Novel linker compounds and their ligand-drug conjugates

Abstract

The present invention provides a novel linker compound and a ligand-drug conjugate thereof. This can stably deliver an active ingredient to a target site, rapidly release the active ingredient at the target site, and thus can increase the effectiveness of the active ingredient and prevent the active ingredient from causing side effects at positions other than the target position.

Description

Technical Field

[0001] The present invention relates to novel linker compounds and their ligand-drug conjugates, and more particularly to novel linker compounds of Formula 1 and ligand-drug conjugates of Formula 2.

Background Art

[0002] Bioactive substances such as drugs and diagnostic substances have target-specific activity in vivo. For example, a drug has an inhibitory or therapeutic effect on specific target cells, and a diagnostic substance reacts with a specific protein in the body for diagnosis.

[0003] On the other hand, since bioactive substances can be toxic to non-target exogenous substances, techniques have been proposed that enable the drug effect to selectively appear in target cells while suppressing the side effects of the drug.

[0004] For example, an antibody-drug conjugate (ADC) is a targeted technology that binds a drug or toxin to an antibody that binds to a receptor in vivo and then selectively releases the drug or toxin from the target cell to exhibit the desired drug effect. Since the ADC releases the drug or toxin only under specific conditions and selectively delivers the drug or toxin to the target cell while minimizing side effects on normal cells, it has better efficacy than antibody therapeutics and can significantly reduce the risk of side effects.

[0005] These antibody-drug conjugates generally consist of a common "antibody-linker-drug (toxin)" structure. The linker not only simply connects the antibody and the drug, but also enables the antibody-drug conjugate to stably reach the target cell during circulation in the body. Then, the drug is separated by dissociation of the antibody-drug in the target cell (for example, as a result of hydrolysis by an enzyme), thereby selectively exerting its effect in the target cell. Therefore, the stability of the linker has a significant impact on the efficacy and systemic toxicity of the antibody-drug conjugate (Discovery Medicine 2010, 10(53):329~39).

[0006] The linkers of antibody-drug conjugates can generally be classified into non-cleavable and cleavable types.

[0007] As non-cleavable linkers, thioethers are mainly used. Instead of the bond between the drug and the linker dissociating inside the cell, the bond between the linker and the antibody dissociates, and the drug bound to the linker separates from the antibody. Thiol-maleimide linkers are mainly used, but they have the disadvantages of low chemical and plasma stability, as well as low efficacy.

[0008] As cleavable linkers, linkers that can be separated by chemical methods or hydrolyzed by enzymatic reactions are mainly used.

[0009] As linkers having a chemical separation mechanism, linkers composed of disulfide, hydrazone, or oxime bonds are typically used. However, chemically separated linkers can dissociate the drug at a position unrelated to the target site depending on the conditions in the blood or cells, resulting in toxic side effects.

[0010] To solve this problem, linkers that are selectively hydrolyzed inside target cells by enzymatic reactions have been developed. For example, a linker hydrolyzed by an enzymatic reaction is not directly linked to the drug, but is linked through a self-immolative group (SIG) intervening between the drug and the linker, and the drug is dissociated through a mechanism such as 1,6-elimination or cyclization after hydrolysis by the enzymatic reaction (Clinical Cancer Res. 2005, 11, 843 - 852).

[0011] However, in this technical field, there is still a need to develop linkers having excellent plasma stability and chemical stability, capable of rapidly releasing the drug selectively inside target cells, and having excellent versatility to form conjugates with various antibodies and drugs.

Summary of the Invention

Problems to be Solved by the Invention

[0012] One object of the present invention is to provide a linker compound of Formula 1, Formula 1-1 or Formula B and a ligand-drug conjugate of Formula 2 or Formula 2-1.

[0013] Another object of the present invention is to provide a pharmaceutical composition, an imaging composition, or a composition for detection, comprising a compound of Formula 1, Formula 1-1 or Formula B, or a ligand-drug conjugate of Formula 2 or Formula 2-1.

Advantages of the Invention

[0014] The compound or ligand-drug conjugate of the present invention can stably deliver an active agent such as a drug, toxin, fluorophore, affinity ligand, diagnostic substance, or detection probe to a target site, and can rapidly release the active agent in a specific environment of the target site.

[0015] The compound or ligand-drug conjugate of the present invention can have excellent stability at blood temperature and neutral conditions, and can rapidly release the active agent under acidic conditions, for example, in the microenvironment of a tumor.

Brief Description of the Drawings

[0016]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Mode for Carrying Out the Invention

[0017] Each description and embodiment disclosed in this application can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application are included within the scope of this application. In addition, the scope of this application cannot be considered to be limited to the specific description described below. In one aspect of the present invention, the following formula 1: [Formula 1] A-(L 1 ) k -U j provides a linker compound represented by the formula, or a pharmaceutically acceptable salt thereof. In addition, in another aspect of the present invention, the following formula 2:

[0018]

Chemical formula

[0019] In formula 1 or formula 2 of the present invention, L 1 is a divalent or polyvalent linking group, k is 0 or 1, and j is from 1 to 10.

[0020] In formula 1 or formula 2 of the present invention, A is absent, H or a bonding functional group, and A' is a divalent linking group derived from the bonding functional group of A.

[0021] In Formula 2 of the present invention, n is a real number from 1 to 10, and E is a ligand or protein having receptor-binding properties. In Formula 1 or Formula 2 of the present invention, U is the following Formula A:

[0022]

Chemical formula

[0023]

Chemical formula

[0024]

Chemical formula

[0025] In Formula 1, when L 1 is a divalent linking group, one side of L 1 is bonded to A and the other side is bonded to U. In this case, one U is bonded to L 1 . Alternatively, when L 1 contains a branched structure or a dendrimer structure (i.e., when L 1 is a polyvalent linking group), a plurality of U' can be bonded to L 1 . In this case, the number j of U' bonded to L 1 can be from 1 to 10. In one embodiment, j is from 1 to 5. In one embodiment, j is 1.

[0026] In the above formula A, one of Z 1 and Z 3 is selected from the group consisting of NR 3 , O, S, and Se, and the other of Z 1 and Z 3 as well as Z 2are each independently CH or N. -(V) h When present, each independently replaces H in NH or CH. In this case, R 3 is H or C1-C8 hydrocarbyl. In the above formula A, the benzene ring and -(L 2 ) l -PL is bonded to the carbon atom

[0027] [ka] is A-(L 1 ) k -Represents a bond with.

[0028] In one embodiment, Z 1 and Z 3 On the other hand, NR 3 , O, S, and Se; Z 1 and Z 3 the other and Z 2 are each independently C or N bonded to V. 3 is H or C1-C8 alkyl. In one embodiment, R 3 can be H, C1-C4 alkyl or C1-C3 alkyl.

[0029] In one embodiment, Z 1 ~Z 3 Any one of may contain a heteroatom selected from the group consisting of N, O, S, and Se. 1 ~Z 3 Two or more of may each independently contain a heteroatom selected from the group consisting of N, O, S, and Se.

[0030] In one embodiment, Z 1 and Z 3 On the other hand, NR 3 , O, S and Se, and the other and Z 2 can be CH, in which case any of the CHs can be replaced with V.

[0031] In one embodiment, Z 1 and Z 3 one of which is selected from the group consisting of NR 3 , O, S, and Se, and Z 1 and Z 3 the other of and Z 2 one of which may be N, and Z 1 ~Z 3 the remaining one of which may be CH or C bonded to V.

[0032] In one embodiment, when one or more of Z 1 ~Z 3 are CH, V may be substituted with the carbon atom of CH. For example, when Z 2 is CH, V may be substituted with Z 2 .

[0033] In one embodiment, the compound represented by Formula 1 or Formula 2 may be a derivative of indole, benzothiophene, benzofuran, benzoselenophene, indazole, benzimidazole, benzoxazole, benzisoxazole, or benzothiazole. In one embodiment, the ring of Formula A

[0034] [Chemical formula] may be selected from the following group:

[0035] [Chemical formula] .

[0036] The benzene ring of the condensed ring structure of Formula A above can be substituted with an optional substituent as long as it does not have an undesirable effect on the 1,6-elimination reaction starting from the inducing group T. In one embodiment, the substituent W of the benzene ring is H, C1~C 12It may be selected from the group consisting of saturated or unsaturated hydrocarbyl, halogen, halo-C1-C8 alkyl, CN, NO2, OH, C1-C8 alkoxy, hydroxy-C1-C8 alkyl, C1-C8 alkoxy-C1-C8 alkyl, SH, C1-C8 alkylthio, mercapto-C1-C8 alkyl, amino, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, amino-C1-C8 alkyl, C1-C8 monoalkylamino-C1-C8 alkyl, C1-C8 dialkylamino-C1-C8 alkyl, carboxy, C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyloxy, carboxy-C1-C8 alkyl, C1-C8 alkoxycarbonyl-C1-C8 alkyl, carbamoyl, mono-C1-C8 alkylcarbamoyl, di-C1-C8 alkylcarbamoyl, carbamoyl-C1-C8 alkyl, mono-C1-C8 alkylcarbamoyl-C1-C8 alkyl and di-C1-C8 alkylcarbamoyl-C1-C8 alkyl. In Formula 1 and Formula 2, p may be an integer from 0 to 2. In one embodiment, p may be 0.

[0037] Z of the condensed ring of Formula A above 1 , Z 2 and Z 3 The 5-membered ring containing may be optionally substituted with V.

[0038] In Formula A, V is an electron-withdrawing group, an electron-donating group, -CH2-(L 2 ) l -PL-. h and l are each 0 or 1. For example, V may be an electron-withdrawing group. For example, V may be -CH2-(L 2 ) l -PL-.

[0039] In some embodiments, V is halogen, CN, NO2, formyl, C1-C8 alkylcarbonyl, carboxy, C1-C8 alkoxycarbonyl, carboxy-C1-C8 alkyl, carbamoyl, mono-C1-C8 alkylcarbamoyl, di-C1-C8 alkylcarbamoyl, C1-C8 alkyl, C1-C8 alkenyl, OH, C1-C8 alkoxy, SH, C1-C8 alkylsulfanyl, NH2, mono-C1-C8 alkylamino, di-C1-C8 alkylamino or C6-C 18 aryl. In one embodiment, V is -CH2-PL or -CH2-L 2 -PL.

[0040] In some embodiments, V can be carboxy, C1-C8 alkoxycarbonyl, carboxy-C1-C8 alkyl, NH2, mono-C1-C8 alkylamino, or di-C1-C8 alkylamino. For example, V can be carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, carboxymethyl, carboxyethyl, carboxypropyl, amino, aminomethyl, aminoethyl, or aminopropyl.

[0041] In one embodiment, when V is -CH2-(L 2 ) l -PL, L 2 , PL and l can each independently be the same as the definitions described below for L 2 , PL and l in formula A. In this case, formula A includes two examples of -(L 2 ) l -PL, each of which may be the same as or different from each other. Self-cleaving linker In formula A of the present invention, L 2 is a self-cleaving linker selected such that cleavage of the bond between L 2 and the benzene ring and the carbon atom to which A-(L 1 ) k - is attached facilitates cleavage of the bond between L 2 and PL. l can be 0 or 1. When l is 0, PL is the benzene ring and A-(L 1) k - may be directly bonded to the carbon atom to which it is attached.

[0042] When the compound of Formula 1 contains a self - detaching linker, the L 2 group is cleaved from the benzene ring and the carbon atom to which A-(L 1 ) k - is attached through a 1,6 - elimination reaction induced by the inducing group T, and PL - or PL - H can be released from L 2 . In one embodiment, L 2 is at least one linker selected from the group consisting of -OC(=O)-, -S(=O)2-,

[0043]

Chemical formula

[0044] In one embodiment, PL may be at least one activator selected from the group consisting of a drug, a toxin, a fluorophore, an affinity ligand, a diagnostic substance, and a detection probe. Specifically, the heteroatom (N, O, or S) contained in the drug, toxin, fluorophore, affinity ligand, diagnostic substance, and detection probe may be bonded to -CH2-(L 2 ) l -. Therefore, as long as it contains a heteroatom capable of forming the aforementioned bond or a functional group containing such a heteroatom can be further introduced, it can be used as the PL of the present invention, and it should be noted that the PL of the present invention is not limited to the specific activators exemplified herein. For example, PL may include a functional group in which H of a primary or secondary amine group, H of a hydroxy group, or H of a carboxyl group is removed, a functional group in which the lone pair of electrons of the nitrogen atom of a tertiary amine group is donated, or a functional group linked to a nitrogen atom through an addition reaction of an imine group.

[0045] Drugs include erlotinib (Tarceva; Genentech / OSI Pharm.); bortezomib (Velcade; Millennium Pharm.); fulvestrant (Faslodex; AstraZeneca); SU11248 (Pfizer); letrozole (Femara; Novartis); imatinib mesylate (Gleevec; Novartis); PTK787 / ZK 222584 (Novartis); oxaliplatin (Eloxatin; Sanofi); 5-fluorouracil (5-FU); leucovorin; rapamycin (sirolimus, Rapamune; Wyeth); lapatinib (Tykerb, GSK572016; GlaxoSmithKline); lonafarnib (SCH 66336); sorafenib (BAY 43-9006; Bayer Labs.); gefitinib (Iressa; Astrazeneca); AG1478, AG1571 (SU 5271; Sugen); alkylating agents (e.g., thiotepa or cytoxan (registered trademark); cyclophosphamide); alkyl sulfonates (e.g., busulfan, improsulfan or piposulfan); aziridines (e.g., benzodopa, carboquone, meturedopa or uredopa); ethyleneimine, methylmelamine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolmelamine; acetogenins (e.g., bullatacin or bullatacinone); camptothecin including synthetic analog topotecan; bryostatin; calistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, or bizelesin); cryptophycins (e.g., cryptophycin 1 or cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eribulin; pancratistatin; sarcodictyin; spongistatin;Nitrogen mustards (e.g., chlorambucil, chloronaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novobiocin, phenesterine, prednimustine, trophosphamide or uracil mustard); nitrous ureas (e.g., carmustine, chloroozotocin, fotemustine, lomustine, nimustine or ranimnustine); antibiotics (e.g., calicheamicin gamma 1I and calicheamicin omega I1 or dynemicin A selected from dynemicin as an enediyne antibiotic); bisphosphonates (e.g., clodronate); esperamicin, neocarzinostatin chromophore or related pigment protein enediyne antibiotic chromophore, aclacinomycin, actinomycin, antrmycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, ADRLIMYCIN; doxorubicin (adriamycin) (e.g., morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin or deoxydoxorubicin), epirubicin, esorubicin, marcellomycin, mitomycin (e.g., mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodrubicin, streptomigrin, streptozocin, tubercidin, ubenimex, dinostatin or zorubicin); antimetabolites (e.g., 5-fluorouracil (5-FU)); folic acid analogs (e.g., denopterin, methotrexate, pteropterin or trimethoprim); purine analogs (e.g., fludarabine, 6-mercaptopurine, thiampurine or thiguanine);Pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine or floxuridine); androgens (e.g., calusterone, drostanolone propionate, epithiostanol, mepitiostane or testolactone); anti-adrenal agents (e.g., aminoglutethimide, mitotane or trilostane); folic acid supplements (e.g., folinic acid); aceglutamide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamin; demeclocycline; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids (e.g., maytansine or ansamitocin); trichothecenes (e.g., T-2 toxin, verracurin A, roridin A or anguidine); mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK (registered trademark); polysaccharides; razoxane; rizoxin; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially, T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids (e.g., taxol (TAXOL); paclitaxel (taxol; Bristol-Myers Squibb Oncology, Princeton, N.J.), abraxane (ABRAXANE) (trademark) without cremophor, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumber, I11.) or taxotere);Docetaxel (Taxotere); Chlorambucil; Gemcitabine; 6-Thioguanine; Mercaptopurine; Platinum analogs (e.g., cisplatin or carboplatin); Vinblastine; Platinum; Etoposide, Ifosfamide; Mitoxantrone; Vincristine; Vinorelbine (Navelbine); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DFMO); Retinoids (e.g., retinoic acid); Capecitabine; and pharmaceutically acceptable salts, solvates, acids, or derivatives thereof, can be selected from the group consisting of, but not limited to, these.;

[0046] Additional drugs other than the drugs described above include: (i) antihormonal agents that regulate or inhibit hormonal action in tumors, such as tamoxifen (NOLVADEX; including tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and fareston; including toremifene, estrogen antagonists, and selective estrogen receptor modulators (SERMs); (ii) aromatase inhibitors that inhibit aromatase enzyme and regulate estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGASE); megestrol acetate, aromasin; exemestane, femara; letrozole, and arimidex; anastrozole; (iii) antiandrogenic agents, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (1,3-dioxolan nucleoside cytidine analog); (iv) aromatase inhibitors; (v) protein kinase inhibitors; (vi) lipid kinase inhibitors; (vii) antisense oligonucleotides, particularly those that inhibit gene expression in signal transduction pathways related to adherent cells, such as PKC-α, Raf, H-Ras; (viii) ribozymes, such as VEGF inhibitors, such as angiostatin ribozyme and HER2 expression inhibitors; (ix) vaccines, such as gene therapy vaccines; allovectin; vaccines, leuvectin vaccines, and vaxid vaccines; proleukin; rIL-2; lurtotecan; topoisomerase 1 inhibitors; abarelix; rmRH; (x) antiangiogenic agents, such as bevacizumab (avastin, Genentech); and (xi) including, but not limited to, pharmaceutically acceptable salts, solvates, acids, or derivatives thereof.

[0047] In one embodiment, the drug may be selected from cytokines, immunomodulatory compounds, anti-cancer agents, anti-viral agents, antibacterial agents, anti-fungal agents, anthelmintics, or combinations thereof.

[0048] Cytokines are small cell signaling protein molecules secreted by many cells and can be signaling molecules widely used in intercellular communication. Cytokines include monokines, lymphokines, conventional polypeptide hormones, and the like. Exemplary cytokines include growth hormone (e.g., human growth hormone, N-methionyl human growth hormone, or bovine growth hormone); parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones (e.g., follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), or luteinizing hormone (LH)); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-α, tumor necrosis factor-β; Müllerian inhibiting substance; mouse gonadotropin-related peptide; inhibin; activin; vascular endothelial growth factor; integrin, thrombopoietin (TPO); nerve growth factor (e.g., NGF-β); platelet-derived growth factor; transforming growth factor (TGF) (e.g., TGF-α or TGF-β); insulin-like growth factor-I, insulin-like growth factor-II; erythropoietin (EPO); osteogenic factor; interferon (e.g., interferon-α, interferon-β, or interferon-γ); colony-stimulating factor (CSF) (e.g., macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), or granulocyte-CSF (G-CSF)); interleukin (IL) (e.g., IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, or IL-12); tumor necrosis factor (e.g., TNF-α or TNF-β); and polypeptide factors (e.g., LIF or kit ligand (KL)), but are not limited thereto. In addition, the term "cytokine" may also include proteins derived from natural sources or from biologically active equivalents of cytokines from recombinant cell culture and natural sequences.

[0049] The immunomodulatory compound can be selected from the group consisting of aminocaproic acid, azathioprine, bromocriptine, chloroquine, chlorambucil, cyclosporine, cyclosporine A, danazol, DHEA (dehydroepiandrosterone), dexamethasone, etanercept, hydroxychloroquine, hydrocortisone, infliximab, meloxicam, methotrexate, cyclophosphamide, mycophenolate mofetil, prednisone, sirolimus, and tacrolimus.

[0050] The anticancer agent can be selected from the group consisting of methotrexate, taxol, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosourea, cisplatin, carboplatin, mitomycin, dacarbazine, procarbazine, topotecan, nitrogen mustard, cytoxan, etoposide, 5-fluorouracil, BCNU (bis-chloroethyl nitrosourea), irinotecan, camptothecin, exatecan, velotecan, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, chlorambucil, melphalan, carmustine, lomustine, busulfan, treosulfan, decarbazine, etoposide, teniposide, topotecan, 9-aminocamptothecin, crisnatol, mitomycin C, trimetrexate, mycophenolic acid, thiazofurin, ribavirin, EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide), hydroxyurea, deferoxamine, floxuridine, doxifluridine, raltitrexed, cytarabine (ara C), cytosine arabinoside, fludarabine, tamoxifen, raloxifene, megestrol, goserelin, leuprolide acetate, flutamide, bicalutamide, EB1089, CB1093, KH1060, verteporfin, phthalocyanine, photosensitizer Pe4, demethoxy-hypocrellin A, interferon-alpha, interferon-gamma, tumor necrosis factor, gemcitabine, berberine, levamide, talamide, lovastatin, 1-methyl-4-phenylpyridinium ion, staurosporine, actinomycin D, dactinomycin, bleomycin A2, bleomycin B2, peplomycin, epirubicin, pirarubicin, zorubicin, mitoxantrone, verapamil and thapsigargin.The antiviral agent can be selected from the group consisting of penciclovir, valacyclovir, ganciclovir, foscarnet, ribavirin, idoxuridine, vidarabine, trifluridine, acyclovir, famcicyclovir, amantadine, rimantadine, cidofovir, antisense oligonucleotide, immunoglobulin, and interferon. The antibacterial agent can be selected from the group consisting of chloramphenicol, vancomycin, metronidazole, trimethoprin, sulfamethazole, quinupristin, dalfopristin, rifampicin, spectinomycin, and nitrofurantoin. The antifungal agent can be selected from the group consisting of amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, peru balsam, ciclopirox olamine, piroctone olamine, zinc pyrithione, and selenium disulfide. The anthelmintic agent can be selected from the group consisting of mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, niclosamide, praziquantel, albendazole, rifampicin, amphotericin B, melarsoprol, eflornithine, metronidazole, tinidazole, and miltefosine.

[0051] "Toxin" refers to a harmful substance produced within a living cell or organism. A toxin can be a small molecule, peptide, or protein that is capable of interacting with body tissues that interact with biological macromolecules such as enzymes or cell receptors, or being absorbed to cause disease. In addition, "toxin" includes phytotoxins and animal toxins. Exemplary animal toxins include, but are not limited to, diphtheria toxin, botulium toxin, tetanus toxin, shiga toxin, cholera toxin, tetrodotoxin, brevetoxin, and saxitoxin. Exemplary phytotoxins include, but are not limited to, ricin and AM-toxin.

[0052] For example, small molecule toxins can include, but are not limited to, auristatin, tubulysin, geldanamycin (Kerr et al., 1997, Bioconjugate Chem. 8(6):781-784), maytansinoid (European Patent Application Publication No. 1391213, ACR 2008, 41, 98-107), calicheamicin (U.S. Patent Application Publication No. 2009105461, Cancer Res. 1993, 53, 3336-3342), daunomycin, doxorubicin, methotrexate, vindesine, SG2285 (Cancer Res. 2010, 70(17), 6849-6858), dolastatin, auristatin of dolastatin analog (U.S. Patent No. 563548603), cryptophycin, camptothecin, rhizoxin derivative, CC-1065 analog or derivative, duocarmycin, enediyne antibiotic, esperamicin, epothilone, PBD (pyrrolobenzodiazepine) derivative, α-amanitin, and toxoid. Toxins can exhibit cytotoxic and cell growth inhibitory activities by, for example, tubulin binding, DNA binding, and topoisomerase inhibition.

[0053] An affinity ligand can include a molecule capable of forming a complex with a target biomolecule. An affinity ligand can be a molecule that transmits a signal by binding to a predetermined position of a target protein. An affinity ligand can be a substrate, inhibitor, stimulant, neurotransmitter, or radioisotope.

[0054] The term "detection probe" can refer to a substance or a part of a substance that can be detected by spectroscopic, photochemical, biochemical, immunochemical, radioactive, or chemical means. For example, useful detection probes can 32 P, 35 S, fluorescent dyes, high electron density reagents, enzymes (e.g., those commonly used in ELISA), biotin-streptavidin, dioxigenin, haptens, and proteins for which antisera or monoclonal antibodies are available, or nucleic acid molecules containing sequences complementary to the target. Detection probes can often generate a measurable signal such as a radioactive, chromogenic, or fluorescent signal and can be used to quantify the amount of the bound detectable moiety in a sample. Quantification of the signal can be achieved, for example, by scintillation counting, densitometry, flow cytometry, ELISA, or direct analysis by mass spectrometry of intact or subsequently digested peptides (one or more peptides can be assayed).

[0055] The above probes can include (i) substances capable of providing a detectable signal, (ii) substances capable of modifying a detectable signal generated by a first or second probe, such as fluorescence resonance energy transfer (FRET), by giving rise to a first or second probe that reacts with each other, (iii) substances capable of stabilizing the interaction with an antigen or ligand or increasing the binding affinity, (iv) substances capable of affecting electrophoretic mobility or cell invasiveness by physical parameters such as charge, hydrophobicity, etc., and (v) substances capable of regulating ligand affinity, antigen-antibody binding, or the formation of ionic complexes. In one embodiment, PL is MMAF (monomethyl auristatin F), auristatin F, MMAE (monomethyl auristatin E), SN-38, p-nitrophenol, xanthene carboxylic acid, abiraterone, gefitinib, PBD dimer, α-amanitin, seco-DUBA, doxorubicin, lapatinib, imatinib, erlotinib, exatecan, velotecan, and the following formula:

[0056]

Chem.

[0057]

Chem.

[0058]

Chem.

[0059] T can be selectively cleaved in vivo by a chemical reaction or an enzymatic reaction. That is, T (or the bond between T and Y if Y is present) can be selectively cleaved under specific in vivo conditions, thereby stably delivering PL to the target site and selectively releasing PL at the target site.

[0060] In one embodiment, T may be linked to the benzene ring through a heteroatom such as an oxygen atom, a sulfur atom, or a nitrogen atom. That is, in formula A, Y that connects the inducing group T to the compound moiety can be -O-, -NH-, and S.

[0061] [[ID=4,9]] In one embodiment, -(Y) y -T is -β-galactoside, -β-glucuronide, -O-SO3 -, -NO2, -valine-citrulline derivative, -valine-alanine derivative, -OC(O)(CH2) r COR t1 , -O(CH2)-Ar 1 -NO2, -S-C(O)(CH2) s COR t2 , -S(CH2)-Ar 2 -NO2 and -BR t3 R t4 may be selected from the group consisting of.

[0062] β-Galactoside and β-glucuronide may be linked to the benzene ring via an oxygen atom bonded to the C1 position of the β-galactoside moiety and the β-glucuronide moiety. The valine-citrulline derivative and the valine-alanine derivative may be linked to the benzene ring via the nitrogen atom of the valine moiety. That is, the -β-galactoside, -β-glucuronide, -valine-citrulline derivative, and -valine-alanine derivative in the present specification may be moieties having the following structures.

[0063]

Chemical formula

[0064] R t5 is OH, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, or -NH(CH2CH2O) fR t6 can be, and R t6 can be H or C1-C4 alkyl, and f can be an integer from 1 to 10. In one embodiment, -(Y) y -T is

[0065]

Chemical formula

[0066]

Chemical formula

[0067] For example, when Y is absent (y = 0) and T is -NO2 or -BR t3 R t4 this can be cleaved under reducing conditions and protonolysis conditions, respectively. Optional self-destructive spacer unit In formula A of the present invention, L 3 , when present, is an optional self-destructive spacer group that is sequentially cleaved when T is cleaved. The 1,6-elimination reaction induced by the cleavage of T under specific conditions in vivo separates L 3 from a part of the compound. Therefore, L 3 has a structure that can transfer the electrons generated when T is cleaved to the benzene ring and PL of formula A. In one embodiment, -(X) x -L 3 - may be

[0068]

Chemical formula

[0069]

Chemical formula

[0070] In formula A of the present invention, i can be 0 or 1. In one embodiment, when i is 0, a self-destructive spacer group cannot be present, and -(Y) y -T may be directly connected to the benzene ring. In one embodiment, in formula A of the present invention, i can be 0 (i.e., no self-destructive spacer group is present), and the self-cleaving linker L 2 can be -O(C=O)-. In such a case, formula A of the present invention is the following formula A-1:

[0071]

Chemical formula

[0072] In formula A-1, Z 1 , Z 2 , Z 3The definitions of V, Y, T, W, PL, h, y, and p are as described above with respect to Formula A. Linking unit In Formula 1 of the present invention, A is absent, H, or a linking functional group. When L 1 is present (k = 1), A is H or a linking functional group, and when L 1 is absent (k = 0), A is also absent.

[0073] The linking functional group can refer to a functional group contained in a ligand or a protein (E in Formula 2) or a functional group contained in a linker precursor that forms L in Formula 1 through a reaction such as addition or substitution, which can be linked. That is, the linking functional group can be any functional group that can provide a bond between a ligand or a protein (E) and L in Formula 1, or (when L 1 is absent) between U in Formula 1 and another linker. In the field of ligand-drug conjugates, various functional groups for the bond between a ligand and a linker are known in the art. Therefore, those skilled in the art can select an appropriate linking functional group considering the structures and properties of the ligand and the linker, and it should be noted that the linking functional group of the present invention is not limited to the specific functional groups exemplified herein. For example, the linking functional group can bind to a ligand or a protein (E) having receptor-binding properties or a linker precursor through a click chemical reaction. In one embodiment, when L 1 in Formula 1 is absent (i.e., k is 0), the linking functional group may further bind to a linker precursor and then bind to a ligand or a protein (E) having receptor-binding properties through a functional group contained in the linker precursor. In this case, the compound of Formula 1 has a structure of "A-U", and the ligand-drug conjugate of Formula 2 has a structure of "E-linker-A-U". In another embodiment, when L 1 in Formula 1 is present (i.e., k is 1), the linking functional group may bind to a further linker precursor to form an extended linker, and then may bind to a ligand having receptor-binding properties through a functional group contained in the further linker precursor. 1 is absent (i.e., k is 0), the linking functional group may further bind to a linker precursor and then bind to a ligand or a protein (E) having receptor-binding properties through a functional group contained in the linker precursor. In this case, the compound of Formula 1 has a structure of "A-U", and the ligand-drug conjugate of Formula 2 has a structure of "E-linker-A-U". In another embodiment, when L 1 in Formula 1 is present (i.e., k is 1), the linking functional group may bind to a further linker precursor to form an extended linker, and then may bind to a ligand having receptor-binding properties through a functional group contained in the further linker precursor.

[0074] Thus, when A is a linking functional group, the compound according to formula 1 of the present invention is for the purpose of binding to a further linker precursor or ligand or protein (E) having receptor binding properties, and can be, for example, an intermediate for providing a ligand-drug conjugate. On the other hand, when A is absent or is H, the compound according to formula 1 of the present invention can be a complex containing an active agent (PL) that is not assumed to bind to a ligand having receptor binding properties. The complex can be used for various purposes such as changing the properties (e.g., water solubility) of the active agent, targeting, etc. In one embodiment, the linking functional group is halogen, OH, C1-C8 alkoxy, hydroxylamino, COH, C1-C8 alkylcarbonyl, carboxy, C1-C8 alkoxycarbonyl, tosyl, tosylate, amino, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, NHNH2, N3, haloacetamide, maleimidyl, succinimidyl, SH, SO3H, C1-C8 alkylsulfonyl,

[0075]

Chemical formula

[0076]

Chemical formula

[0077]

Chemical formula

[0078]

Chemical formula

[0079] In one embodiment, A-L of Formula 1 1 can be formed by a bond between a precursor of A and a precursor of L 1 . The bond between a precursor of A and a precursor of L 1 can be achieved through a click chemical reaction bond, an amide bond, a urea bond, an ester bond, a carbamate bond, a disulfide bond, or a maleimide bond, but is not limited thereto.

[0080] For example, the precursor of A may contain at least one functional group selected from the group consisting of hydroxy, amino, azide, alkynyl, conjugated dienyl, alkenyl, cyclooctynyl, maleimidyl, SO2N3, alkoxysulfinyl, oxiranyl, aziridinyl, oxo, hydrazinyl, hydroxyamino, mercapto, and 1,3-dicarbonyl. In addition, the precursor of L 1 may contain a functional group that chemically reacts with the precursor of A to form an A-L 1 bond. Alternatively, a linker precursor having the structure A-L 1 may be bonded to the remaining portion of the compound of Formula 1.

[0081] In one embodiment, L 1 is optionally a C1-C alkylene optionally containing a divalent or polyvalent functional group selected from the group consisting of amide, sulfonamide, amino, ether, carbonyl, triazole, tetrazole, sugar derivative, sulfoester, and dendrimer in the middle of the chain 200 and may be alkylene. The C1-C 200 alkylene group is a C1-C 150 alkylene group, a C1-C 100 alkylene group, a C1-C 80 alkylene group, a C1-C 60 alkylene group, a C1-C 50 alkylene group, a C1-C 40 alkylene group, a C1-C 30 alkylene group, a C1-C 20 alkylene group, or a C1-C 10 alkylene group. The sugar derivative refers to any chemical structure formed by a covalent bond between a sugar molecule and another group. For example, the sugar derivative may contain a glycosidic bond. The dendrimer refers to an ordered three-dimensional molecular structure having a branched unit centered around a core. In the field of ligand-drug conjugates, linkers with various dendrimer structures are known (see, for example, Lee et al., Nat. Biotechnol. 2005, 23, 1517-26; Almutairi et al.; Proc. Natl. Acad. Sci. 2009, 106, 685-90), and for example, it may be beneficial to increase the ratio of the ligand to the drug.

[0082] In one embodiment, when L 1 contains a polyvalent functional group, that is, when L 1 contains a branched structure or a dendrimer structure, a plurality of U' can be bonded to L 1 . In this case, the number of U bonded to L 1 can be 1 to 10. In one embodiment, j can be 1 to 5. For example, j can be 1.

[0083] In one embodiment, the structure for the L 1 -U bond (for example, a carboxyl group, an aminocarbonyl group, an amino group, etc.) may be required as a substituent for a carbon atom at the position where L 1 is bonded to the partial U represented by formula A.

[0084] In one embodiment, L 1 is C1-C 10 alkylene, oxyethylene, amide, triazole ring, tetrazole ring, ether, carbonyl, or a combination thereof. In one embodiment, L 1 is -(CH2) na -; -(CH2CH2O) ma -; -(CH2OCH2) mb -; -(OCH2CH2) mc -; -C(=O)-;

[0085] [Chemical formula] Or any one selected from the group consisting of a combination thereof. Here, R d can be H or C1-C8 alkyl, and na and ma to mc can each independently be an integer from 0 to 10. In one embodiment, na and ma to mc can each independently be an integer from 1 to 8, an integer from 1 to 6, or an integer from 1 to 4. When two or more of the above-described functional groups are combined with each other, the order of the functional groups is not limited. In one embodiment, in formula 1, k can be 1, and A-L 1-R a1 C≡C-(CH2) n1 -;N3-(CH2) n2 -;

[0086] [ka] In this case, R a1 , R b1 , R f1 , R f2 , R i1 and R d1 ~R d10 may each independently be H or C1-C8 alkyl. c1 , R e1 , R g1 , R h1 and R h2 are each independently H, C1-C8 alkyl, C1-C8 alkylcarbonyl (e.g., acetyl), C1-C8 alkoxycarbonyl (e.g., tert-butoxycarbonyl), or C 6~ C 12 It may be aryl-C1-C4 alkoxycarbonyl (e.g., benzyloxycarbonyl). n1 to n18 and m1 to m14 may each independently be an integer of 0 to 10. In one embodiment, n1 to n18 and m1 to m14 may each independently be an integer of 0 to 8, an integer of 0 to 6, or an integer of 0 to 5. In one embodiment, n1 to n18 and m1 to m14 may each independently be an integer of 1 to 8, an integer of 1 to 6, or an integer of 1 to 5. Exemplary Compounds of Formula 1 In one embodiment, the compound of the present invention represented by formula 1 may be a compound represented by the following formula:

[0087] [ka] In the above formula, A, L 1 , k, R 3、and PL is as described above with respect to Formula 1. In the above formula, V” represents an electron-withdrawing group. For example, V” can be carboxy, carboxy-C1-C8 alkyl, or C1-C8 alkoxycarbonyl. For example, V” can be carboxy, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl.

[0088] The structure A-(L 1 ) k -, V”, L 2 、and -(Y) y -T- combinations are merely illustrative, and compounds of Formula 1 having various combinations thereof can be readily prepared based on the examples described below and the disclosure of this application. It should be understood that all such compounds are included within the scope of this application.

[0089] In one embodiment, the compound represented by Formula 1 of the present invention can have one PL. In this case, for example, the compound represented by Formula 1 can be selected from the group consisting of the compounds shown in Table A attached.

[0090] In one embodiment, the DAR2-type compound can contain a functional group capable of forming a bond with a ligand such as an antibody for preparing a ligand-drug conjugate, such as a maleimide functional group. Examples of these compounds are shown in attached Table B. DAR4-type compound (Formula 1-1) In one embodiment, when the linking group L of Formula 1 according to the present invention 1 has a branched structure or a dendrimer structure (i.e., when L 1 is a polyvalent linking group), it can result in a compound of Formula 1 to which two or more active agents are attached. In one embodiment, the compound represented by Formula 1 of the present invention can be a compound represented by the following Formula 1-1.

[0091]

Chemical formula

[0092] In Formula 1-1, U 1 and U 2 each have the same meaning as U in Formula 1, and U 1 and U 2 may be the same as or different from each other.

[0093] In Formula 1-1, L 11 and L 12 each have the same meaning as L in Formula 1, and L 1 and L 11 and L 12 may be the same as or different from each other.

[0094] In Formula 1-1, j is from 1 to 10. In one embodiment, j is from 1 to 5. For example, j can be 1.

[0095] Regarding Formula A, L 1 and U, the content described in Formula 1 can be similarly applied to A, U 1 and U 2 , as well as L 11 and L 12 in Formula 1-1 where applicable. In Formula 1-1, L 1a and L 1b are each independently a direct bond;

[0096]

Chemical formula

[0097]

Chemical formula

[0098] [Chemical formula] when it is, q3 is not 0. In one embodiment, L 1a and / or L 1b is a direct bond, and when q2 and q3 are 0, L 11 and L 12 linker structure of, for example, a divalent or polyvalent functional group selected from amide, sulfonamide, amino, ether, carbonyl, triazole, tetrazole, sugar derivative group, sulfonate ester and dendrimer in the middle of the chain, optionally containing a C1 to C 200 alkylene can be directly bonded to the central N atom.

[0099] In one embodiment, q1 can be an integer from 0 to 8, an integer from 1 to 8, or an integer from 1 to 6. In one embodiment, q2 and q3 can each independently be an integer from 0 to 8, an integer from 0 to 6, or an integer from 0 to 4. In one embodiment, q4 can be an integer from 1 to 8, an integer from 1 to 6, or an integer from 1 to 4. In one embodiment, the

[0100] [Chemical formula] is the following structure:

[0101] [Chemical formula] (the definitions of q2 and q3 are as described above) can be selected from. In one embodiment, A in the above formula 1-1 is halogen, OH, C1-C8 alkoxy, hydroxylamino, COH, C1-C8 alkylcarbonyl, carboxy, C1-C8 alkoxycarbonyl, tosyl, tosylate, amino, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, NHNH2, N3, haloacetamide, maleimidyl, succinimidyl, SH, SO3H, C1-C8 alkylsulfonyl,

[0102] [Chemical formula] C1-C8 alkoxysulfonyl, 2-pyridyldisulfide, PO3H2, OPO3H2, -N≡C, -NCS, C4-C 10 dienyl, C2-C8 alkenyl, C2-C8 alkynyl, C4-C 10 cycloalkynyl and a functional group selected from the group consisting of C2-C8 alkynylcarbonyl, or may consist of these. R f can each independently be H or C1-C8 alkyl. For example, in formula 1-1, A is maleimidyl, hydroxylamino, carboxy, amino, N3, C2-C8 alkynyl, or

[0103] [Chemical formula] can be.

[0104] In one embodiment, L 11 and L 12 can each independently be a C1-C 200 alkylene optionally containing a divalent or polyvalent functional group selected from the group consisting of amide, sulfonamide, amino, ether, carbonyl, triazole, tetrazole, sugar derivative, sulfoester and dendrimer in the middle of the chain. The C1-C 200 alkylene group is a C1-C 150 alkylene group, a C1-C 100 alkylene group, a C1-C 80 alkylene group, a C1-C60 an alkylene group, C1-C 50 an alkylene group, C1-C 40 an alkylene group, C1-C 30 an alkylene group, C1-C 20 an alkylene group or C1-C 10 can be an alkylene group. In one embodiment, L 11 and L 12 are each independently, -(CH2) na -; -(CH2CH2O) ma -; -(CH2OCH2) mb -; -(OCH2CH2) mc -; -C(=O)-;

[0105]

Chemical formula

[0106]

Chemical formula

[0107]

Chemical formula

[0108]

Chemical formula

[0109] In the above formula, q1-q4, n1, n8 and m8 are as described above with respect to Formula 1-1. In the above formula, PL has the same meaning as PL in Formula 1. In the above formula, Z 1 is a heteroatom selected from NR 3 , O, S and Se. R 3is H or C1-C8 hydrocarbyl. In the above formula, V” represents an electron-withdrawing group. For example, V” can be carboxy, carboxy-C1-C8 alkyl, or C1-C8 alkoxycarbonyl. For example, V” can be carboxy, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. In the above formula, the -O-CO- group of the -O-CO-PL group is an optional self-destructive spacer group and may not be present (i.e., the -PL group is directly linked to the -CH2- group) or can be replaced with the functional groups described above with respect to the “optional self-destructive spacer group”.

[0110] In one embodiment, the compound represented by Formula 1-1 can be selected from the compounds listed in the attached Table C. Method for preparing the compound of Formula 1 The novel linker compound of Formula 1 according to the present invention can be easily prepared by selecting appropriate solvents, starting materials, intermediates, reaction conditions, etc. based on the examples in this specification and the technical knowledge of those skilled in the art of organic synthesis.

[0111] In one embodiment, the compound of Formula 1 having a benzothiophene core and a β-galactoside-inducing group is A-(L 1 ) k - is propargyl (HCCCH2-), but can be prepared by the following Reaction Scheme 1.

[0112]

Chemical formula

[0113] In step 2, a propargyl group can be introduced into the COH bonded to the benzene ring. For example, the product of step 1 can react with propargyl halide (HCCCH2-Hal; Hal is a halogen). In this case, additive substances such as 1,2-diiodoethane and zinc powder can be used. The reaction of step 2 can be carried out by stirring sonication under temperature conditions of -10°C to 40°C, -10°C to 30°C, 0°C to 40°C or 0°C to 30°C.

[0114] In step 3, a self-eliminating linker -OCO- can be introduced. As precursors for the self-eliminating linker -OCO-, bis(4-nitrophenyl) carbonate, 4-nitrophenyl chloroformate, etc. can be used. In the reaction of step 3, additive substances such as DIPEA and pyridine can be used. Step 3 can be carried out under low temperature conditions of -40°C to 10°C, -40°C to 0°C, -30°C to 10°C, -30°C to 0°C, -20°C to 10°C or -20°C to 0°C.

[0115] In step 4, PL can be introduced. For example, PL can be introduced by replacing it with a precursor such as PL-H for a leaving group (e.g., p-nitrophenyl) linked to -OCO-. In the reaction of step 4, additive substances such as HOBt, pyridine, DIPEA, etc. can be used depending on the type of PL. Step 4 can be carried out under low-temperature conditions of -40°C to 10°C, -40°C to 0°C, -30°C to 10°C, -30°C to 0°C, -20°C to 10°C, or -20°C to 0°C.

[0116] In step 5, the protecting group of the protected galactoside can be deprotected through hydrolysis, thereby converting it to galactoside. Hydrolysis can be carried out with an acid such as hydrochloric acid or a base such as potassium carbonate, sodium hydroxide, or lithium hydroxide. Step 5 can be carried out under temperature conditions of -40°C to 40°C, -40°C to 30°C, -20°C to 40°C, -20°C to 30°C, -10°C to 40°C, or -10°C to 30°C.

[0117] Each step of Reaction Scheme 1 can be carried out in a suitable solvent selected from the group consisting of organic solvents such as methanol, DMF, MC, ACN, THF, EA, and distilled water. In addition, after the reaction is completed in each step, the product can be purified through dilution, extraction, and chromatography using a suitable solvent. In one embodiment, each step of Reaction Scheme 1 can be carried out under a nitrogen atmosphere.

[0118] In one embodiment, PL, A, L 1 and V can omit some steps of Reaction Scheme 1. For example, if PL can react with a hydroxymethyl group directly linked to the benzene ring even when -OCO- is absent, or can bind to a methyl group, step 3 can be omitted. Linker compound of Formula B In one aspect of the present invention, the following formula B:

[0119]

Chemical formula

[0120] In the above formula B, V' is -CH2-(L 2 ) l -PL.

[0121] In the above formula B, L 2 is a self-cleaving linker selected such that cleavage of the bond between -CH2- of V' and L 2 promotes cleavage of the bond between L 2 and PL.

[0122] In the above formula B, PL is an active agent linked to L 2 or -CH2- of V' via a heteroatom selected from N, O, and S.

[0123] In the above formula B, one of Z a and Z b is selected from the group consisting of N, NR 3 , O, S, and Se, the other of Z a and Z b is CH or N, and R 3 is H or C1-C8 hydrocarbyl.

[0124] In the above formula B, T is an inducing group that, when cleaved, can initiate the release of PL and, if present, L 2 through a 1,6-elimination reaction.

[0125] In the above formula B, L 3 is an optional self-destructive spacer group that, if present, is sequentially cleaved when T is cleaved.

[0126] In the above formula B, X and Y are each independently selected from -O-, -NH-, and -S-, i, l, x, and y are each independently 0 or 1, and p is an integer from 0 to 2.

[0127] L of formula B above 2 PL, X, Y, L 3 Specific embodiments of and T are as described above with respect to formula 1, and the content thereof described above with respect to formula 1 can be similarly applied to formula B where applicable. In one embodiment, the compound represented by formula B described above is of the following formula:

[0128]

Chemical formula

[0129] The novel linker compound represented by formula B above is a complex comprising an activator (PL) that is not assumed to bind to a ligand having receptor binding properties. The complex can be used for various purposes such as changing the properties (e.g., water solubility) of the activator, targeting, etc. Ligand-drug conjugate represented by Formula 2 In one aspect of the present invention, the following formula 2:

[0130]

Chemical formula

[0131]

Chemical formula

[0132] The ligand can be selected from the group consisting of a peptide, a tumor cell-specific peptide, a tumor cell-specific aptamer, a tumor cell-specific carbohydrate, a tumor cell-specific monoclonal or polyclonal antibody, and an antibody fragment.

[0133] In one embodiment, the protein is C1 to C 20 It can be selected from the group consisting of a hydrocarbyl, an oligopeptide, a polypeptide, an antibody, a fragment of an antigenic polypeptide, and an artificial antibody (Repebody). In one embodiment, the C-terminus of the protein can be the light chain or the heavy chain of an antibody.

[0134] In one embodiment, the antibody can be selected from the group consisting of an intact polyclonal antibody, an intact monoclonal antibody, an antibody fragment, a single-chain Fv (scFv) variant, a multispecific antibody, a bispecific antibody, a chimeric antibody, a humanized antibody, a human antibody, a fusion protein containing an epitope of an antibody, and a modified immunoglobulin molecule containing an antigen recognition site.

[0135] In one embodiment, the antibody can be selected from the group consisting of muromonab-CD3, abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab (Herceptin), etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab-I131, cetuximab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab pegol, romiplostim, AMG-531 (romiplostim), CNTO-148 (golimumab), CNTO-1275 (ustekinumab), ABT874 (briakinumab), LEA-29Y (belatacept), belimumab, TACI-Ig (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), second generation anti-CD20, ACZ-885 (canakinumab), tocilizumab, atorizumab, mepolizumab, pertuzumab, Humax CD20 (ofatumumab), tremelimumab (CP-675 206), tisilimumab, MDX-010 (ipilimumab), IDEC-114 (galiximab), inotuzumab, Humax EGFR (zalutumumab), aflibercept (VEGF Trap-Eye), Humax-CD4 (zanilimumab), Ala-Ala (hOKT3 gamma1), otelixizumab (ChAglyCD3;TRX4), catumaxomab, MT-201 (adecatumumab), pregovomab, CH-14.18 (dinutuximab), WXG250 (dilenuximab), AMG-162 (denosumab), AAB-001 (bapineuzumab), motavizumab, MEDI524 (motavizumab), efumgumab, Aurograb (registered trademark), laxibacumab, third generation anti-CD20, LY2469298 (ocaratuzumab), and bertuzumab.

[0136] In one embodiment, the antibody can be a monoclonal antibody (mAb).

[0137] In the above formula (2), A' is a divalent linking group derived from the linking functional group (A) of formula (1). For example, A' may include a functional group formed by an addition reaction of a double bond contained in the linking functional group. In one embodiment, when the linking functional group is maleimidyl, A' may be a functional group formed by participating in an addition reaction of a double bond in the 5-membered ring of maleimidyl. The subject matter regarding the linking functional group (A) of formula (1) described above can be similarly applied to A' where applicable.

[0138] In one embodiment, the ligand E can be an antibody. For example, the antibody may include a functional group that binds to A in formula (1) to form the E-A' binding structure of formula (2). If necessary, the functional group for the above binding can be introduced into the antibody, and the types of such functional groups and the methods for introducing the functional groups are known in the art. In one embodiment, the binding structure of the ligand E and A' can be represented by a portion represented by one of the following formulas. In the following formulas, * can be the remaining portion of the antibody. In the following formulas, * The S, NH, CONH, C6H3-OH, Se, and triazole ring moieties directly bonded to can be -SH of cysteine, -NH2 of lysine, -C(=O)NH2 of glutamine, -C6H4-OH of tyrosine, -SeH of selenocysteine, and -N3 of a non-natural amino acid present at a specific position of the ligand E and

[0139]

Chemical formula

[0140]

Chemical formula

[0141] In formula (2), U, L 1 , k, and j are U, L of formula (1) 1can be the same as U, L, k, and j in Formula 1 described above. For the subject matter of U, L, k, and j, when applicable, it can be applied to U, L in Formula 2 in a similar manner. In one embodiment, when E in Formula 2 above is an antibody and PL of U is a drug, the compound represented by Formula 2 can be provided as an antibody-drug conjugate. 1 For U, L, k, and j, when applicable, it can be applied to U, L in Formula 2 in a similar manner. 1 can be applied to U, L, k, and j in a similar manner. In one embodiment, when E in Formula 2 above is an antibody and PL of U is a drug, the compound represented by Formula 2 can be provided as an antibody-drug conjugate. In one embodiment, the compound represented by Formula 2 above can be the following formula:

[0142]

Chemical formula

[0143]

Chemical formula

[0144] In the above formula, n is a real number from 1 to 10. In one embodiment, n can be a real number from 1 to 8, a real number from 1 to 6, a real number from 1 to 4, or a real number from 1 to 2. In one embodiment, the conjugate represented by Formula 2 is the following formula:

[0145] [Chemical formula] JPEG2025524337000049.jpg126149 can be selected from the group consisting of conjugates represented by

[0146] In the above formula, mAb represents the antibody moiety. In the above formula, n is a real number from 1 to 10. In one embodiment, n can be a real number from 1 to 8, a real number from 1 to 6, a real number from 1 to 4, or a real number from 1 to 2. Exemplary DAR2-type ligand-drug conjugates In one embodiment, the compound represented by Formula 2 can be selected from the compounds listed in the attached Table D. The specific n values listed in Table D can vary as real numbers from 1 to 10. In one embodiment, n can be a real number from 1 to 8, a real number from 1 to 6, a real number from 1 to 4, or a real number from 1 to 2. DAR4-type ligand-drug conjugate (Formula 2-1) In one embodiment, the linking group L of Formula 2 according to the present invention 1 when having a branched structure or a dendrimer structure (i.e., when L 1 is a polyvalent linking group), a ligand-drug conjugate of Formula 2 to which a plurality of active agents are bound can be provided. In one embodiment, the compound represented by Formula 2 is the following Formula 2-1:

[0147] [Chemical formula] It can be a ligand-drug conjugate represented by

[0148] In Formula 2-1, E is a ligand or protein having receptor binding properties, and A' is a divalent linking group derived from the binding functional group (A) of Formula 1. Regarding E and A', the subject matter described in Formula 2 can also be applied to Formula 2-1 in the same manner.

[0149] In Formula 2-1, U 1 and U 2 each have the same meaning as U in Formula 1, and U 1 and U 2 may be the same as or different from each other. In addition, L 11 and L 12 each have the same meaning as L 1 in Formula 1, and L 11 and L 12 may be the same as or different from each other.

[0150] In Formula 2-1, j is from 1 to 10. In one embodiment, j is from 1 to 5. For example, j is 1.

[0151] Regarding Formula A, L 1 and U, the subject matter described in Formula 1 can be applied to A, U 1 and U 2 in Formula 2-1 respectively, as well as L 11 and L 12 in the same manner. In addition, regarding U 1 and U 2 as well as L 11 and L 12 in Formula 1-1, the subject matter described in Formula 1-1 can be applied to Formula 2-1 in the same manner respectively. In Formula 2-1, L 1a and L 1b are each independently a direct bond;

[0152] [Chemical formula] can be selected from. In this case, R e is H or C1-C8 alkyl. In Formula 2-1, q1, q2, and q3 can each independently be an integer from 0 to 10. In Formula 2-1, q4 can be an integer from 1 to 10. Further, L 1a when

[0153] [Chemical formula] is the case, q2 is not 0, and L 1b when

[0154] [Chemical formula] is the case, q3 is not 0.

[0155] In one embodiment, q1 can be an integer from 0 to 8, an integer from 1 to 8, or an integer from 1 to 6. In one embodiment, q2 and q3 can each independently be an integer from 0 to 8, an integer from 0 to 6, or an integer from 0 to 4. In one embodiment, q4 can be an integer from 1 to 8, an integer from 1 to 6, or an integer from 1 to 4.

[0156] L 1a and L 1b Regarding q1, q2, q3, and q4, the subject matter described in Formula 1-1 can be similarly applied in Formula 2-1 respectively.

[0157] In Formula 2-1, n can be a real number from 1 to 10. In one embodiment, n can be a real number from 1 to 6, a real number from 1 to 4, or a real number from 1 to 2. In one embodiment, the ligand-drug conjugate represented by Formula 2-1 is the following formula:

[0158] [Chemical formula] (In the above formula, mAb is the antibody part. In the above formula, q1 to q4, n, U 1 and U 2 , R d1 , R d5 , R e , n1, n3, n4, n8, n14 and n15, m2, m8 and m10 are as described above with respect to Formula 1-1 or Formula 2-1) can be a conjugate represented by In one embodiment, the ligand-drug conjugate represented by Formula 2-1 has the following formula:

[0159]

Chemical formula

[0160] In the above formula, mAb is the antibody part. In the above formula, q1 to q4, n1, n8 and m8 are as described above with respect to Formula 1-1. In the above formula, PL has the same meaning as PL in Formula 1. In the above formula, Z 1 is a heteroatom selected from NR 3 , O, S and Se. R 3 is H or C1-C8 hydrocarbyl. In the above formula, V” represents an electron-withdrawing group. For example, V” can be carboxy, carboxy-C1-C8 alkyl, or C1-C8 alkoxycarbonyl. For example, V” can be carboxy, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. In the above formula, the -O-CO- group of the -O-CO-PL group is an optional self-cleavable spacer group and may not be present (i.e., the -PL group is directly linked to a -CH2- group) or can be replaced with the functional groups described above with respect to the “optional self-cleavable spacer group”.

[0161] In one embodiment, the ligand-drug conjugate represented by Formula 2-1 can be selected from the compounds listed in the attached Table E. The specific n values listed in Table E can vary as real numbers in the range of 1 to 10. For example, n can be a real number from 1 to 6, a real number from 1 to 4, or a real number from 1 to 2. Definitions As used herein, the term "hydrocarbyl" refers to a functional group consisting of carbon and hydrogen, and refers to a saturated, partially unsaturated or fully unsaturated straight-chain, branched-chain or cyclic hydrocarbon. Hydrocarbyl can include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, etc. Non-limiting examples of hydrocarbyl can include methyl, ethyl, propyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, etc.

[0162] The term "alkyl" refers to a fully saturated branched-chain or unbranched (or straight-chain or chain-like) hydrocarbon. Alkyl can be a substituted or unsubstituted alkyl. C1-C8 alkyl can be C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkyl. Non-limiting examples of alkyl can include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, isoamyl, or n-hexyl.

[0163] The term "alkenyl" includes straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms, 2 to 5 carbon atoms, or 2 to 4 carbon atoms containing one or more double bonds at any position. For example, alkenyl can include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, etc.

[0164] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon chain having at least one triple bond. Alkynyl is preferably a straight-chain or branched-chain having 2 to 8 carbon atoms, and examples of alkynyl may include 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, and the like.

[0165] The term "alkoxy" refers to an alkyl bonded to an oxygen atom. For example, C1-C8 alkoxy may be C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkoxy. Alkoxy may be methoxy, ethoxy, or propoxy.

[0166] The term "cycloalkyl" includes monocyclic or polycyclic saturated carbon rings containing 3 to 8 carbon atoms. Examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0167] The term "cycloalkenyl" includes non-aromatic monocyclic or polycyclic rings having 3 to 8 carbon atoms and containing at least one carbon-carbon double bond. Examples may include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

[0168] The term "cycloalkynyl" refers to a monocyclic or polycyclic unsaturated hydrocarbon ring having 4 to 10 carbon atoms and containing at least one triple bond. Examples may include monocyclic alkynyl groups such as cyclooctynyl groups and cyclodecynyl groups. The broadest meaning of "cycloalkynyl" includes structures in which one or more carbon atoms of a hydrocarbon ring containing at least one triple bond between carbon atoms are replaced by heteroatoms such as N.

[0169] The term "dienyl" refers to an unsaturated branched-chain or unbranched C4-C having two double bonds between two adjacent carbon atoms 10Refers to an aliphatic substituent. Examples include, but are not limited to, 2,4-pentadienyl, 2,4-hexadienyl, 4-methyl-2,4-pentadienyl, etc.

[0170] The term "halogen" atom refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, iodine, etc.

[0171] The term "haloalkyl" refers to an alkyl substituted with one or more halogen atoms.

[0172] The term "hydroxy" refers to the OH functional group (hydroxyl group).

[0173] The term "mercapto" refers to the SH functional group.

[0174] The term "cyano" is CN and refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

[0175] The term "oxo" refers to =O, and "substituted with oxo" means that the carbon atom has an =O substituent in the form of -C(=O)-.

[0176] The term "nitro" refers to NO2.

[0177] The term "amino" refers to -NH2.

[0178] The term "alkylamino" refers to a functional group in which one or two hydrogen atoms of amino (-NH2) are substituted by one or two of the above-mentioned alkyls, including both monoalkylamino and dialkylamino, and the two alkyls in dialkylamino may be the same or different. Specifically, mono C1-C8 alkylamino may be one in which one hydrogen atom of the amino (-NH2) group is substituted by C1-C8 alkyl, and di C1-C8 alkylamino may be one in which two hydrogen atoms of the amino (-NH2) group are substituted by the same or different C1-C8 alkyls. For example, mono C1-C8 alkylamino (-NH (C1-C8 alkyl)) may include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, etc. Di C1-C8 alkylamino (-N (C1-C8 alkyl) 2) may include, for example, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, ethylpropylamino, ethylisopropylamino, ethylisobutylamino, isopropylisobutylamino, methylhexylamino, ethylhexylamino, etc.

[0179] The term "carboxy" refers to -COOH.

[0180] The term "carbamoyl" refers to -CONH2.

[0181] The terms "N-mono C1-C8 alkylcarbamoyl" and "N,N-di C1-C8 alkylcarbamoyl" refer to those in which one hydrogen atom or two hydrogen atoms bonded to the nitrogen atom of carbamoyl (-CONH2) are substituted by C1-C8 alkyl. In N,N-di C1-C8 alkylcarbamoyl, the two C1-C8 alkyls may be the same or different from each other.

[0182] The term "alkanoyl" refers to the alkyl as defined above, having a predetermined number of carbon atoms bonded through a carbonyl bridge (i.e., -(C=O)-alkyl). For example, alkanoyl includes methanoyl (formyl: -COH), ethanoyl (acetyl: -COCH3), propanoyl (-COCH2CH3), butanoyl (-CO(CH2)2CH3), etc.

[0183] The term "alkanoylamino" refers to an amino substituted with an alkanoyl group (i.e., -NH(C=O)-alkyl). The nitrogen atom of alkanoylamino can be further substituted with a substituent, for example, an alkyl group. For example, alkanoylamino includes formylamino (-NHCOH), acetylamino (-NHCOCH3), propanoylamino (-NHCOCH2CH3), butanoylamino (-NHCO(CH2)2CH3), etc.

[0184] The terms "cyano-C1-C8 alkyl", "halo-C1-C8 alkyl", "hydroxy-C1-C8 alkyl", "C1-C8 alkoxy-C1-C8 alkyl", "C1-C8 alkoxy-C1-C8 alkoxy-C1-C8 alkyl", "carboxy-C1-C8 alkyl", "amino-C1-C8 alkyl", "carbamoyl-C1-C8 alkyl", "N-mono C1-C8 alkylcarbamoyl-C1-C8 alkyl" and "N,N-di C1-C8 alkylcarbamoyl-C1-C8 alkyl" each refer to a C1-C8 alkyl substituted at the end or in the middle with cyano, halogen, hydroxy, alkoxy, carboxy, amino, carbamoyl, N-mono C1-C8 alkylcarbamoyl and N,N-di C1-C8 alkylcarbamoyl, respectively.

[0185] The term "glycosyl" refers to a functional group formed by the condensation reaction of sugar molecules.

[0186] The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom. The heterocyclyl ring group can be monocyclic or bicyclic. The bicyclic heterocyclyl can be a spiro, bridged, or fused ring group. Heterocyclyl can contain 3 to 20 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, 3 to 7 ring atoms, 3 to 6 ring atoms, 4 to 9 ring atoms, 4 to 8 ring atoms, 4 to 7 ring atoms, or 4 to 6 ring atoms. The heteroatom can be any one or more selected from the group consisting of N, O, and S. The heteroatom can be 1 to 3, 1, or 2 heteroatoms selected from the group consisting of N, O, and S.

[0187] Non-limiting examples of heterocyclyl can include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophenyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, etc.

[0188] The term "heterocyclyloxy" refers to a functional group in which an oxygen atom is directly linked to the ring of a heterocycle.

[0189] The term "heteroaryl" or "heteroarylene" refers to a monocyclic or bicyclic aromatic moiety containing one or more heteroatoms selected from the group consisting of N, O, and S, with the remaining ring atoms being carbon. The heteroaryl group can contain, for example, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. The heteroaryl group can contain 5 to 10 ring elements, 5 to 7 ring elements, or 5 or 6 ring elements. Heteroaryl can be a 5- to 6-membered heteroaryl containing one or two N, O, or S. The heteroaryl group can be a monocyclic group, a bicyclic group, or a tricyclic group. The bicyclic group can be a spiro ring group, a bridged ring group, and a fused ring group.

[0190] Non-limiting examples of "heteroaryl" include pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, thienyl, thiophenyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazolyl, pyrid-2-yl, pyrid-3-yl, 2-pyrazin-2-yl, pyrazin-4-yl, pyrazin-5-yl, 2-pyrimidin-2-yl, 4-pyrimidin-2-yl, 5-pyrimidin-2-yl, indolyl, and the like.

[0191] The term "linking functional group" refers to a functional group that can form a covalent bond through an addition, substitution, condensation reaction, or the like with a functional group contained in a ligand or protein, or a functional group contained in a linker precursor.

[0192] As used herein, the term "moiety" refers to a part of a compound corresponding to the parent compound of that moiety when the parent compound is attached to a compound of Formula 1 or a conjugate of Formula 2. This is understood from the content that even when a part of the whole compound is referred to herein as a compound or an active agent, it refers to the "moiety" of the compound or active agent.

[0193] In the present invention, "precursor" refers to a compound as a reactant that finally provides a desired moiety through a chemical reaction or the like.

[0194] In the present invention, the "linker precursor" refers to a compound that forms a desired linker structure or a part thereof through a chemical reaction. For example, as PEG linkers, various substances are known such as hydroxy-PEG linker, alkynyl-PEG linker, bromo-PEG linker, DBCO-PEG linker, azide-PEG linker, amino-PEG linker, maleimide-PEG linker, etc. In addition, linker compounds such as aminooxy-PEG linker, tetrazine-PEG linker, tosylate-PEG linker, thiol-PEG linker, aldehyde-PEG linker, phosphonate-PEG linker, hydrazide-PEG linker, iodo-PEG linker, carboxyl-PEG linker are also widely used in related fields. As another example, as linkers having a DBCO (dibenzocyclooctyne) group, amine-reactive DBCO (DBCO-NHS, DBCO-sulfo-NHS ester, DBCO-PEG-NHS ester, DBCO-NHCO-PEG-NHS ester, etc.), carboxyl / carbonyl-reactive DBCO (DBCO-amine, DBCO-PEG-amine, etc.), -SH group-reactive DBCO (DBCO-maleimide, DBCO-PEG-maleimide, etc.), DBCO-PEG-t-butyl ester, DBCO-alcohol, DBCO-PEG-alcohol, DBCO-PEG-DBCO, bis-DBCO-PEG and various other substances are known. The linker precursors of the present invention include various linkers known in the field of ligand-conjugates and are not limited to the linker structures exemplified herein. Available linker precursors, preparation methods, reaction conditions, etc. are well-known in the related fields.

[0195] The term "dendrimer" refers to an ordered three-dimensional molecular structure having branched units centered around a core.

[0196] The term "1,6-elimination reaction" refers to a reaction in which the cleavage of a covalent bond occurs at a specific position in the molecular structure of a compound, resulting in the cleavage of the covalent bond at a position separated by 5 atoms (the 1,6-position relationship).

[0197] In one embodiment, when β-galactose is separated from galactosidase, the compound of Formula 1 having a benzothiophene core and a β-galactoside-inducing group undergoes a 1,6-elimination reaction to release PL - or PL-H.

[0198]

Chemical Formula

[0199]

Chemical Formula

[0200]

Chemical Formula

[0201]

Chemical Formula

[0202] In addition, the compound of formula 1 or the ligand-drug conjugate of formula 2 according to the present invention can exhibit excellent target cell selectivity and excellent active agent release characteristics. The compound of the present invention can rapidly dissociate and release the active agent by reacting with enzymes such as galactosidase and glucuronidase under the conditions of pH 4 to 5. Therefore, the compound of the present invention can effectively release the active agent in the environment within target cells (for example, lysosomes of tumors).

[0203] In one aspect of the present invention, there is provided a pharmaceutical composition comprising a linker compound of formula 1, formula 1-1 or formula B or a ligand-drug conjugate of formula 2 or formula 2-1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0204] In another aspect of the present invention, there is provided a composition for imaging or a composition for detection comprising a linker compound of formula 1, formula 1-1 or formula B or a ligand-drug conjugate of formula 2 or formula 2-1, or a pharmaceutically acceptable salt thereof.

[0205] The linker compound of formula 1, formula 1-1 or formula B and the ligand-drug conjugate of formula 2 or formula 2-1 according to the present invention can be mixed with a solvent and provided as a composition.

[0206] The composition can be prepared in a form injectable as a liquid solution or as a suspension. Additionally, the composition can be prepared in a solid form suitable for injection as an emulsion or a polypeptide encapsulated in liposomes. The compounds or ligand-drug conjugates of the present invention can be combined with a pharmaceutically acceptable carrier, including any carrier that does not induce the production of antibodies harmful to the subject receiving the carrier. Suitable carriers can typically include slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, amino acid polymers, amino acid copolymers, lipid aggregates, etc. The protein can be formulated into a vaccine in its neutral or salt form.

[0207] The composition can contain diluents such as water, physiological saline, glycerol, ethanol, etc. Auxiliary substances such as wetting agents or emulsifiers, pH buffers, etc. can be added to the composition. The composition can be administered parenterally by injection or via subcutaneous or intramuscular injection. Further formulations can be provided, for example, as suppositories or oral preparations. Oral compositions can be provided as solutions, suspensions, tablets, pills, capsules, or sustained-release formulations.

[0208] The composition can be administered by a method compatible with the dosage form. The composition contains a therapeutically effective amount of the compound or ligand-drug conjugate according to the present invention. A therapeutically effective amount refers to a dosage in a single dose or a multiple-dose schedule that is effective in treating or preventing a disease or disorder. The dosage administered is determined by the type of active agent contained in the compound or ligand-drug conjugate of the present invention and / or the type of ligand or protein that binds to the receptor. Additionally, the dosage administered can vary depending on the health and physical condition of the subject being treated, the desired degree of protection, and other relevant factors.

[0209] For example, a therapeutically effective amount of the compound or ligand-drug conjugate of the present invention or a pharmaceutical composition containing the same can be used for the treatment or prevention of proliferative diseases, autoimmune diseases, or infectious diseases.

[0210] For example, the composition can be used for the treatment of cancer or tumors. For example, the composition can be administered to a patient for treating or preventing an infection by a pathogen (e.g., virus, bacterium, fungus, parasite, etc.). These methods include administering to a mammal a therapeutically or prophylactically effective amount of a compound or conjugate under conditions such that the disease or disorder or its symptoms are treated or prevented or the disease or disorder is treated or prevented.

[0211] In the above composition, the compound or conjugate of the present invention can be administered in the form of its pharmaceutically acceptable salt, hydrate, or solvate. In one embodiment, it can be administered with a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and / or pharmaceutically acceptable additive substance. The pharmaceutically effective amounts and types of pharmaceutically acceptable salts or solvates, excipients, and additive substances can be determined using standard methods (see Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition, 1990).

[0212] As used herein, the term “pharmaceutically acceptable salt” includes organic salts and inorganic salts. Examples include, but are not limited to, hydrochloride, hydrobromide, iodate, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantonate, bitartrate, ascorbate, succinate, maleate, genticinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt can include another molecule (e.g., acetate ion, succinate ion, and other counterions, etc.) and can also include one or more charged atoms or one or more counterions.

[0213] Exemplary solvates that can be used are solvates with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine, including but not limited to.

Examples

[0214] Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and do not limit the scope of the present invention to these examples. The abbreviations used in this specification are as follows. Abbreviations not listed in the following list of abbreviations have the meanings commonly used in the field of organic synthesis: Ac: Acetyl AcOH: Acetic acid EA: Ethyl acetate MC: Methylene chloride DMF: Dimethylformamide EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HOBt: 1-Hydroxybenzotriazole hydrate ACN: Acetonitrile THF: Tetrahydrofuran DCC: N,N'-Dicyclohexylcarbodiimide DMAP: 4-Dimethylaminopyridine NHS: N-Hydroxysuccinimide DIPEA: Diisopropylethylamine TEA: Triethylamine Boc: tert-Butyloxycarbonyl LAH: Lithium aluminum hydride TFA: Trifluoroacetic acid AgOTf: Silver trifluoromethanesulfonate KO t Bu: Potassium tert-butoxide MMAF-OMe: Monomethyl auristatin F methyl ester PPTS: Pyridinium p-toluenesulfonate TBAI: Tetrabutylammonium iodide DIBAL-H: Diisobutylaluminum hydride TEMPO: 2,2,6,6-Tetramethylpiperidine 1-oxyl, 2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical MMAE: Monomethyl auristatin E NCS: N-Chlorosuccinimide Preparation Example 1: Preparation of Linker P-1

[0215]

Chem.

[0216] [Chemical] Compound P-2a (2-[2-(2-aminoethoxy)ethoxy]acetic acid, TCI, CAS No. 134978-97-5, 1.28 g, 7.87 mmol) was dissolved in 1,4-dioxane (30 mL) at 0 °C under a nitrogen atmosphere, and then sodium hydrogen carbonate (1.32 g, 15.74 mmol) and di-tert-butyl dicarbonate (Boc anhydride, 2.06 g, 9.44 mmol) dissolved in distilled water (15 mL) were added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, EA (300 mL), distilled water (250 mL), and 2N hydrochloric acid aqueous solution (50 mL) were added, and the organic layer was extracted 5 times. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain linker P-2 (2.32 g, quantitatively obtained). The obtained linker P-2 was used in the next reaction without further purification. 1 H-NMR (400 MHz, CDCl3) δ 4.93 (brs, 1H), 4.17 (s, 2H), 3.78 - 3.76 (m, 2H), 3.68 - 3.65 (m,2H), 3.62 - 3.56 (m, 2H), 3.38 - 3.32 (m, 2H), 1.45 (s, 9H). Preparation Example 3: Preparation of Linker P-3

[0217] [Chemical] Step 1: Preparation of Compound P-3b Compound P-3a (tetraethylene glycol, Daejung Chemicals & Metals, CAS No. 112-60-7, 10 g, 51.49 mmol) was dissolved in MC (200 mL) at 0 °C under a nitrogen atmosphere, and then 4-methylbenzenesulfonyl chloride (24.54 g, 128.72 mmol) and potassium hydroxide (8.67 g, 154.46 mmol) were added. The mixture was stirred at room temperature for 15 h. After completion of the reaction, MC (100 mL) and distilled water (200 mL) were added, and the organic layer was extracted twice. The obtained organic layer was dehydrated over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain compound P-3b in the form of a colorless oil (18.98 g, 73.3%). 1 1H-NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 4H), 7.34 (d, J = 8.0 Hz, 4H), 4.16 - 4.14 (m,4H), 3.69 - 3.66 (m, 4H), 3.57 - 3.55 (m, 8H), 2.44 (s, 6H); MS m / z: 503[M+H] + . Step 2: Preparation of compound P-3c Compound P-3b (18.98 g, 37.76 mmol) was dissolved in DMF (95 mL) at room temperature under a nitrogen atmosphere, and then sodium azide (7.36 g, 113.36 mmol) was added. The mixture was stirred at 60 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, EA (200 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL) were added, and the organic layer was extracted twice. The obtained organic layer was dehydrated over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain compound P-3c in the form of a colorless liquid (8.96 g, 97.1%). 1 1H-NMR (400 MHz, CDCl3) δ 3.69 - 3.66 (m, 12H), 3.40 - 3.37 (m, 4H); MS m / z: 267[M+Na] + . Step 3: Preparation of linker P-3 Compound P-3c (4.17 g, 17.06 mmol) was dissolved in EA (32 mL), diethyl ether (32 mL), and 5% aqueous hydrochloric acid solution (64 mL) at 0 °C under a nitrogen atmosphere. Then, triphenylphosphine (4.47 g, 17.06 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic layer, and MC (100 mL) was added to the aqueous layer, and the aqueous layer was washed three times. The obtained aqueous layer was concentrated under reduced pressure to obtain linker P-3 in the form of a colorless liquid (4.12 g, 95%). 1 H-NMR (400 MHz, CDCl3) δ 8.27 (brs, 2H), 3.86 - 3.83 (m, 2H), 3.72 - 3.68 (m, 10H), 3.47 - 3.45 (m, 2H), 3.26 - 3.24 (m, 2H). Preparation Example 4: Preparation of Linker P-4

[0218]

Chemical Structure

[0219]

Chemical Structure

[0220]

Chem.

[0221]

Chemical formula

[0222]

Chem.

[0223]

Chem.

[0224] [Chemical formula] Step 1: Preparation of Compound C-3b Compound C-3a (benzo[b]thiophen-4-ol, Ambeed, CAS No. 3610-02-4, 1.14 g, 7.63 mmol) was dissolved in ACN (50 mL) at 0 °C under a nitrogen atmosphere, and then potassium carbonate (2.63 g, 19.07 mmol) and benzyl bromide (1 mL, 8.39 mmol) were gradually added, and the mixture was stirred at 0 °C for 30 minutes. The reaction temperature was raised to room temperature, and the mixture was stirred for an additional 16 hours. After completion of the reaction, EA (350 mL) and distilled water (350 mL) were added to extract the organic layer. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain Compound C-3b in the form of a bright orange oil (1.87 g, 99%). 1H-NMR (400 MHz, CDCl3) δ 7.57 (d, J = 5.6 Hz, 1H), 7.50 - 7.47 (m, 3H), 7.42 - 7.38 (m, 2H),7.35 - 7.32 (m, 2H), 7.27 - 7.23 (m, 1H), 6.81 (d, J = 8 Hz, 1H), 5.22 (s, 2H). Step 2: Preparation of Compound C-3c Compound C-3b (1.87 g, 7.8 mmol) was dissolved in THF (60 mL) at room temperature under a nitrogen atmosphere. The solution was cooled to -78 °C, and then a solution of n-butyllithium (2.5 M n-BuLi in hexane, 1.42 mL, 3.56 mmol) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. DMF (0.78 mL) was slowly added to the mixture, and the mixture was stirred at the same temperature for an additional 30 minutes. Distilled water (300 mL) was added to the mixture at the same temperature to terminate the reaction, and then EA (300 mL) was added to extract the organic layer. The obtained organic layer was dehydrated over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain Compound C-3c in the form of a pale yellow oil (1.36 g, 65%). 1 H-NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.25 (s, 1H), 7.50 - 7.37 (m, 7H), 6.85 (d, J = 7.6Hz, 1H), 5.24 (s, 2H). Step 3: Preparation of Core C-3 Compound C-3c (300 mg, 1.11 mmol) was dissolved in MC (20 mL) under a nitrogen atmosphere at -78 °C, and then boron trichloride solution (1 M BCl3 in MC, 2.2 mL, 2.20 mmol) was gradually added. The mixture was stirred for 30 minutes. After completion of the reaction, EA (10 mL) and distilled water (10 mL) were gradually added dropwise at -50 °C to terminate the reaction, and then EA (100 mL) and distilled water (100 mL) were added at room temperature to extract the organic layer. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Core C-3 in the form of a light yellowish brown solid (174 mg, 87.4%). 1 1H-NMR (400 MHz, DMSO-d6) δ 10.62 (brs, 1H), 8.41 (s, 1H), 7.46 (d, J = 8 Hz, 1H), 7.39 (t, J =8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H). Preparation Example 11: Preparation of Core C-4

[0225]

Chemical Structure

[0226] [Chemical formula] Step 1: Preparation of Compound C-5a Compound C-3c (2.1 g, 7.82 mmol) prepared in Step 2 of Preparation Example 10 was dissolved in MC (40 mL) at room temperature under a nitrogen atmosphere, and then ethyl (triphenylphosphoranylidene) acetate (5.45 g, 15.6 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the organic layer was extracted twice with MC (100 mL) and distilled water (100 mL). The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain Compound C-5a in the form of a white solid (2.5 g, 95%). 1H-NMR (400 MHz, CDCl3) δ 7.85 (d, J = 15.6 Hz, 1H), 7.69 (s, 1H), 7.48 - 7.46 (m, 2H), 7.43 - 7.35 (m, 4H), 7.31 - 7.27 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.25 (d, J = 15.6 Hz, 1H), 5.21 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). Step 2: Preparation of Compound C-5b Compound C-5a (4.7 g, 13.3 mmol) was dissolved in THF (150 mL) and methanol (500 mL) at room temperature under a nitrogen atmosphere, 5% palladium on carbon (5% Pd / C, 5.67 g) was added, and then the mixture was reacted under a hydrogen atmosphere for 1 hour. After completion of the reaction, the solution was filtered using celite and concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound C-5b in the form of a white solid (4.3 g, 91%). 1 H-NMR (400 MHz, CDCl3) δ 7.48 - 7.41 (m, 1H), 7.42 - 7.34 (m, 4H), 7.26 - 7.25 (m, 1H), 7.18 (t, J = 8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.22 (t, J = 8.0 Hz, 2H), 2.74 (t, J = 8.0 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). Step 3: Preparation of Compound C-5c Compound C-5b (485 mg, 1.42 mmol) was dissolved in MC (30 mL) at -78 °C under a nitrogen atmosphere, and then dichloromethyl methyl ether (Merck, CAS number 4885-02-3, 400 μL, 4.27 mmol) and titanium tetrachloride solution (1 M TiCl4 in MC, 4.3 mL, 4.27 mmol) were added sequentially and slowly, and the mixture was stirred for 2 hours while maintaining the temperature. After completion of the reaction, distilled water (250 mL) was slowly added dropwise to terminate the reaction, and MC (250 mL) was added to extract the organic layer twice. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound C-5c (290 mg, 55%). 1 1H-NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.49 - 7.35 (m, 6H), 6.94 (d, J = 8.4 Hz, 1H), 5.30 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.27 (t, J = 7.6 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). Step 4: Preparation of Core C-5 Compound C-5c (279 mg, 0.81 mmol) was dissolved in MC (16 mL) at -78 °C under a nitrogen atmosphere, and then boron trichloride solution (1 M BCl3 in MC, 2.44 mL, 2.44 mmol) was added slowly, and the mixture was stirred for 1.5 hours. After completion of the reaction, the temperature was raised to -50 °C, and then distilled water (15 mL) was added dropwise to terminate the reaction. The temperature was raised to 0 °C, and 2N aqueous sodium hydroxide solution (5 mL) was added dropwise. The organic layer was extracted twice from the mixture using MC (30 mL). The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Core C-5 in the form of a white solid (150 mg, 66%). 1H-NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 5.94 (s, 1H), 4.16 (q, J = 6.8 Hz, 2H), 3.29 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H). Preparation Example 13: Preparation of Core C-6

[0227]

Chem.

[0228]

Chemical Structure

[0229]

Chemical Structure

[0230]

Chemical Structure

[0231]

Chemical Structure

[0232]

Chemical Structure

[0233]

Chemical Structure

[0234]

Chemical Structure

[0235]

Chemical Structure

[0236] [Chemical] Step 1: Preparation of Compound A-1a Core C-1 (99.1 mg, 0.42 mmol) was dissolved in MC (15 mL) at 0 °C under a nitrogen atmosphere, and then acetobromo-α-D-galactose (192 mg, 0.46 mmol) and benzyltributylammonium chloride (132 mg, 0.42 mmol) were added. 5N aqueous sodium hydroxide solution (255 μL, 1.27 mmol) was gradually added to this reaction solution, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, MC (50 mL) and distilled water (50 mL) were added, and the organic layer was extracted three times. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound A-1a in the form of an ivory solid (131.3 mg, 55%). 1 H-NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.38 (s, 1H), 6.80 (d, J = 8Hz, 1H), 5.64 (dd, J =10.4, 8 Hz, 1H), 5.50 (d, J =3.2 Hz, 1H), 5.29 (d, J = 8Hz, 1H), 5.16 (dd, J =10.4, 3.2 Hz, 1H), 4.34 (s, 3H), 4.26 - 4.09 (m, 3H),3.93 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). Step 2: Preparation of Compound A-1b Compound A-1a (131.3 mg, 0.23 mmol) was dissolved in THF (3 mL) at 0 °C under a nitrogen atmosphere, and then sodium borohydride (26.5 mg, 0.70 mmol) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, distilled water (50 mL) was added to terminate the reaction, and EA (50 mL) was added to extract the organic layer twice. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound A-1b in the form of a yellow solid (101.5 mg, 77%). 1 1H-NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.12 (d, J = 8 Hz, 1H), 6.63 (d, J = 8 Hz, 1H), 5.61(dd, J = 10.4, 8 Hz, 1H), 5.48 (d, J = 2.8 Hz, 1H), 5.16 - 5.12 (m, 2H), 4.99 -4.97 (m, 2H), 4.41 (s, 3H), 4.28 - 4.08 (m, 3H), 3.91 (s, 3H), 2.20 (s, 3H),2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H). Step 3: Preparation of Compound A-1c Compound A-·1b (101.5 mg, 0.18 mmol) was dissolved in MC (5 mL) at 0 °C under a nitrogen atmosphere, and then 4-nitrophenyl chloroformate (108.5 mg, 0.54 mmol) and DIPEA (156 μL, 0.89 mmol) were added sequentially. The mixture was stirred for 20 hours. After completion of the reaction, EA (30 mL) and distilled water (30 mL) were added to extract the organic layer. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound A-1c (44.1 mg, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.25 (d, J = 9.2 Hz, 2H), 7.35 (s, 1H), 7.23 (d, J = 8 Hz, 1H),7.08 (d, J = 9.2 Hz, 2H), 6.69 (d, J = 8 Hz, 1H), 5.62 (dd, J =10.4, 8 Hz, 1H),5.49 (d, J = 2.8 Hz, 1H), 5.44 (m, 2H), 5.18 (d, J = 8 Hz, 1H), 5.15 (dd, J = 10.4,3.6 Hz, 1H), 4.27 (m, 1H), 4.24 (s, 3H), 4.20 - 4.09 (m, 2H), 3.91 (s, 3H),2.21 (s, 3H), 2.06 (m, 6H), 2.04 (s, 3H). Step 4: Preparation of Compound A-1 Compound A-1c (37.2 mg, 0.054 mmol) was dissolved in methanol (1.5 mL) and ACN (1.5 mL) at 0 °C under a nitrogen atmosphere, and then potassium carbonate (52.4 mg, 0.38 mmol) was added. The mixture was stirred for 1.5 h while the temperature was raised from 0 °C to room temperature. After completion of the reaction, 2N aqueous hydrochloric acid solution (1 mL) was added to terminate the reaction, and the reaction solution was diluted with ACN (1 mL) and distilled water (1 mL), and then purified using preparative HPLC and lyophilized to obtain Compound A-1 in the form of a white solid (5 mg, 18%). 1 H-NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 9.2 Hz, 2H), 7.47 (s, 1H), 7.38 (d, J = 8 Hz, 1H),7.32 (d, J = 9.2 Hz, 2H), 6.76 (d, J = 8 Hz, 1H), 5.59 (s, 2H), 5.33 (m, 1H),4.94 - 4.92 (m, 2H), 4.68 (m, 1H), 4.57 (m, 1H), 4.18 (s, 3H), 3.85 (s, 3H),3.73 (m, 1H), 3.64 (m, 1H). Example I-2: Preparation of Compound A-2

[0237]

Chem.

[0238] [ka] Compound A-3 was obtained in the same manner as in Example I-2, except that MMAF-OMe was used instead of compound PL-1 in step 4 of Example I-2 (10.4 mg, 65%) in the form of a white solid; EI-MS m / z: 1101 [M+H] + . Example I-4: Preparation of Compound A-4

[0239] [ka] Compound A-4 was obtained in the form of a white solid in a manner similar to that of Example I-2 using core C-4 as the starting material, except that MMAF-OMe was used instead of compound PL-1 in step 4 of Example I-2 (11.7 mg, 64%); EI-MS m / z: 1145 [M+H] + . Example I-5: Preparation of Compound A-5

[0240] [ka] Using core C-5 as the starting material in the same manner as in Example I-2, except that MMAF-OMe was used instead of compound PL-1 in step 4 of Example I-2, compound A-5 was obtained in the form of a white solid (7.7 mg, 60%); EI-MS m / z: 1172 [M+H] + . Example I-6: Preparation of Compound A-6

[0241] [ka] Step 1: Preparation of Compound A-6a Core C-3 (174 mg, 0.976 mmol) was dissolved in MC (30 mL) at room temperature under a nitrogen atmosphere, and then acetobromo-α-D-galactose (440 mg, 1.07 mmol) and benzyltributylammonium chloride (Sigma-Aldrich, CAS No. 23616-79-7, 304 mg, 0.976 mmol) were sequentially added. A 5N aqueous sodium hydroxide solution (586 μL, 2.93 mmol) was added to this reaction solution, and the mixture was stirred for 5 hours. After completion of the reaction, MC (100 mL) and distilled water (100 mL) were added to extract the organic layer. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain compound A-6a (250 mg, 50.4%). 1 1H-NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.09 (s, 1H), 7.59 (d, J = 8 Hz, 1H), 7.44 (t, J = 8Hz, 1H), 6.95 (d, J = 8 Hz, 1H), 5.64 (dd, J =10.4, 8 Hz, 1H), 5.50 (d, J = 3.2Hz, 1H), 5.23 (d, J = 8 Hz, 1H), 5.18 (dd, J =10.4, 8 Hz, 1H), 4.27 (m, 1H),4.20 - 4.11 (m, 2H), 2.21 (s, 3H), 2.06 (s, 6H), 2.05 (s, 3H). Step 2: Preparation of Compound A-6b Compound A-6a (250 mg, 0.49 mmol) was dissolved in THF (10 mL) at 0 °C under a nitrogen atmosphere, and then sodium borohydride (46.5 mg, 1.225 mmol) was added, and the mixture was stirred for 1 hour. After completion of the reaction, distilled water (50 mL) was added to terminate the reaction, and EA (50 mL) was added to extract the organic layer. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain compound A-6b (230 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8 Hz, 1H), 7.28-7.22 (m, 2H), 6.93 (d, J = 8 Hz, 1H), 5.60 (dd, J =10.4, 8 Hz, 1H), 5.48 (d, J = 2.4 Hz, 1H), 5.16-5.12 (m, 2H), 4.91 (d, = 5.2 Hz, 2H), 4.31 (dd, J =11.2, 7.2 Hz, 1H), 4.16-4.10 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H). Step 3: Preparation of Compound A-6c Compound A-6b (300 mg, 0.58 mmol) was dissolved in concentrated hydrochloric acid (8 mL) at 0 °C under a nitrogen atmosphere, and then the mixture was stirred at 0 °C for 1 h. After completion of the reaction, EA (50 mL) and distilled water (50 mL) were added to extract the organic layer. The obtained organic layer was dehydrated over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give Compound A-6c in the form of a white solid (300 mg, 96.7%); MS m / z: 529 [M+H] + . Step 4: Preparation of Compound A-6d Compound A-6c (300 mg, 0.56 mmol) was dissolved in DMF (15 mL) at room temperature under a nitrogen atmosphere, then sodium azide (55 mg, 0.84 mmol) was added, and the mixture was stirred at 60 °C for 2 h. After completion of the reaction, EA (100 mL) and distilled water (200 mL) were added to extract the organic layer. The obtained organic layer was dehydrated over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to give Compound A-6d (230 mg, 75.6%). 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8 Hz, 1H), 7.32 (s, 1H), 7.28 (t, J = 8 Hz, 1H), 6.94(d, J = 8 Hz, 1H), 5.61 (dd, J = 10.4, 8 Hz, 1H), 5.50 (d, J = 2.4 Hz, 1H),5.17-5.14 (m, 2H), 4.60 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 4.26(dd, J =11.2, 6.8 Hz, 1H), 4.20-4.11 (m, 2H), 2.20 (s, 3H), 2.07 (s, 3H),2.05(s, 3H), 2.04 (s, 3H); MS m / z: 558 [M+Na] + . Step 5: Preparation of Compound A-6e A-6d (230 mg, 0.42 mmol) was dissolved in MC (15 mL) at -78 °C under a nitrogen atmosphere, and then dichloromethyl methyl ether (116 μL, 1.26 mmol) and titanium tetrachloride solution (1 M TiCl4 in MC, 1.28 mL, 1.26 mmol) were sequentially and gradually added, and the mixture was stirred for 1 hour while maintaining the temperature. After completion of the reaction, cooled distilled water (100 mL) was gradually added dropwise to terminate the reaction, and EA (100 mL) was added to extract the organic layer. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound A-6e in the form of a white solid (130 mg, 53.7%). 1H-NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.84 (d, J = 8 Hz, 1H), 7.40 (s, 1H), 7.08 (d, J = 8Hz, 1H), 5.66 (dd, J =10.4, 8 Hz, 1H), 5.52 (d, J = 3.2 Hz, 1H), 5.29 (d, J = 8Hz, 1H), 5.19 (dd, J =10.4, 3.2 Hz, 1H), 4.65 (d, J = 14.4 Hz, 1H), 4.52 (d, J= 14.4 Hz, 1H), 4.31-4.17 (m, 3H), 2.21 (s, 3H), 2.09 (s, 3H), 2.05 (s, 6H); MS m / z: 586 [M+Na] + . Step 6: Preparation of Compound A-6f Compound A-6e (130 mg, 0.23 mmol) was dissolved in THF (10 mL) at 0 °C under a nitrogen atmosphere, and then sodium borohydride (22 mg, 0.575 mmol) was added. The mixture was stirred for 1 hour. After completion of the reaction, distilled water (100 mL) was added to terminate the reaction, and EA (100 mL) was added to extract the organic layer. The obtained organic layer was dehydrated over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain Compound A-6f (120 mg, 92.3%). 1H-NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.28 (d, J = 8 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 5.61(dd, J =10.4, 8 Hz, 1H), 5.49 (d, J = 2.8 Hz, 1H), 5.17-5.14 (m, 2H), 4.89 (d,J = 5.6 Hz, 2H), 4.61 (d, J = 14.4 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.26(dd, J = 11.2, 6.8 Hz, 1H), 4.20-4.11 (m, 2H), 2.20 (s, 3H), 2.07 (s, 3H), 2.05(s, 3H), 2.04 (s, 3H), 1.79 (t, J = 5.6 Hz, 1H). Step 7: Preparation of Compound A-6g Compound A-6f (120 mg, 0.21 mmol) was dissolved in MC (3 mL) at 0 °C under a nitrogen atmosphere, and then 4-nitrophenyl chloroformate (85 mg, 0.42 mmol), pyridine (51 μL, 0.63 mmol), and DIPEA (55 μL, 0.32 mmol) were sequentially added. The mixture was stirred at 0 °C for 30 minutes and at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with MC (50 mL), and 2N aqueous hydrochloric acid solution (50 mL) was added to extract the organic layer twice. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography to obtain Compound A-6g (116.3 mg, 75%). 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.2 Hz, 2H), 7.39 - 7.37 (m, 4H), 6.96 (d, J = 8 Hz,1H), 5.62 (dd, J = 10.4, 8 Hz, 1H), 5.50 (d, J = 3.2 Hz, 1H), 5.48 (s, 2H),5.19 - 5.15 (m, 2H), 4.63 (d, J = 14.4 Hz, 1H), 4.57 (d, J = 14.4 Hz, 1H), 4.26(m, 1H), 4.20 - 4.11 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.04(s, 3H). Step 8: Preparation of Compound A-6h Compound A-6g (18.7 mg, 0.025 mmol) and Compound PL-1 (6.7 mg, 0.031 mmol) were dissolved in DMF (500 μL) at 0 °C under a nitrogen atmosphere, and then HOBt (5.2 mg, 0.038 mmol), pyridine (500 μL) and DIPEA (11.1 μL, 0.064 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the organic layer was extracted twice with EA (50 mL) and 2N aqueous hydrochloric acid solution (50 mL). The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography to obtain A-6h in the form of a white solid (17.9 mg, 86%). 1H-NMR (400 MHz, CDCl3) δ 7.37 - 7.32 (m, 1H), 7.28 - 7.22 (m, 2H), 7.19 - 6.85 (m, 5H), 5.61(m, 1H), 5.50 (m, 1H), 5.18 - 5.09 (m, 4H), 4.64 - 4.48 (m, 3H), 4.39 - 4.13(m, 3H), 3.25 -3.23 (m, 3H), 2.90 - 2.88 (m, 3H), 2.32 (m, 1H), 2.20 (s, 3H),2.07 - 2.04 (m, 9H), 0.98 - 0.83 (m, 3H), 0.72 - 0.55 (m, 3H); EI-MS m / z: 812 [M+H] + . Step 9: Preparation of Compound A-6 Compound A-6h (17.9 mg, 0.022 mmol) was dissolved in methanol (1 mL) and THF (0.5 mL) at 0 °C under a nitrogen atmosphere, then potassium carbonate (21.3 mg, 0.154 mmol) was added, and the mixture was stirred at 0 °C for 40 minutes. After completion of the reaction, 2N aqueous hydrochloric acid solution (1 mL) was added to terminate the reaction, the reaction solution was diluted with ACN (1 mL) and distilled water (1 mL), and then purified using preparative HPLC and lyophilized to obtain Compound A-6 in the form of a white solid (7.5 mg, 53%); EI-MS m / z: 644 [M+H] + . Example I-7: Preparation of Compound A-7

[0242]

Chemical Structure

[0243]

Chemical Structure

[0244]

Chemical Structure

[0245]

Chemical formula

[0246]

Chemical formula

[0247]

Chemical Structure

[0248]

Chemical Structure

[0249]

Chemical Structure

[0250]

Chem.

[0251]

Chem.

[0252]

Chem.

[0253]

Chemical Structure

[0254] [Chemistry] Compound A-19 was obtained in the form of a white solid using compound A-13c as the starting material by the same means as in Example I-2, except that MMAF-OMe was used instead of compound PL-1 in Step 4 of Example I-2 (8 mg, 58%); EI-MS m / z: 1171 [M+H] + . Example I-20: Preparation of Compound A-20

[0255] [Chemistry] Compound A-20 was obtained in the form of a white solid using compound A-14a as the starting material by the same means as in Example I-2, except that MMAF-OMe was used instead of compound PL-1 in Step 4 of Example I-2 (12.1 mg, 68%); EI-MS m / z: 1129 [M+H] + . Example I-21: Preparation of Compound A-21

[0256] [Chemistry] Compound A-21 was obtained in the form of a white solid using core C-8 as the starting material by the same means as in Example I-2, except that MMAF-OMe was used instead of compound PL-1 in Step 4 of Example I-2 (17.2 mg, 74%); EI-MS m / z: 1085 [M+H] + . Example I-22: Preparation of Compound A-22

[0257] [Chemistry] Steps 1-7: Preparation of Compound A-22g Compound A-22g was obtained in the form of a white solid by the same means as in Steps 3 to 8 of Example I-6, except that compound A-21b was used instead of compound A-6b in Step 3 of Example I-6, and MMAF-OMe was used instead of compound PL-1 in Step 8 of Example I-6 (21.3 mg, 61%); EI-MS m / z: 1140 [M+H] + . Step 8: Preparation of Compound A-22 Compound A-22g (15.7 mg, 0.013 mmol) was dissolved in THF (1 mL) at room temperature under a nitrogen atmosphere, then triphenylphosphine (5.4 mg, 0.0195 mmol) and distilled water (0.3 mL) were sequentially added, and the mixture was stirred for 16 hours. A 2N aqueous sodium hydroxide solution (10 μL) was added to the above reaction solution at room temperature, the mixture was stirred for an additional 1 hour, then a 2N aqueous hydrochloric acid solution was slowly added dropwise to adjust the pH of the reaction solution to 3, the reaction solution was purified using preparative HPLC, and then freeze-dried to obtain compound A-22 in the form of a white solid (10.5 mg, 65%); MS m / z: 1113 [M+H] + . Example I-23: Preparation of Compound A-23

[0258]

Chemical formula

[0259]

Chemical formula

[0260]

Chemical formula

[0261]

Chemical formula

[0262]

Chemical Structure

[0263]

Chemical Structure

[0264]

Chemical Structure

[0265]

Chemical formula

[0266]

Chemical Structure

[0267]

Chemical Structure

[0268]

Chemical Structure

[0269]

Chemical Structure

[0270]

Chemical Structure

[0271]

Chemical Structure

[0272]

Chemical Structure

[0273]

Chemical Structure

Claims

1. The following formula 1: [Formula 1] A-(L １ ) ｋ -U ｊ [Wherein, L １ is a divalent or polyvalent linking group; k is 0 or 1, and j is from 1 to 10; A is absent, H or a linking functional group; U is the following formula A: 【Chemical 1】 (Wherein, PL is an activator linked to L via a heteroatom selected from N, O, and S, ２ or to ２ １ ), or to a carbon atom to which a benzene ring and A-(L ｋ - are attached; L ２ is a self - detaching linker selected such that the cleavage of the bond between L ２ and the carbon atom to which the benzene ring and A-(L １ ) ｋ are attached promotes the cleavage of the bond between L ２ and PL; W is an optional substituent of the benzene ring; Z １ and Z ３ One of them is selected from the group consisting of NR ３ , O, S and Se, and Z １ and Z ３ The other of them and Z ２ are each independently CH or N, and -(V) ｈ When present, each independently replaces H of NH or CH; 【Chemical 2】 represents the bond with A-(L １ ) ｋ -; R ３ is H or C １ -C ８ hydrocarbyl; V is an electron-withdrawing group, an electron-donating group, or -CH ２ -(L ２ ) ｌ -PL-; T, when cleaved, is an inducing group capable of initiating the release of PL and, if present, L through a 1,6-elimination reaction; ２ and; L ３ is, when present, an optional self-destructive spacer group that is sequentially cleaved when T is cleaved; X and Y are each independently selected from -O-, -NH-, and S; h, i, l, x and y are each independently 0 or 1, and p is an integer from 0 to 2) is a moiety represented by] A linker compound represented by, or a pharmaceutically acceptable salt thereof.

2. Said ring of said formula A [Chemical Formula 3] is selected from the following group: [Chemical Formula 4] The linker compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. V is halogen, CN, NO ２ , formyl, C １ ~C ８ alkylcarbonyl, carboxy, C １ ~C ８ alkoxycarbonyl, carbamoyl, mono C １ ~C ８ alkylcarbamoyl, di C １ ~C ８ alkylcarbamoyl, C １ ~C ８ alkyl, C １ ~C ８ alkenyl, OH, C １ ~C ８ alkoxy, SH, C １ ~C ８ alkylsulfanyl, NH ２ , mono C １ ~C ８ alkylamino, di C １ ~C ８ alkylamino, C ６ ~C １８ aryl, -CH ２ -PL and -CH ２ -L ２ selected from the group consisting of The linker compound according to claim 1.

4. W is H, C １ ~C １２ a saturated or unsaturated hydrocarbyl, halogen, halo-C １ ~C ８ alkyl, CN, NO ２ , OH, C １ ~C ８ alkoxy, hydroxy-C １ ~C ８ alkyl, C １ ~C ８ alkoxy-C １ ~C ８ alkyl, SH, C １ ~C ８ alkylthio, mercapto-C １ ~C ８ amino, mono C １ ~C ８ alkylamino, di C １ ~C ８ alkylamino, amino-C １ ~C ８ alkyl, C １ ~C ８ monoalkylamino-C １ ~C ８ alkyl, C １ ~C ８ dialkylamino-C １ ~C ８ alkyl, carboxy, C １ ~C ８ alkoxycarbonyl, C １ ~C ８ alkoxycarbonyloxy, carboxy-C １ ~C ８ alkyl, C １ ~C ８ alkoxycarbonyl-C １ ~C ８ alkyl, carbamoyl, mono C １ ~C ８ alkylcarbamoyl, di C １ ~C ８ alkylcarbamoyl, carbamoyl-C １ ~C ８ alkyl, mono C １ ~C ８ alkylcarbamoyl-C １ ~C ８ Alkyl and diC １ -C ８ Alkylcarbamoyl-C １ -C ８ Selected from the group consisting of alkyl, The linker compound according to claim 1.

5. -(Y) ｙ -T is [Chemical Formula 5] ; -O-SO ３ － ; -NO ２ ; -OC(O)(CH ２ ) ｒ COR ｔ１ ; -O(CH ２ )-Ar １ -NO ２ ; -S-C(O)(CH ２ ) ｓ COR ｔ２ ; -S(CH ２ )-Ar ２ -NO ２ and -BR ｔ３ R ｔ４ [Wherein, 【Chemical Formula 6】 is in a form in which the -OH group is protected by a protecting group or substituted by a substituent; R ｔ１ and R ｔ２ are each C １ to C ８ alkyl, Ar １ and Ar ２ are each C ５ to C ２０ arylene or heteroarylene; R ｔ３ and R ｔ４ are each independently hydrogen, C １ to C ８ alkoxy or hydroxy; R ｔ５ is OH, mono-C １ -C ８ alkylamino, di-C １ -C ８ alkylamino or -NH(CH ２ CH ２ O) ｆ R ｔ６ (wherein R ｔ６ is H or C １ -C ４ alkyl); f is an integer from 1 to 10, and r and s are each an integer from 1 to 5) is selected from the group consisting of moieties represented by] The linker compound according to claim 1.

6. -(X) ｘ -L ３ - is 【Chemical Formula 7】 and R ８ and R ９ each independently is H, halogen, C １ ~C ８ alkyl, CN and NO ２ selected from the group consisting of, and o is an integer from 0 to 2 The linker compound according to claim 1.

7. PL is an active agent selected from a drug, a toxin, a fluorophore, an affinity ligand, a diagnostic substance or a detection probe, The linker compound according to claim 1.

8. Said drug is selected from cytokines, immunomodulatory compounds, anti-cancer agents, anti-viral agents, antibacterial agents, anti-fungal agents, anthelmintics or combinations thereof, The linker compound according to claim 7.

9. PL is 【Chemical Formula 8】 selected from the group consisting of] The linker compound according to claim 1.

10. L ２ is —OC(=O)—, —S(=O) ２ —, 【Chemical Formula 9】 selected from the group consisting of] R １０ ~R １２ are each independently H, C １ ~C ８ alkyl, amino-C １ ~C ８ alkyl, mono- or di(C １ ~C ８ alkyl)amino-substituted C １ ~C ８ alkyl, or -(CH ２ CH ２ O) ｇ R １３ wherein R １３ is H or C １ ~C ４ is alkyl, and g is an integer of 1 to 10 The linker compound according to claim 1.

11. Said linking functional group is a functional group capable of binding to a ligand or protein having receptor binding properties, or a linker precursor, by a click chemical reaction, The linker compound according to claim 1.

12. The binding functional group is halogen, OH, C １ -C ８ alkoxy, hydroxylamino, COH, C １ -C ８ alkylcarbonyl, carboxy, C １ -C ８ alkoxycarbonyl, tosyl, tosylate, amino, mono C １ -C ８ alkylamino, di C １ -C ８ alkylamino, NHNH ２ , N ３ , haloacetamido, maleimidyl, succinimidyl, SH, SO ３ H, C １ -C ８ alkylsulfonyl, 【Chemical Formula 10】 , C １ ~C ８ alkoxysulfonyl, 2 - pyridyldisulfide, PO ３ H ２ , OPO ３ H ２ , -N≡C, -NCS, C ４ ~C １０ dienyl, C ２ ~C ８ alkenyl, C ２ ~C ８ alkynyl, C ４ ~C １０ cycloalkynyl and C ２ ~C ８ and contains a functional group selected from the group consisting of alkynylcarbonyl, R ｆ is H or C １ ~C ８ alkyl, The linker compound according to claim 1.

13. A-L １ is formed by a bond between a precursor of A and a precursor of L １ wherein the precursor of A contains at least one functional group selected from the group consisting of hydroxy, amino, azido, alkynyl, conjugated dienyl, alkenyl, cyclooctynyl, maleimidyl, SO ２ N ３ , alkoxysulfinyl, oxiranyl, aziridinyl, oxo, hydrazinyl, hydroxyamino, mercapto and 1,3-dicarbonyl, and the precursor of L １ contains a functional group that chemically reacts with the precursor of A to form an A-L １ bond. The linker compound according to claim 1.

14. L １ is C optionally containing a divalent or polyvalent functional group selected from the group consisting of amide, sulfonamide, amino, ether, carbonyl, triazole, tetrazole, sugar derivative group, sulfonate ester and dendrimer in the middle of the chain １ ~C ２００ alkylene The linker compound according to claim 1.

15. L １ is -(CH ２ ) ｎａ -; -(CH ２ CH ２ O) ｍａ -; -(CH ２ OCH ２ ) ｍｂ -; -(OCH ２ CH ２ ) ｍｃ -; -C(=O)-; 【Chemical 11】 including any one selected from the group consisting of or combinations thereof, R ｄ is H or C １ ~C ８ is alkyl, na and ma to mc are each independently integers from 0 to 10, The linker compound according to claim 1.

16. A-L １ - is R ａ１ C≡C-(CH ２ ) ｎ１ -; N ３ -(CH ２ ) ｎ２ -; 【Chemical Formula 12】 selected from the group consisting of] R ａ１ 、 R ｂ１ 、 R ｆ１ 、 R ｆ２ 、 R ｈ１ 、 R ｈ２ 、 R ｉ１ and R ｄ１ ~R ｄ１０ are each independently H or C １ ~C ８ alkyl, R ｃ１ 、R ｅ１ 、R ｇ１ 、R ｈ１ and R ｈ２ are each independently H, C １ ~C ８ alkyl, C １ ~C ８ alkylcarbonyl, C １ ~C ８ alkoxycarbonyl, or C ６～ C １２ aryl-C １ ~C ４ alkoxycarbonyl, and n1 to n18 and m1 to m14 are each independently integers from 0 to 10, The linker compound according to claim 1.

17. The compound represented by Formula 1 is selected from the group consisting of compounds represented by the following formula: 【Chemical Formula 13】 (wherein, A, L １ , k, R ３ and PL are as defined in claim 1, and V” represents an electron-withdrawing group) The linker compound according to Claim 1.

18. Formula A is the following Formula A-1: The linker compound according to Claim 1. 【Chemical 14】 (wherein the definitions of Z １ , Z ２ , Z ３ , V, Y, T, W, PL, h, y and p are as defined in claim 1)

19. The compound represented by Formula 1 is the following Formula 1-1: (wherein A has the same meaning as A defined in Claim 1, 【Chemical Formula 15】 j is from 1 to 10; q1, q2 and q3 are each independently an integer from 0 to 10, and q4 is an integer from 1 to 10; U １ and U ２ each have the same meaning as U defined in claim 1, and U １ and U ２ may be the same as or different from each other; provided that when it is, q3 is not 0) L １１ and L １２ each has the same meaning as L defined in claim 1 １ and L １１ and L １２ may be the same as or different from each other; L １ａ and L １ｂ are each independently, directly bonded; 【Chemical 16】 selected from, R ｅ is H or C １ ~C ８ is alkyl; The linker compound according to Claim 1. However, L １ａ is 【Chemical 17】 If it is the case, q2 is not 0, but L １ｂ is 【Chemical Formula 18】

20. In the above Formula 1-1 has the following structure: (wherein the definitions of q2 and q3 are as defined in Claim 19) The linker compound according to Claim 19. 【Chemical 19】

21. 【Chemical 20】 Selected from; n1, n2, n3, n4, n8, n14 and n15, and m1, m2, m8 and m10 are each independently an integer from 1 to 8, The linker compound according to Claim 19.

22. L １１ and L １２ are each independently, -(CH ２ ). ｎ１ -; -(CH ２ CH ２ O). ｍ１ -(CH ２ ). ｎ２ -; -(CH ２ CH ２ O). ｍ２ -(CH ２ ). ｎ３ -NR ｄ１ CO-(CH ２ ). ｎ４ -; -(CH ２ CH ２ O). ｍ１０ -(CH ２ ). ｎ１５ -CONR ｄ５ -(CH ２ ). ｎ１４ -; and 【Chemical 21】 The compound represented by Formula 1-1 is the following formula: R ｄ１ and R ｄ５ are each independently H or C １ ~C ８ alkyl, n1, n3, n4, n8, n14 and n15, m2, m8 and m10 are each independently an integer from 1 to 8) The linker compound according to Claim 19.

23. The following Formula B: 【Chemical 22】 (wherein, q1 to q4, U １ and U ２ are as defined in claim 19, R ｄ１ , R ｄ５ and R ｅ each independently represents H or C １ ~C ８ alkyl, (wherein X and Y are each independently selected from -O-, -NH-, and S; i, l, x and y are each independently 0 or 1, and p is an integer from 0 to 2) The linker compound represented by, or a pharmaceutically acceptable salt thereof.

24. 【Chemical 23】 Selected from the group consisting of compounds represented by the following formula: V’ is -CH ２ -(L ２ ) ｌ -PL; L ２ is a self - detaching linker selected such that cleavage of the bond between - CH ２ - of V' and L ２ promotes cleavage of the bond between L ２ and PL; PL is an activator linked to L via a heteroatom selected from N, O, and S, ２ or to the -CH ２ - of V'; Z ａ and Z ｂ One of them is selected from the group consisting of N, NR ３ , O, S and Se, and the other of Z ａ and Z ｂ is CH or N; R ３ is H or C １ -C ８ hydrocarbyl; T, when cleaved, is an inducing group that enables the release of PL and, if present, L through a 1,6-elimination reaction; ２ and; L ３ is, when present, an optional self-destructive spacer group that is sequentially cleaved when T is cleaved; The linker compound according to Claim 23.

25. The following Formula 2: (wherein E is a ligand or protein having receptor binding properties; 【Chemical 24】 A' is a divalent linking group derived from the binding functional group of A; n is a real number from 1 to 10; The ligand-drug conjugate represented by, or a pharmaceutically acceptable salt thereof.

27. 【Chemical 25】 ​ ​ ​ ​ A, U, L １ , the definitions of k and j are as defined in claim 1) ​ ​ ​ wherein the protein is selected from the group consisting of C １ to C ２０ hydrocarbyl, oligopeptide, polypeptide, a fragment of an antigenic polypeptide, and an artificial antibody (repebody). ​ ​ The antibody is selected from the group consisting of an intact polyclonal antibody, an intact monoclonal antibody, an antibody fragment, a single-chain Fv (scFv) variant, a multispecific antibody, a bispecific antibody, a chimeric antibody, a humanized antibody, a human antibody, a fusion protein containing an antigenic determinant of an antibody, and a modified immunoglobulin molecule containing an antigen recognition site. The ligand-drug conjugate according to claim 26. **Claim 28** The antibody is selected from the group consisting of muromonab-CD3, abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab (Herceptin), etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab-I131, cetuximab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab pegol, romiplostim, AMG-531 (romiplostim), CNTO-148 (golimumab), CNTO-1275 (ustekinumab), ABT874 (briakinumab), LEA-29Y (belatacept), belimumab, TACI-Ig (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), second-generation anti-CD20, ACZ-885 (canakinumab), tocilizumab, atorizumab, mepolizumab, pertuzumab, Humax CD20 (ofatumumab), tremelimumab (CP-675 206), tisilimumab, MDX-010 (ipilimumab), IDEC-114 (galiximab), inotuzumab, Humax EGFR (zalutumumab), aflibercept (VEGF trap-eye), Humax-CD4 (zanilimumab), Ala-Ala (hOKT3 gamma1), otelixizumab (ChAglyCD3; TRX4), catumaxomab, MT-201 (adecatumumab), pregobumab, CH-14.18 (dinutuximab), WXG250 (dilenuximab), AMG-162 (denosumab), AAB-001 (bapineuzumab), motavizumab, MEDI524 (motavizumab), efamulumab, Aurglob (registered trademark), laksibacumab, third-generation anti-CD20, LY2469298 (ocaratuzumab), and bertuzumab. The ligand-drug conjugate according to claim 26.

29. E is an antibody, and the E-A' binding structure of Formula 2 is 【Chemical 26】 (wherein ＊ is the remaining part of the antibody) containing The ligand-drug conjugate according to claim 25.

30. The conjugate represented by Formula 2 is the following conjugate: 【Chemical 27】 (wherein mAb represents the antibody moiety; V” is an electron-withdrawing group; m8 and n8 are each independently an integer from 1 to 10; Z １ is a heteroatom selected from NR ３ , O, S and Se, and R ３ is H or C １ to C ８ hydrocarbyl; PL is the active agent moiety; n is a real number from 1 to 10) selected from The ligand-drug conjugate according to claim 25.

31. The ligand-drug conjugate represented by Formula 2 is the following formula: 【Chemical 28】 [Chemical] (wherein mAb is the antibody moiety and n is a real number from 1 to 10) selected from the group consisting of conjugates represented by The ligand-drug conjugate according to claim 30.

32. The compound represented by Formula 2 is the following Formula 2-1: 【Chemical 29】 (wherein E is a ligand or protein having receptor-binding properties; A’ is a divalent linking group derived from the binding functional group of A defined in claim 1; U １ and U ２ each have the same meaning as U defined in claim 1, and U １ and U ２ may be the same as or different from each other; j is from 1 to 10; L １１ and L １２ each have the same meaning as L defined in claim 1 １ and L １１ and L １２ may be the same as or different from each other; L １ａ and L １ｂ are each independently 【Chemical 30】 selected from, and R ｅ is H or C １ ~C ８ is alkyl; q1, q2 and q3 are each independently an integer from 0 to 10, and q4 is an integer from 1 to 10; However, L １ａ is 【Chemical 31】 If it is the case, q2 is not 0, but L １ｂ is 【Chemical 32】 wherein q3 is not 0 when n is a real number from 1 to 10) is a compound represented by The ligand-drug conjugate according to claim 25.

33. The conjugate represented by Formula 2-1 is the following formula: 【Chemical 33】 (wherein mAb is the antibody moiety; q1 to q4, U １ and U ２ is as defined in claim 32, R ｄ１ 、 R ｄ５ and R ｅ are each independently H or C １ ~C ８ alkyl, n1, n3, n4, n8, n14 and n15, m2, m8 and m10 are each independently an integer from 1 to 8) selected from the group consisting of conjugates represented by The ligand-drug conjugate according to claim 32.

34. The conjugate represented by Formula 2-1 is the following formula: 【Chemical 34】 【Chem.】 (wherein mAb is the antibody moiety and n is a real number from 1 to 10) selected from the group consisting of conjugates represented by The ligand-drug conjugate according to claim 32.

35. A pharmaceutical composition comprising the ligand-drug conjugate according to any one of claims 25 to 34 and a pharmaceutically acceptable carrier or additive.

36. For the treatment or prevention of a proliferative disease, an autoimmune disease or an infectious disease, The pharmaceutical composition according to claim 35.

37. An imaging composition comprising the ligand-drug conjugate according to any one of claims 25 to 34.

38. A composition for detection, comprising the ligand-drug conjugate according to any one of claims 25 to 34.

Images