingly, the present invention provides a drug-linker in which a compound which is an active camptothecin derivative represented by the chemical formula 1, preferably a compound of chemical formula 2 to 10, is linked to a linker.

[0072] Preferably, the drug linker according to the present invention may have a structure of Chemical Formula 2a to Chemical Formula 10a, but is not limited thereto. In Chemical Formula 2a to Chemical Formula 10a, L represents a linker.

[0073] [Chemical Formula 2a]

[0074]

[0075] [Chemical Formula 3a]

[0076]

[0077] [Chemical Formula 4a]

[0078]

[0079] [Chemical Formula 5a]

[0080]

[0081] [Chemical Formula 6a]

[0082]

[0083] [Chemical Formula 7a]

[0084]

[0085] [Chemical Formula 8a]

[0086]

[0087] [Chemical Formula 9a]

[0088]

[0089] [Chemical Formula 10a]

[0090]

[0091]

[0092] In the present invention, the linker may be in a form that is cleavable under specific intracellular environments and / or conditions, i.e., such that the drug can be released from the antibody through cleavage of the linker in the intracellular environment.

[0093] For example, the linker can be a peptide linker that can be cleaved by a cleavage agent present in the intracellular environment, for example, in a lysosome or an endosome, and can be cleaved by an intracellular peptidase or protease enzyme, for example, a lysosomal or endosomal protease. Typically, the peptide linker has a length of at least two amino acids. The cleavage agent can include cathepsin B and cathepsin D, plasmin, and hydrolyzes the peptide to release the drug into the target cell. The peptide linker can be cleaved by a thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissues, and examples thereof include, but are not limited to, Gly-Gly-Phe-Gly (GGFG), Phe-Leu, or Gly-Phe-Leu-Gly linkers. Additionally, the peptide linker may be cleaved by, for example, an intracellular protease, and may be a Val-Cit linker or a Phe-Lys linker.

[0094] In the present invention, the cleavable linker is pH-sensitive and may be susceptible to hydrolysis at a specific pH value. Generally, a pH-sensitive linker indicates that it can be hydrolyzed under acidic conditions. For example, it may be an acid-labile linker that can be hydrolyzed in lysosomes, such as a hydrazone, a semicarbazone, a thiosemicarbazone, a cis-aconitic amide, an orthoester, an acetal, a ketal, etc.

[0095] Additionally, in the present invention, the linker may be cleaved under reducing conditions, and for example, a disulfide linker may correspond thereto. Various disulfide bonds may be formed using SATA (Nsuccinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3- (2-pyridyldithio)propionate), SPDB (Nsuccinimidyl-3- (2-pyridyldithio)butyrate), and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio) toluene).

[0096] The above linker may include a beta-glucuronide linker that is recognized and hydrolyzed by beta-glucuronidase, which is present in large numbers in lysosomes or is overexpressed in some tumor cells. For example, a beta-glucuronide linker disclosed in Korean Patent Publication No. 2015-0137015, such as a beta-glucuronide linker containing a self-immolative group, may be used.

[0097] Additionally, the linker may be, for example, a non-cleavable linker, and the drug is released through an antibody hydrolysis step, producing, for example, an amino acid-linker-drug conjugate. This type of linker may be a thioether group or a maleimidocaproyl group, and may maintain stability in blood.

[0098]

[0099] Preferably, the linker according to the present invention may include GGFG. According to one embodiment of the present invention, a portion of at least one amino acid side chain constituting the linker may be substituted with a hydrophilic functional group capable of separation under specific conditions. The hydrophilic functional group is preferably a monovalent hydrophilic functional group, and examples thereof include, but are not limited to, an ester or carbonate having a PEG (Polyethylene Glycol) group having 3 to 100 ethylene glycol repeating units or a beta-glucuronide.

[0100] More preferably, the linker may have a structure of chemical formula 11 or chemical formula 12, but is not limited thereto.

[0101]

[0102] In the above chemical formula 12, n can be an integer from 3 to 10.

[0103]

[0104] In the present invention, when the carrier in the carrier-drug conjugate is an antibody, the drug and / or drug-linker, which is a compound of Chemical Formula 2 to Chemical Formula 10, or a compound of Chemical Formula 2a to Chemical Formula 10a, may be randomly conjugated via lysine in the antibody, or may be conjugated via cysteine ​​exposed when the disulfide bond chain is reduced. In some cases, the linker-drug may be conjugated via lysine or cysteine ​​present in a genetically engineered tag, for example, a peptide or protein.

[0105]

[0106] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by chemical formula 1 according to the present invention, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate comprising the same.

[0107] In addition, according to one specific example of the present invention, a method for treating or preventing cancer is provided, comprising administering a therapeutically effective amount of a compound represented by the above chemical formula 1, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate comprising the same to a subject in need thereof. The subject may be a mammal including a human.

[0108]

[0109] In the present invention, the cancer includes all cancers that can be treated by inhibition of topoisomerase I and / or inhibition of one or more cancer-associated survival genes selected from the group consisting of survivin, Mcl-1, XIAP, and cIAP2, and may be solid cancer or hematological cancer. For example, 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, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal 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, It may be at least one selected from the group consisting of duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, 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 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, blood cancer, and thymic cancer, but is not limited thereto. Additionally, the above cancer includes not only primary cancer but also metastatic cancer.

[0110] As used herein, the terms "patient," "subject," and "subject" refer to an animal, such as a mammal. In certain embodiments, the patient is a human. In other embodiments, the patient is a non-human animal, such as a dog, cat, domestic animal (e.g., a horse, pig, or donkey), chimpanzee, or monkey.

[0111]

[0112] The term "therapeutically effective amount" used in the present invention refers to the amount of the compound represented by the above chemical formula 1, or an isomer thereof, or a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate comprising the same, which is effective in the treatment or prevention of cancer. Specifically, the "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or in multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and since the compound represented by the chemical formula 1 of the present invention or an isomer thereof or a pharmaceutically acceptable salt thereof, or a carrier-drug conjugate comprising the same, exhibits a dose-dependent effect, the administration dosage can be easily determined by those skilled in the art according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in amounts exceeding the determined administration dosage.

[0113]

[0114] In addition, according to one specific example of the present invention, the present invention provides the use of a compound represented by any one of the chemical formulae 1 to 10, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate comprising the same, for use in the manufacture of a medicament for use in the treatment or prevention of cancer.

[0115] The compound represented by any one of the above chemical formulae 1 to 10 for the manufacture of a pharmaceutical, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same, may be mixed with a pharmaceutically acceptable excipient, diluent, carrier, etc., and may be manufactured into a composite preparation together with other active agents to have a synergistic effect of the active ingredients.

[0116] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are contradictory.

[0117]

[0118] In this specification, the anticancer effect or therapeutic effect of an anticancer agent may refer to an action that occurs while a patient is suffering from a specific cancer, such as reducing the severity of the cancer, reducing the tumor size, or delaying or slowing the progression of the cancer.

[0119] For example, the anticancer effect of an anticancer drug can be measured in vitro and / or in vivo by measuring the cell viability (the degree of cytotoxicity or changes in cell number) of cancer cells treated with the drug. For example, this can be indirectly confirmed through drug response testing using cell lines or non-clinical animal models (xenografts). Furthermore, the anticancer effect of an anticancer drug can be directly confirmed in cancer patients, and related data can be derived and used as a database. Furthermore, animal model PK parameters and / or toxicity profiles can be considered in parallel when designing dosing guidelines for anticancer drugs.

[0120] The anticancer effect of an anticancer drug is expressed as the % maximum effect of the anticancer drug, which is in vitro data, for example, IC 50 , IC 60 , IC 70 , IC 80 and IC 90 It can be inferred from, and confirmed in nonclinical animal models and clinical cancer patients through in-vivo data such as the drug's peak blood concentration (Cmax) and / or the area under the blood drug concentration-time curve (AUC).

[0121] The reactivity of an anticancer drug refers to the clinical sensitivity in terms of anticancer effect.

[0122] When referring to treatment with anticancer drugs, "sensitivity" and "sensitive" are relative terms referring to the extent to which a compound is effective in alleviating or reducing the progression of the tumor or disease being treated.

[0123] An "effective patient anticancer effect / response" can be, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or greater inhibition of patient response, as measured by any suitable means, such as gene expression, cell counts, assay results, etc.

[0124]

[0125] In this specification, the dosage is the dose at which the medicinal effect is expected. In the present invention, the medicinal effect may be an anticancer effect. The reactivity (anticancer effect) of an anticancer agent is the degree of response, and the % maximum effect (Maximum effect) of the anticancer agent, for example, IC 50 , IC 60 , IC 70 , IC 80 and IC 90 , the value that exhibits toxicity to normal cells (LC 50 ) may be.

[0126] For example, oral dosage forms can be formulated using various formulation techniques known in the art. For example, they may include a biodegradable (hydrolyzable) polymeric carrier that adheres to the oral mucosa. They are designed to slowly erode over a predetermined period of time, thereby providing essentially total drug delivery.

[0127] Drug delivery in oral dosage forms avoids the disadvantages of oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and / or first-pass inactivation in the liver. For biodegradable (hydrolyzable) polymeric carriers, virtually any such carrier may be used as long as the desired drug release profile is not compromised, and the carrier is compatible with any other ingredients present in the oral dosage unit. Typically, polymeric carriers comprise hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the oral mucosa. An example of a polymeric carrier useful herein is an acrylic acid polymer (e.g., a carbomer). In some embodiments, non-limiting examples of other ingredients that may be incorporated into the oral dosage form include disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, and the like. In some embodiments, the oral dosage form may be in the form of a conventionally formulated tablet, lozenge, or gel for oral or sublingual administration.

[0128] In some embodiments, administration of the compound is continued at the physician's discretion if the patient's condition improves; alternatively, the dose of the drug to be administered may be temporarily reduced or temporarily discontinued for a length of time (i.e., a “drug holiday”). The length of a drug holiday may vary from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. In some embodiments, the dose reduction during a drug-free period is 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0129] Once improvement occurs in the patient's condition, a maintenance dose is administered, if necessary. Subsequently, the dosage, frequency, or both may be reduced as a function of symptoms, to a level that maintains the improved disease, disorder, or condition. However, patients require intermittent treatment over a long period of time if any symptoms recur.

[0130] The amount of a given formulation that would correspond to such a quantity will vary depending on factors such as the specific compound, the severity of the disease, the identity (e.g., body weight) of the subject to be treated, but can nevertheless be routinely determined in a manner known in the art, for example, depending on the formulation to be administered, the route of administration, and the particular circumstances surrounding the subject to be treated. In general, however, the dosage employed in adult human treatment will typically range from 0.02 to 5000 mg / day, or from about 1 to 1500 mg / day.

[0131] A single dose herein may be provided as a single dose or as divided doses administered simultaneously, for example as two, three, four or more sub-doses.

[0132] In some embodiments, the oral dosage form is a unit dosage form suitable for single administration of precise dosages. In a unit dosage form, the dosage form is divided into unit doses containing appropriate amounts of one or more compounds. In some embodiments, the unit dose is in the form of a tablet containing discrete quantities of the dosage form. Non-limiting examples include packaged tablets or capsules, and powder vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-reclosable containers. Alternatively, multi-dose, reclosable containers may be used, in which case it is typical to include a preservative in the composition.

[0133] In some embodiments, the parenteral injection formulation is provided in unit dosage form, including but not limited to ampoules, or in multi-dose containers, with an added preservative.

[0134] Typically, it is prepared in unit dose injectable form for parenteral administration, i.e., bolus, intravenous, and intratumoral injection, together with a pharmaceutically acceptable parenteral vehicle. It is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) as a lyophilized preparation or aqueous solution.

[0135] The camptothecin derivative represented by Chemical Formula 1 according to the present invention has more desirable properties than existing camptothecin derivatives in terms of efficacy, toxicity, selectivity, duration of action, administration, handling, stability, and / or production potential, and has the advantage of maximizing the efficacy of main drug target modulation through an additional mechanism of action that (i) simultaneously inhibits Bcl family members such as Survivin, a resistance protein, and / or (ii) inhibits the function of efflux pumps.

[0136] Furthermore, the carrier-drug conjugate comprising the camptothecin derivative represented by chemical formula 1 according to the present invention has the advantage of providing high safety by minimizing toxicity while exhibiting high therapeutic efficacy.

[0137] The present invention provides compounds of chemical formulae 2 to 10 as examples of compounds corresponding to chemical formula 1, and among these, the compound of chemical formula 2 has high toxicity and selectivity for cancer cells when produced alone or in the form of an ADC.

[0138] Figure 1 is a drawing showing the structural formulas of various camptothecin-based anticancer drugs (SN-38, Exatecan, Dxd, FL118).

[0139] Figure 2 shows the results of an in vitro cell viability analysis of compound 2 in FaDu cell lines and NHEK cell lines.

[0140] Figure 3 shows the results of an in vitro cell viability analysis of compound 2 in the KPL-4 cell line.

[0141] Figure 4 shows the results of an in vitro cell viability analysis of compound 2 in the MDA-MB-453 cell line.

[0142] Figure 5 shows the results of an in vitro cell viability analysis of compound 2 in the MDA-MB-468 cell line.

[0143] Figure 6 shows the results of the bystander killing effect analysis of compound 2-based ADC in MDA-MB-468 and KPL-4 cell lines.

[0144] Figure 7 shows the results of an in vitro cell viability analysis of compound 2-based ADC in the MDA-MB-453 cell line.

[0145] Figure 8 shows the results of an in vitro cell viability analysis of compound 2-based ADC in the MDA-MB-468 cell line.

[0146] Hereinafter, the present invention will be described in more detail through examples. However, the following examples are intended only to clearly illustrate the technical features of the present invention and do not limit the scope of protection of the present invention.

[0147]

[0148] [Example 1]

[0149] Preparation of materials

[0150] FaDu, A549, FaDu, NHEK KPL-4, MDA-MB-453, and MDA-MB-468 used in the present 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 Symeres.

[0151]

[0152] Analysis conditions, etc.

[0153] Analysis conditions: U_AN_ACID, Apparatus: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320nm, PDA: 210-320nm, MSD: Agilent G6135B ESI, pos / neg 100-1000, ELSD G7102A: Evap 40℃, Neb 40℃, Gas flow 1.6ml / min, Column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 μm, Temp: 40℃, Flow: 0.6 mL / min, Gradient: t0 = 5% B, t2min = 98% B, t2.7min = 98% B, Post time: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile

[0154]

[0155] Acidic preparative MPLC (Luna)

[0156] Device Type: Reveleris ™prep MPLC; Column: Phenomenex LUNA C18(3)(150x25mm, 10μ); Flow: 40mL / min; Column temp: room temperature; Eluent A: 0.1% (v / v) formic acid in water, Eluent B: 0.1% formic acid (v / v) in acetonitrile; Gradient; Detection UV: 220, 254, 340 nm, ELSD.

[0157]

[0158] Acidic preparative MPLC (Reprosil)

[0159] Device Type: Reveleris ™ prep MPLC; Column: Dr. Maisch Reprosil C18 150x25 mm, 10μ); Flow: 40 mL / min; Column temp: room temperature; Eluent A: 0.1% (v / v) formic acid in water, Eluent B: 0.1% formic acid (v / v) in acetonitrile; Gradient; Detection UV: 220, 254, 340 nm, ELSD.

[0160]

[0161] Synthesis of camptothecin derivatives

[0162] Example 1-1. Synthesis of camptothecin derivative of chemical formula 2 (compound 2)

[0163] (S)-3-Hydroxybutanoic acid (19 mg, 0.18 mmol) was dissolved in 1 mL of N,N-dimethylformamide, HATU (69 mg, 0.18 mmol) was added, and the reaction mixture was stirred at room temperature 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]dioxolo[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 min and stored at -20°C overnight. The reaction mixture was purified by acidic preparative MPLC (Luna10-50), and the product fraction was lyophilized to give a pale yellow solid. (Yield: 35 mg, 73%)

[0164]

[0165] U_AN_ACID: m / z 534.2 [M+H] +

[0166] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d,J= 8.7 Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.29 (d,J= 8.7 Hz, 2H), 5.58 - 5.50 (m, 1H), 5.46 - 5.35 (m, 2H), 5.25 - 5.11 (m, 2H), 4.62 (d,J= 4.4 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.08 - 2.98 (m, 2H), 2.28 (dd,J= 13.6, 7.4 Hz, 1H), 2.18 (dd,J= 13.6, 5.9 Hz, 1H), 2.14 - 1.99 (m, 2H), 1.92 - 1.77 (m,J= 7.1 Hz, 2H), 1.08 (d,J= 6.2 Hz, 3H), 0.87 (t,J= 7.3 Hz, 3H).

[0167]

[0168] Example 1-2. Synthesis of camptothecin derivative of chemical formula 3 (compound 3)

[0169] (S)-3,3,3-Trifluoro-2-hydroxypropanoic acid (11.59 mg, 0.080 mmol) was dissolved in N,N-dimethylformamide (2 ml) and HATU (30.6 mg, 0.080 mmol) was added.

[0170] The mixture was stirred for 3 min, then (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxolo[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, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was directly purified by acidic preparative MPLC (Luna10-50), and the product fractions were lyophilized to obtain the product as an off-white solid. (Yield: 19 mg, 49%)

[0171]

[0172] The above compound (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione can be obtained by the method described in, but not limited to, PCT / KR2023 / 009854.

[0173] U_AN_ACID: m / z 574.2 [M+H] +

[0174] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (d,J= 8.6 Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 7.18 (d,J= 6.2 Hz, 1H), 6.48 (s, 1H), 6.29 (d,J= 7.1 Hz, 2H), 5.61 - 5.52 (m, 1H), 5.46 - 5.35 (m, 2H), 5.21 (d,J= 19.2 Hz, 1H), 5.06 (d,J= 19.2 Hz, 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= 7.3 Hz, 3H).

[0175]

[0176] Example 1-3. Synthesis of camptothecin derivative of chemical formula 4 (compound 4)

[0177] (R)-2-Hydroxybutyric acid (20.9 mg, 0.201 mmol) was dissolved in 1 mL 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 h.

[0178] Then, 0.3 mL of the 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]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione (30 mg, 0.067 mmol) and triethylamine (0.019 ml, 0.134 mmol) in N,N-dimethylformamide (2 ml). The mixture was stirred at room temperature for 23 h. The reaction mixture was directly purified by acidic preparative MPLC (Luna10-50) which gave an off-white solid after lyophilization of the product fractions. (Yield: 25 mg, 69%)

[0179]

[0180] U_AN_ACID: m / z 534.2 [M+H] +

[0181] 1 H NMR (400 MHz, DMSO) δ 8.39 (d, J = 8.9 Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.48 (s, 1H), 6.29 (d, J = 3.6 Hz, 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 = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0182]

[0183] Example 1-4. Synthesis of camptothecin derivative of chemical formula 5 (compound 5)

[0184] A suspension of (1S,10S)-1-amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxolo[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) in dichloromethane (dry) (1 mL) was cooled to 0°C. A solution of acryloyl chloride (5.44 μl, 0.067 mmol) in 0.1 mL of DCM was added dropwise. The reaction mixture was stirred at 0°C, and after 30 minutes, 0.15 equivalents of acrylonitrile chloride was added as a stock solution in DCM. 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 fractions were collected and lyophilized to give a pale yellow, fluffy solid. (Yield: 22 mg, 65%)

[0185]

[0186] U_AN_ACID: m / z 502.2 [M+H] +

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d,J= 8.8 Hz, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 6.49 (s, 1H), 6.30 (d,J= 4.2 Hz, 2H), 6.28 - 6.21 (m, 2H), 5.69 (dd,J= 8.5, 3.7 Hz, 1H), 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= 7.3 Hz, 3H).

[0188]

[0189] Example 1-5. Synthesis of camptothecin derivative of chemical formula 6 (compound 6)

[0190] (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]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[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 h. The mixture was purified by acid preparative MPLC (Luna5-40), and the product fraction was lyophilized to obtain a light yellow solid (yield: 28 mg, 62%).

[0191]

[0192] U_AN_ACID: m / z 574.2 [M+H] +

[0193] 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d,J= 8.8 Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.29 (d,J= 6.4 Hz, 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= 2.9 Hz, 1H), 3.77 (s, 1H), 3.10 - 2.97 (m, 2H), 2.24 - 2.13 (m, 1H), 2.10 - 1.99 (m, 2H), 1.93 - 1.78 (m, 4H), 1.72 - 1.60 (m, 2H), 1.55 - 1.34 (m, 4H), 0.87 (t,J= 7.3 Hz, 3H).

[0194]

[0195] Example 1-6. Synthesis of camptothecin derivative of chemical formula 7 (compound 7)

[0196] (1S,10S)-1-Amino-10-ethyl-10-hydroxy-1,2,3,10,13,16-hexahydro-11H,14H-benzo[de][1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[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) and (1R,4R)-4-hydroxycyclohexane-1-carboxylic acid (16 mg, 0.11 mmol), HATU (42 mg, 1 Eq, 0.11 mmol) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was purified by acid preparative MPLC (Luna5-40), and the product fraction was lyophilized. (Yield: 32 mg, 48%)

[0197]

[0198] U_AN_ACID: m / z 574.2 [M+H] +

[0199] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d,J= 8.8 Hz, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 6.50 (s, 1H), 6.29 (d,J= 6.6 Hz, 2H), 5.55 - 5.35 (m, 3H), 5.18 - 4.95 (m, 2H), 4.56 (d,J= 4.4 Hz, 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= 7.3 Hz, 3H).

[0200]

[0201] Example 1-7. Synthesis of camptothecin derivative of chemical formula 8 (compound 8)

[0202] (1S,3S)-3-Hydroxycyclobutane-1-carboxylic acid (21 mg, 0.18 mmol) was dissolved in 2 ml of N,N-dimethylformamide, HATU (70 mg, 0.18 mmol) was added, and 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]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-11,14-dione methanesulfonate (50 mg, 92 μmol) and DIPEA (32 μL, 0.18 mmol) in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred at room temperature for 2 h. An additional 0.15 mL of activated acid solution was added, and after 20 min, DIPEA (16 μL, 92 μmol) was added. After 20 minutes, when complete conversion was reached, the reaction mixture was injected into a syringe, filtered, and purified through acidic preparative MPLC (Luna5-40), and the product fraction was freeze-dried to obtain a light yellow fluffy solid. (Yield: 30 mg, 60%)

[0203]

[0204] U_AN_ACID: m / z 546.2 [M+H] +

[0205] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d,J= 8.8 Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.48 (s, 1H), 6.29 (d,J= 3.3 Hz, 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= 6.4 Hz, 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= 7.3 Hz, 3H).

[0206]

[0207] Example 1-8. Synthesis of camptothecin derivative of chemical formula 9 (compound 9)

[0208] (1R,3R)-3-hydroxycyclobutane-1-carboxylic acid (21 mg, 0.18 mmol) was dissolved in 1 mL of N,N-dimethylformamide, HATU (69 mg, 0.18 mmol) was added, and 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]dioxolo[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) in N,N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was purified by acidic preparative MPLC (Luna10-50), and the product fraction was lyophilized to obtain a yellow solid. (Yield: 29 mg, 59%)

[0209]

[0210] U_AN_ACID: m / z 546.2 [M+H] +

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d,J= 8.8 Hz, 1H), 7.40 (s, 1H), 7.23 (s, 1H), 6.47 (s, 1H), 6.28 (d,J= 4.3 Hz, 2H), 5.58 - 5.49 (m, 1H), 5.46 - 5.34 (m, 2H), 5.26 - 4.82 (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= 7.4 Hz, 2H), 0.87 (t,J= 7.3 Hz, 3H).

[0212]

[0213] Example 1-9. Synthesis of camptothecin derivative of chemical formula 10 (compound 10)

[0214] (R)-3-Hydroxybutanoic acid (19 mg, 0.18 mmol) was dissolved in 1 mL of N,N-dimethylformamide, HATU (69 mg, 0.18 mmol) was added, and the reaction mixture was stirred at room temperature 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]dioxolo[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) in N,N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with 2 mL DMSO and filtered through a nylon filter. The filter was washed twice with 4 mL DMSO. All fractions were individually purified by acid preparative MPLC (Luna 10-50), pooled, and freeze-dried to obtain a white solid (yield: 25 mg, 52%).

[0215]

[0216] U_AN_ACID: m / z 534.2 [M+H] +

[0217] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d,J= 8.8 Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 6.30 (d,J= 6.1 Hz, 2H), 5.59 - 5.47 (m, 1H), 5.41 (s, 2H), 5.26 - 5.05 (m, 2H), 4.65 (d,J= 4.7 Hz, 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= 6.2 Hz, 3H), 0.87 (t,J= 7.3 Hz, 3H).

[0218]

[0219] [Example 2]

[0220] Preparation of antibody-drug conjugates

[0221] An antibody-drug conjugate comprising the compound of the present invention was prepared by conjugating the compound of the present invention's chemical formula 2 to trastuzumab via the linker of the above chemical formula 11, and its anticancer efficacy was tested.

[0222] The above antibody-drug conjugate is manufactured as follows.

[0223] Trastuzumab was buffer exchanged with Reduction buffer (150 mM NaCl, 50 mM Histidine pH 6.0) using a PD-10 desalting column, and 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.

[0224] Afterwards, excess TCEP was removed using a PD-10 desalting column, and the conjugation reaction was performed by reacting the drug-linker of chemical formula 2a having the linker of chemical formula 11 at 165 μM and the reduced antibody at 13.8 μM at 25°C for 1 hour in a reaction buffer (25 mM Histidine pH 6.0) containing 15% DMSO.

[0225] At this time, the drug-antibody ratio (DAR) is approximately 8. After the conjugation reaction, the excess drug-linker was removed using a PD-10 desalting column, and the final antibody-drug conjugate was obtained.

[0226]

[0227] [Example 3]

[0228] Confirmation of the anticancer effect of compound 2

[0229] 3-1. Evaluation of cell viability efficacy of compound 2

[0230] In this example, in order to confirm the anticancer efficacy of the compound of chemical formula 2 obtained according to Example 1-1, the effect on FaDu and NHEK (Normal Human Epidermal Keratinocytes) was confirmed.

[0231] 3000 FaDu and NHEK cell lines were seeded per well in a 96-well plate and incubated (37°C, 5% CO2). After 24 hours, 100 μl of drug at 9 concentrations (serial dilution of 1 / 5 each starting from 1000 nM) was treated to the cells. At this time, the compound of chemical formula 2 according to the present invention was treated (Dxd was treated as a control group). After incubation for 3 days (37°C, 5% CO2), 100 μl of CellTiter-Glo reagent (CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, G7571) was added to each well and pipetted. After incubation for 10 minutes at RT, luminescence was measured. When the luminescence value at 0 drug concentration is considered 100%, the concentration that shows 50% of the luminescence value is IC 50 It's worth it.

[0232] As shown in Fig. 2, compound 2 of the present invention (compound of chemical formula 2) exhibited excellent cytotoxicity in the FaDu cell line. In addition, compound 2 exhibited relatively low cytotoxicity in NHEK (Normal Human Epidermal Keratinocytes) cells, confirming superior safety compared to Dxd.

[0233]

[0234] 3-2. Evaluation of Cell Viability Efficacy of Compound 2

[0235] In the same manner as in Example 3-1, cancer cell lines KPL-4, MDA-MB-453, and MDA-MB-468 were seeded and incubated, and then treated with compound 2 (compound of chemical formula 2) after 24 hours. Referring to Figures 3, 4, and 5, when the efficacy of compound 2 alone was evaluated in various cancer cell lines, compound 2 showed cytotoxic efficacy similar to or superior to DXd.

[0236]

[0237] 3-3. Bystander-killing effect of compound 2-based ADC

[0238] The bystander killing effect of the ADC (Compound 2-linker-trastuzumab, TRA-Compound 2 in Figure 6) manufactured according to Example 2 was confirmed.

[0239] In the same manner as in Example 3-1, cancer cell lines KPL-4 and MDA-MB-468 were seeded and incubated, and treated with the compound of chemical formula 2 (Compound 2) after 24 hours. At this time, the untreated group, Trastuzumab, Enhertu, Kadcyla (T-DM1), isotype-Dxd, and isotype-Compound 2 were treated as controls, respectively. After incubation for 5 days (37°C, 5% CO2), the cells were stained with anti-HER2 FITC antibody, and then all cells were diluted in buffer. The total number of cells was counted using a flow cytometry (Beckman Coulter) device, and the number of cells expressing FITC fluorescence was measured.

[0240] Referring to Figure 6, Compound 2-based ADC exhibits a bystander killing effect similar to that of Enhertu, and its efficacy is superior to that of Kadcyla (T-DM1). Furthermore, it exhibited superior cytotoxicity than Enhertu in the HER2-positive KPL-4 cell line.

[0241]

[0242] 3-4. Cell viability and efficacy evaluation of compound 2-based ADC

[0243] In the same manner as in Example 3-1, cancer cell lines MDA-MB-453 and MDA-MB-468 were seeded and incubated, and then treated with compound 2-based ADC after 24 hours. Tra-Compound 2, a HER2-targeting ADC based on compound 2, was evaluated for efficacy in various cancer cell lines with different HER2 expression levels, and it exhibited superior cytotoxicity efficacy compared to Tra-DXd in HER2-positive cell lines. In addition, it was confirmed that compound 2-based ADC was safer than Dxd by showing low cytotoxicity in HER2-negative cell lines (see Figs. 7 and 8). That is, it can be seen that the compound 2-based ADC manufactured according to the present invention has superior selectivity for cancer cells and exhibits high toxicity compared to existing drugs (Dxd) even when using the same antibody.

[0244] In summary, according to the above results, it can be seen that the compound belonging to the chemical formula 1 of the present invention not only exhibits toxicity against cancer cells alone, but also exhibits high toxicity against cancer cells in the form of an ADC combined with a linker-antibody. In particular, it was confirmed that the compound of the chemical formula 2, when produced in the form of an ADC, has significant toxicity against cancer cells compared to existing drugs and has high selectivity for target cancer cells, so that it can be used as an excellent anticancer agent.

[0245]

[0246] The present invention has been described above, focusing on preferred embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. A compound represented by the following chemical formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 1] In the above 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, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted C2-C10 heteroaryl group, a C1-C10 mono- or dialkylamino, nitro, and cyano group.

2. In paragraph 1, a compound represented by chemical formula 2 or an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 2] 3. Carrier-Drug Conjugate comprising a compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 1] In the above 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, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted C2-C10 heteroaryl group, a C1-C10 mono- or dialkylamino, nitro, and cyano group.

4. In the third paragraph, the carrier-drug conjugate, wherein the compound of the chemical formula 1 is a compound represented by the following chemical formula 2: [Chemical Formula 2] 5. A carrier-drug conjugate according to claim 3, characterized in that the carrier is an antibody, a peptide, a lipobody, or an aptamer.

6. In the third paragraph, the carrier-drug conjugate is characterized in that the carrier is in a form in which the drug is conjugated to the carrier through a linker.

7. A carrier-drug conjugate according to claim 6, characterized in that the linker comprises GGFG.

8. In the fifth paragraph, the carrier is 4-1BB, 5T4, integrin, Activin, amyloid beta, angiopoietin (angiopoietin 1 or 2), angiopoietin analogue 3, B cell maturation antigen (BCMA), B-cell activating factor (BAFF), B7-H3, complement 5, CCR4, CCR5, CCL11, CD2, CD3, CD4, CD6, CD11a, CD16A, CD19, CD20, CD22, CD25, CD27, CD28, CD30, CD32B, CD33, CD38, CD40, CD45, CD46, CD47, CD52, CD56, CD62, CD70, CD73, CD74, CD79b, CD80, CD105, CD123, CD154, CD166, CD262, CD278, CD319, CD326, 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), Interferon receptor, Interferon gamma, 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, netin-4, nerve growth factor (NGF), OX40, proprotein convertase subtilisin / kexin type 9 (PCSK9), PD-1, PD-L1, phospholipase C, receptor activator of nuclear factors kappa B ligand (RANKL), tyrosine-protein kinase transmembrane receptor (ROR1), sialic acid binding Ig-like lectin 15 ig-like lectin 15 (Siglec-15), transforming growth factor beta (TGFβ), TIGIT (T-cell innunoreceptor with immunoglobulin and ITIM domain), T cell immunoglobulin and mucin-domain containing-3 (Tim-3), tissue factor, tissue factor pathway inhibitor (TFPI), TORP-2, tumor necrosis factor (TNF), thymic stromal lymphopoietin (TSLB), colony stimulating factor 1 receptor (CSF1R),A carrier-drug conjugate characterized by being an antibody, peptide, lipobody, or aptamer that specifically binds to one or more substances (antigens) selected from the group consisting of vascular endothelial growth factor (VEGF), VEGF receptor, and vWF (von Willebrand Factor).

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

10. In the 9th paragraph, the antibody is selected from the group consisting of Urelumab, Utomilumab, Bebtelovimab, Aducanumab, Bapinezumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, Solanezumab, Nesvacumab, Evinacumab, 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, Epratuzumab (Epratuzumab), Basiliximab, Daclizumab, Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab,Mezagitamab, Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Sotigalimab, Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab, Oleclumab, Milatuzumab, Galiximab, Carotuximab, Adecatumumab Adecatumumab, Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Ravulizumab, Lacnotuzumab, Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab, Zalifrelimab, Cetuximab, Depatuxizumab (Depatuxizumab), Futuximab, Imgatuzumab, Matuzumab, Modotuximab, Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab,Zalutumumab, Batoclimab, Nipocalimab, Rozanolixizumab, Burosumab, Farletuzumab, Dinutuximab, Naxitamab, Ragifilimab, Gimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertuzumab, Trastuzumab, Datopotamab Patritumab, Seribantumab, Duligotuzumab, Ficlatuzumab, Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab, Bermekimab, Canakinumab, Gevokizumab, Briakinumab, Ustekinumab Anrukinzumab, Cendakimab, Lebrikizumab, Tralokinumab, Brodalumab, Bimekizumab, Ixekizumab,Secukinumab, Brazikumab, Guselkumab, Mirikizumab, Risankizumab, Tildrakizumab, Nemolizumab, Imsidolimab, Spesolimab, Pascolizumab, Dupilumab, Defemokimab, Mepolizumab, Reslizumab, Benralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Revilimab Levilimab, Sarilumab, Satralizumab, Tocilizumab, Abituzumab, Fabezelimab, Fianlimab, Ieramilimab, Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab, Tavolimab, Telazorlimab, Vonlerolizumab, Alirocumab, Bococizumab, Ebronuximab (Ebronucimab), Evolocumab, Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, Camrelizumab,Cemiplimab, Geptanolimab, Nivolumab, Pembrolizumab, Penpulimab, Pidilizumab, Prolgolimab, Retifanlimab, Sasanlimab, Serplulimab, Sintilimab, Spartalizumab, Tislelizumab, Toripalimab, Ezabenlimab, Zimberelimab, Atezolizumab, Avelumab, Cosibelimab, Sugemalimab (Sugemalimab), Durvalumab, Envafolimab, Subratoxumab, Denosumab, Zilovertamab, Elotuzumab, Domvanalimab, Etigilimab, Ociferlimab, Tiragolumab, Vibostolimab, Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab, Golimumab, Infliximab, Certolizumab (Certolizumab), Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab, Cabiralizumab, Bevacizumab, Brolucizumab,Ranibizumab, Olinvacimab, Icrucumab, Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrindatamab, Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab, Glofitamab, Mosunetuzumab, Odronextamab, Flotetuzumab, Bivecotamab (Vibecotamab), Catumaxomab, Cibisatamab, Talquetamab, Ubamatamab, Emfizatamab, Blinatumomab, Amivantamab, Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naptumomab, Belantamab, Pivekimab, Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibritumomab, Inotuzumab (Inotuzumab), Epratuzumab, Moxetumomab, Brentuximab, Gemtuzumab, Vadastuximab, Lorvotuzumab, Polatuzumab,Tusamitamab, Telisotuzumab, Rovalpituzumab, Depatuxizumab, Farletuzumab, Mirvetuximab, Disitamab, Anetumab, Enfortumab, Sacituzumab, Vobarilizumab, Cadonilimab, Vudalimab, Tebotelimab, Ivonescimab, Erfonrilimab, Ozoralizumab, Faricimab A carrier-drug conjugate characterized by at least one selected from the group consisting of vanucizumab and navicixizumab.

11. A drug-linker comprising a compound of formula 1, a derivative thereof, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof; and a carrier linked to the compound: [Chemical Formula 1] In the above 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, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted C2-C10 heteroaryl group, a C1-C10 mono- or dialkylamino, nitro, and cyano group.

12. In claim 11, the linker is a drug-linker comprising GGFG.

13. A pharmaceutical composition for preventing or treating cancer, comprising a camptothecin derivative according to claim 1, a carrier-drug conjugate according to claim 3, or a drug-linker according to claim 11.

14. In paragraph 13, the cancer is 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, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal 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, Selected from the group consisting of renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, 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 cancer, Wilms' cancer, 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 cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer A pharmaceutical composition characterized by having one or more types.

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