Conjugates of cell-binding molecules and camptothecin analogs

Abstract

To provide conjugates of camptothecin analogs and cell-binding molecules.SOLUTION: Provided are conjugates of camptothecin analogs and cell-binding molecules represented by formula (I), or pharmaceutically acceptable salts, hydrates, or hydrated salts thereof; or polymorphic crystal forms of these compounds; or isotopes, optical isomers, racemates, diastereomers, or enantiomers thereof. In formula (I), T is a cell-binding agent / molecule, and L is a releasable linker.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a conjugate of a camptothecin analog for targeted therapy and a cell surface receptor binding molecule. The present invention also relates to the use of a composition comprising a conjugate of a camptothecin analog and a cell binding molecule for the targeted therapy of cancer, autoimmune diseases, and infectious diseases.

Background Art

[0002] Cancer targeted therapy strategies aim to minimize or overcome side effects by targeting tumors more precisely and avoiding healthy tissues. One such strategy is antibody-drug conjugates (ADCs), which combine the specificity of an antibody for a tumor with the high cytotoxicity of a problematic drug (payload) via a conditionally stable linker, thereby achieving a local concentration of the latter several times higher than that in healthy tissues. Intensive research on ADCs over the past 40 years and significant funding by pharmaceutical companies have led to the US FDA's approval of eight ADCs named "Mylotarg" (gemtuzumab ozogamicin), "Adcetris" (brentuximab vedotin), "Kadcyla" (ado-trastuzumab emtansine), "Besponsa" (inotuzumab ozogamicin), "Polivy" (polatuzumab vedotin-piiq), "Enhertu" (fam-trastuzumab deruxtecan-nxki), "Padcev" (enfortumab vedotin-ejfv), and "Trodelvy" (sacituzumab govitecan), and more than 100 ADC drugs are currently in clinical development (Non-Patent Document 1).

[0003] The payload-linker component in the mode of ADC conjugates affects the homogeneity, circulation stability​ and are known to critically contribute to the pharmacokinetic profile, tolerance, and overall therapeutic effect (Non-Patent Documents 2 to 5). Despite extensive research to improve these parameters for next-generation ADCs, most payloads used to date still remain narrowly selected from maytansine (i.e., DM1 and DM4), auristatin (i.e., MMAE and MMAF), calicheamicin, pyrrolo[2,1-c][1,4]benzodiazepine (P BD) dimer, camptothecin, duocarmycin, and tubulysin (Non-Patent Documents 6 and 7, Non-Patent Document 1; doi: 10.1016 / S0140-6736(19)31774 -X). Among these payloads, for camptothecin (CPT), its ADC compounds such as "Enhertu" (fam-trastuzumab deruxtecan-nxki, or D S-8201a) and sacituzumab govitecan (IMMU-132 or hRS7-SN

[0004] -38) have demonstrated significant clinical effects (PFS and OS) against solid tumors in many clinical trials, indicating that they are a promising option with a broader therapeutic index (TI) than other payloads in ADC construction (Non-Patent Documents 8 and 9). Camptothecin (CPT) was isolated in 1958 from the extract of Camptotheca acuminata, a tree native to China, and this plant has been widely used in traditional Chinese medicine for centuries. Camptothecin interacts with the DNA enzyme topoisomerase I and induces cell death by accumulating a reversible enzyme-camptothecin-DNA ternary complex. ​​​​​​​can be caused (Non-Patent Document 10). In the past 50 years, as shown below, many camptothecin analogs have been disclosed.

[0005]

Chemical Formula

[0006] Many of camptothecin (CPT) and its analogs are extremely insoluble in physiological buffers and high side effects have been confirmed in preclinical trials since the 1970s. In camptothecin ADC, up to 80% aggregates (Non-Patent Document 12), so systemic side effects due to aggregation may limit the success of scale-up production and the achievement of clinical trials. So far in the United States FDA has only approved three water-soluble CPT analogs used in cancer chemotherapy, topotecan, iri notecan, and belotecan (Non-Patent Documents 13 and 14), and one water-soluble CPT analog ADC for targeted immunotherapy for Her2 solid tumors, "Enhertu" ( fam-trastuzumab deruxtecan-nxki, or DS-8201a) (Non-Patent Documents 15 and 16).

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Non-Patent Documents

[0008] [Non-Patent Document 1] Lancet., 2019, 394, 793 - 804 [Non-Patent Document 2] Med. Chem. 54(2011), 3606 [Non-Patent Document 3] mAbs, 4(2012), 362 [Non-Patent Document 4] Bioconjug Chem, 17(2006), 114 [Non-Patent Document 5] Bioconjug Chem. 16(2005), 346 [Non-Patent Document 6] Antibodies (Basel). 2020, 9: E2. doi: 10.3390 / antib9010002 [Non-Patent Document 7] Mol Cancer Res. 2020, 18: 3 - 19. doi: 10.1158 / 1541 - 7786.MCR - 19 - 0582 [Non-Patent Document 8] Curr Treat Options Oncol. 2019 Apr 1;20(5)):37. doi:10.1007 / s11864 - 019 - 0633 - 6; [Non-Patent Document 9] MAbs. 2020, 12(1):1703531,10.1080 / 19420862.2019.1703531 [Non-Patent Document 10] Tetrahedron 59 (2003) 8649 - 8687 [Non-Patent Document 11] ACS Med Chem Lett. 2019, 10(10): 1386 - 1392 [Non-Patent Document 12] Bioconjugate Chem. 2009, 20, 6, 1242 - 1250 [Non-Patent Document 13] Expert Opin Drug Deliv. 2015;12(12):1911 - 21

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Summary of the Invention

Problems to be Solved by the Invention

[0009] We have been working on water-soluble CPT analog ADCs for a long time, applying hydrophilic side chain linkers to CPT analog ADCs (see PCT / CN2019 / 092614), and expanding the treatment window of the ADC.

Means for Solving the Problems

[0010] Here, the present application discloses a water-soluble CPT analog ADC in which the C-10 position of the CPT analog linked to O or NH is important for water solubility and an electron withdrawing group or bulking group is linked to the C-11 position in order to maintain very strong cytotoxicity as compared with natural CPT. C.

[0011] The present invention provides a camptothecin analog conjugated with a cell-binding molecule, a camptothecin analog-linker compound, and a camptothecin analog compound, methods for preparing them and methods for using them, and intermediates useful for their preparation. The camptothecin analog conjugate of the present invention is water-soluble, stable in blood circulation, and a free camptothecin analog compound or ​The metabolite of a camptothecin analog-conjugate compound can cause cell death by being released from the conjugate in the vicinity of or inside abnormal cells.

[0012] In one exemplary embodiment of the present invention, a conjugate of a camptothecin analog represented by the following formula (I), or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof; or a polymorphic crystal structure of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers are provided: [Chemical formula]

[0013] In the formula, T is a cell-binding agent / molecule; L is a releasable linker; [Chemical formula] are independently linkages connecting to the atoms of L and R in the brackets 1 , R 2 , R 3 , or R 5 ; n is 1 to 30, and m is 1 to 10; The inside of the brackets is an effective camptothecin analog, and in the formula, R 1 and R 2 are independently H; linear or branched C1-C6 alkyl, alkyl alcohol , alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), aminoalkyl, oxyalkyl, aminoalkylamino, oxyalkylamino, a minoalkyloxy, oxyalkyloxy, alkylcarboxylic acid, or carbonyl group; C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, aminosi​​​ chloroalkyl, heteroalkylcycloalkyl, alkylcarbonyl, aminoalkylcar bonyl, oxyalkylcarbonyl, alkyl ether, alkyl ester, alkyl amide, oxyalkylamide, aminoalkylamide, oxime; or having NH2 or OH ; R 3 is, independently, H, C(O)NH, C(O)O, SO2R 6 , SO3R 6 , PR 6 R 6’ , POR 6 R 6’ , CH2OP(O)(OR 6 ), C(O)OP(O)(OR 6 ), PO(OR 6 )(OR 6’ ), P(O)(OR 6 )OP(O)(OR 6’ ), C (O)R 6 , C(O)NHR 6 ; straight-chain or branched C1-C6 alkyl, alkyl alcohol , alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), or alkyl carboxylic acid; C2-C6 heteroalkyl, alkylcycloalkyl, hetero cycloalkyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl , alkyl ether, alkyl ester, alkylamide, oxime; C5-C 12 gly coside, NH2, or OH; R 4 is halo (F, Cl, Br, or I), CN, NO2, SO3H, OR 6 , SR 6 , S(O2)R 6 , NHR 6 , N(R 6 )(R 6’ ), C(O)XR6 、N + (R 6 )( R 6’ )(R 6’’ ) is; X is NH or O; R 5 is H, C(O)O, C(O)NH, R 6 C(O), linear or branched C1-C6 alkyl yl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), alkyl carboxylic acid; C2-C6 carbonate, carbamide, he teroalkyl, alkyl cycloalkyl, heterocycloalkyl, heterocycloalkyl yl, heteroalkyl cycloalkyl, alkyl carbonyl, alkyl ether, alkyl e ster, alkyl amide, or amino acid; R 6 、R 6’ 、and R 6’’ are independently H, C1-C6 alkyl, alkyl alcohol yl, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium) 、or alkyl carboxylic acid; C2-C6 heteroalkyl, alkyl cycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkyl cycloalkyl, alkyl carb onyl, alkyl ether, alkyl ester, alkyl amide, or amino acid; or pharmaceutically acceptable salt; Furthermore, R 1 、R 2 、R 3 、and R 6 can independently not exist, and R 2 、R 3 、X 、C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle.

[0014] ​In another embodiment, the linker L of the effective camptothecin analog - binding molecule conjugate has the formula - Ww-(Aa)r-Vv-, wherein, wherein, -W- is an extension unit; w is 0 or 1; each -Aa- is independently an amino acid unit; r is independently an integer in the range of 0 to 12 ; -V- is a spacer unit; and v is 0, 1, or 2 . The extension unit W may independently contain a self - destructing spacer, a peptidyl unit, a hydrazone bond , a disulfide bond, or a thioether bond.

[0015] In another embodiment, the cell - surface binding molecule T may be any type of cell - binding ligand, known or to be known later, such as peptides and non - peptides. Generally, the cell - binding molecule T is an antibody, a single - chain antibody; an antibody fragment that binds to a target cell; a monoclonal antibody; a single - chain monoclonal antibody; a monoclonal antibody fragment that binds to a target cell; a chimeric antibody ; a chimeric antibody fragment that binds to a target cell; a domain antibody; a domain antibody fragment that binds to a target cell; an adnectin that mimics an antibody; DARPins; a lymphokine; a hormone; a vitamin; a growth factor; a colony - stimulating factor; a nutrient transport molecule (transferrin) ; and / or a small molecule, a cell - binding peptide, or a protein attached to albumin, a polymer, a dendrimer, a liposome, a nanoparticle, a vesicle, or a (viral) capsid. Preferably, the binding molecule T is a monoclonal antibody. In yet another aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof

[0016] is used for the treatment of cancer, autoimmune diseases, or infectious diseases in humans or animals.

Brief Description of the Drawings

[0017]

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Modes for Carrying Out the Invention

[0018] Definition of Terms

[0019] "Alkyl" refers to an aliphatic hydrocarbon group or a monovalent group derived from an alkane by removing one or two hydrogen atoms from a carbon atom. It may be linear or branched and have C1-C8 (1-8 carbon atoms) in the chain. "Branched" refers to a linear alkyl group to which one or a plurality of lower-carbon alkyls, such as methyl, ethyl, or propyl groups, are attached. Specific examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl "Branched" refers to a linear alkyl group to which one or a plurality of lower-carbon alkyls, such as methyl, ethyl, or propyl groups, are attached. For example, methyl, ethyl, or propyl groups are attached. Specific examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl , n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl, cyclopentyl, cyclohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2 ,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl, 2, 4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4 -dimethylpentyl, 2-methylheptyl, 3-methylheptyl, n-heptyl, isohe ptyl, n-octyl, and isooctyl are included. The C1-C8 alkyl groups may be unsubstituted or may be substituted with one or more substituents (but not limited to the following substituents). Examples of the substituents include -C1-C8 alkyl, -O-(C1-C8 alkyl), aryl , -C(O)R’, -OC(O)R’, -C(O)OR’, -C(O)NH2, -C(O )NHR’, -C(O)N(R’)2, -NHC(O)R’, -SR’, -S(O)2R’ , -S(O)R’, -OH, -halogen, -N3, -NH2, -NH(R’), -N(R ’)2, and -CN, where R’ is independently selected from C1-C8 alkyl and aryl yl.

[0020] "Halogen" refers to a fluorine, chlorine, bromine, or iodine atom, with fluorine and chlorine atoms being preferred.

[0021] "Heteroalkyl" refers to C2-C8 alkyl in which 1 to 4 carbon atoms are independently replaced by a heteroatom selected from the group consisting of O, S, and N.

[0022] "Carbocycle" is a monocyclic system having 3 to 8 carbon atoms or a Refers to a saturated or unsaturated ring of a bicyclic system. Monocyclic carbocycles have 3 to 6, more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms and are arranged as bicyclic [4,5], 5,5], [5,6], or [6,6], or have 9 to 10 ring atoms and are arranged as bicyclic [5,6] or [6,6]. Representative C3 - C8 carbon cycles (C3 - C8 carbocycles) include, but are not limited to, - cyclopropyl, - cyclobutyl , - cyclopentyl, - cyclopentadienyl, - cyclohexyl, - cyclohexenyl , - 1,3 - cyclohexadienyl, - 1,4 - cyclohexadienyl, - cycloheptyl , - 1,3 - cycloheptadienyl, - 1,3,5 - cycloheptatrieneyl, - cyclo octyl, and - cyclooctadienyl.

[0023] A C3 - C8 carbocycle refers to a saturated or unsaturated non - aromatic hydrocarbon carbocyclic compound having 3, 4, 5, 6, 7, or 8 carbon atoms. A C3 - C8 carbocycle may be unsubstituted or substituted with one or more substituents. The substituents include, but are not limited to, - C1 - C8 alkyl, - O-(C 1 - C8 alkyl), - aryl, - C(O)R’, - OC(O)R’, - C(O)OR ’, - C(O)NH2, - C(O)NHR’, - C(O)N(R’)2, - NHC(O)R ’, - SR’, - S(O)R’, - S(O)2R’, - OH, - halogen, - N3, - N H2, - NH(R’), - N(R’)2, and - CN, where each R’ is independently selected from C1 - C8 alkyl and aryl.

[0024] ​"Alkenyl" refers to an aliphatic hydrocarbon group having a carbon-carbon double bond, which may be linear or branched and have 2 to 8 carbon atoms in the chain. Examples of alkenyl groups include, for example, ethenyl , propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pent tenyl, hexylenyl, heptenyl, octenyl.

[0025] "Alkynyl" refers to an aliphatic hydrocarbon group having a carbon-carbon triple bond, which may be linear or branched and have 2 to 8 carbon atoms in the chain. Examples of alkynyl groups include, for example, ethynyl , propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, 5-pentyn yl, n-pentynyl, hexynyl, heptynyl, octynyl.

[0026] "Alkylene" refers to a saturated, linear or branched or cyclic hydrocarbon group having 1 to 18 carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include methylene ( -CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH 2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), etc., but are not limited to these. -CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH 2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), etc., but are not limited to these. These are not limited thereto.

[0027] "Alkenylene" refers to an unsaturated, linear or branched or cyclic hydrocarbon group having 2 to 18 carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene. Typical alkenylene groups include 1, 2-ethylene (-CH=CH-), but are not limited to these. 2-ethylene (-CH=CH-), but are not limited to these. These are not limited thereto.

[0028] "Alkynylene" refers to an unsaturated, straight-chain, branched-chain, or cyclic hydrocarbon group having 2 to 18 carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Typical alkynylene groups include, but are not limited to, acetylene, propargyl, and 4-pentynyl.

[0029] "Aryl" or Ar refers to an aromatic or heteroaromatic group consisting of one or several rings containing 3 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The term "heteroaromatic group" refers to a group in which one or several carbon atoms, preferably 1, 2, 3, or 4 carbon atoms, on the aromatic group are replaced by O, N, Si, Se, P, or S, preferably O, S, and N. The term aryl or Ar also refers to a group in which one or several H atoms are independently replaced by -R', -halogen, -OR', or -SR', -NR'R'', -N=NR', -N=R', -NR'R' ', -NO2, -S(O)R', -S(O)2R', -S(O)2OR', -OS(O) 2OR', -PR'R'', -P(O)R'R'', -P(OR')(OR''), -P (O)(OR')(OR''), or -OP(O)(OR')(OR''), where said R', R'' are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, arylalkyl, carbonyl, or a pharmaceutical salt.

[0030] "Heterocycle" refers to a ring system in which 1 to 4 ring carbon atoms are independently replaced by heteroatoms from the group of O, N, S, Se, B, Si, and P. Preferably ​​​​​​​The heteroatoms are O, N, and S. The heterocyclic rings are described in The Handbook of Chemistry and Ph ysics, 78th Edition, CRC Press, Inc., 1997 - 1998, pp225 - 226, the disclosure of which is incorporated herein by reference. Preferred non - aromatic heterocyclic rings include, but are not limited to, epoxy, aziridinyl, thianyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxiranyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, pyranyl, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrimidinyl, dihydrothiopyranyl, azepanyl, and fused systems resulting from condensation with a phenyl group.

[0031] The term "heteroaryl" or aromatic heterocyclic ring refers to an aromatic hetero, monocyclic, bicyclic, or polycyclic ring having 3 to 14 members, preferably 5 to 10 members. Examples thereof include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4 - thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoquinolinyl, benzothienyl, isobenzofuranyl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl - N - oxide, and fused systems resulting from condensation with a phenyl group.

[0032] ​​​​​​​"Alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl" ", "heteroaryl", "heterocyclic group", etc. also refer to the corresponding "alkylene", "cycloalkylene" formed by removing two hydrogen atoms, "alkenylene", "alkynylene", "arylene", "heteroarylene", " heterocyclic group" (heterocyclene), etc.

[0033] "Arylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 carbon atom, is bonded to a hydrogen atom and is substituted with an aryl group. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl , 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2 -naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, etc.

[0034] "Heteroarylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 carbon atom, is bonded to a hydrogen atom and is substituted with a heteroaryl group. Typical heteroaryl alkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, etc.

[0035] Examples of "hydroxy protecting groups" include, but are not limited to, methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, benzyl ether , p-methoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether ​​​​Tertiary, triisopropylsilyl ether, t-butyldimethylsilyl ether, triphenyl methylsilyl ether, acetate, substituted acetate, pivalate, benzoate, methanesulfonate, and p-toluenesulfonate are included.

[0036] "Leaving group" refers to a functional group that can be replaced by another functional group. Such leaving groups are well known in the art and include, for example, but are not limited to, halides (e.g., chloride, bromide, and iodide), methanesulfonyl (mesyl), p -toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate. Preferred leaving groups include nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluoro rophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, acid anhydrides formed with itself or other acid anhydrides (e.g., acetic anhydride, formic anhydride); or intermediates generated by condensation reagents for peptide coupling reactions or for Mitsunobu reactions. Selected from the group consisting of: or generated by condensation reagents for peptide coupling reactions or for Mitsunobu reactions. Selected from the intermediates formed thereby.

[0037] The following abbreviations can be used in this specification and have the definitions shown below: Boc, tert-butoxycarbonyl; BroP, bromotrispirolidinophosphonium hexa Fluorophosphate; CDI, 1,1'-carbonyldiimidazole; DCC, dicyclohexylcarbodiimide; DCE, 1,2-dichloroethane; DCM, dichloromethane ; DCC, dicyclohexylcarbodiimide; DCE, 1,2-dichloroethane; DCM, dichloromethane ; DEAD, diethyl azodicarboxylate; DIAD, diisopropyl azodicarboxylate; DIBAL-H, diisobutylaluminum hydride; DIPEA or DEA, diisopropylethylamine; ; DEPC, diethyl phosphorocyanidate; DMA, N,N-dimethylacetamide; DMAP, 4-(N,N-dimethylamino)pyridine; DMF, N,N-dimethylformamide; ; DMAP, 4-(N,N-dimethylamino)pyridine; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DTPA, diethylenetriaminepentaacetic acid; DTT, dithiothreitol; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass spectrometry; ; DMSO, dimethyl sulfoxide; DTPA, diethylenetriaminepentaacetic acid; DTT, dithiothreitol; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass spectrometry; EtOAc, ethyl acetate; Fmoc, N-(9-fluorenylmethoxycarbonyl); HATU, O-(7-azabenzotriazol-1-yl)-N,N,N'-N'-tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; ; DTT, dithiothreitol; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass spectrometry; EtOAc, ethyl acetate; Fmoc, N-(9-fluorenylmethoxycarbonyl); HATU, O-(7-azabenzotriazol-1-yl)-N,N,N'-N'-tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass spectrometry; EtOAc, ethyl acetate; Fmoc, N-(9-fluorenylmethoxycarbonyl); HATU, O-(7-azabenzotriazol-1-yl)-N,N,N'-N'-tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; EtOAc, ethyl acetate; Fmoc, N-(9-fluorenylmethoxycarbonyl); HATU, O-(7-azabenzotriazol-1-yl)-N,N,N'-N'-tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N'-N'-tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; HPLC, high pressure liquid chromatography; NHS, N-hydroxysuccinimide; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; MeCN, acetonitrile; MeOH, methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 - 7.5); Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; Ph, phenyl; phe, L-phenylalanine; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; PyBrop, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T ; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; T LC, thin layer chromatography; UV, ultraviolet light.

[0038] "Amino acid(s)" can be natural and / or non-natural amino acids, preferably α-amino acids Natural amino acids are those encoded by the genetic code and include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine. Non-natural amino acids are derivatives of protein-forming amino acids, such as hydroxyproline, lanthionine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid (a neurotransmitter ), ornithine, citrulline, β-alanine (3-aminopropanoic acid), γ-carboxyglutamate, selenocysteine (present in most eukaryotes but not directly encoded by DNA), pyrroline (found only in some archaea and one bacterium), N-formylmethionine (often the first amino acid of bacterial, mitochondrial, and chloroplast proteins), 5-hydroxytryptophan, L-dihydroxyphenylalanine, triiodothyronine, L-3,4-dihydroxyphenylalanine (DOPA), and O-phosphoserine. The term amino acid also includes amino acid analogs and mimetics. Analogs are compounds having the same general H2N(R)CHCO2H structure as natural amino acids, except that the R group is not found among natural amino acids. Examples of analogs include homoserine, norleucine, methionine-sulfoxide, and methionine methyl ester. It contains sulfonium. Preferably, the amino acid mimetic is a compound that has a structure different from the general chemical structure of α - amino acids but functions in a similar manner. The term "unnatural ami no acid" is intended to represent the "D" stereochemical form, while natural amino acids are in the "L" form . When 1 to 8 amino acids are used in the present application, the amino acid sequence is preferably a cleavage recognition sequence of protease . Many cleavage recognition sequences are known in the art, for example, Matayoshi et al. Science 247: 954 (1990); Dunn et al. Meth. Enzymo l. 241: 254 (1994); Seidah et al. Meth. Enzymol. 244: 175 (1994); Thornberry, Me th. Enzymol. 244: 615 (1994); Weber et al. Meth. Enzymol. 244: 595 (1994); Smith et al. Meth. Enzymol. 244: 412 (1994); and Bouvier et al. Meth. Enzymol. 248: 6 14 (1995); the disclosures of which are incorporated herein by reference. In particular, the sequences are Val -Cit, Ala-Val, Ala-Ala, Val-Val, Val-Ala-Val , Lys-Lys, Ala-Asn-Val, Val-Leu-Lys, Cit-Cit , Val-Lys, Ala-Ala-Asn, Lys, Cit, Ser, and Glu selected from the group consisting of .

[0039] A "glycoside" is a molecule in which a sugar group is linked to another group through its anomeric carbon by a glycosidic bond. Glycosides are O-(O-glycosides), N-(gly (ricocylamine), S-(thioglycoside), or C-(C-glycoside) can be linked by a glycosidic bond. The core empirical formula is C (H2O) m (where m n is different from n, and m and n are <36), where the glycoside includes glucose ( dextrose), fructose (levulose) allose, altrose, mannose, gulose, idose, galactose, talose, galactosamine, glucosamine, sia lic acid, N-acetylglucosamine, sulfoquinovose (6-deoxy-6-sulfo-D- glucopyranose), ribose, arabinose, xylose, lyxose, sorbitol , mannitol, sucrose, lactose, maltose, trehalose, maltodextrin , raffinose, glucuronic acid (glucuronide), and stachyose are included. It can be D-type or L-type, 5-atom cyclic furanose type, 6-atom cyclic pyranose type, or acyclic type, α-isomer (-OH of the anomeric carbon below the plane of the carbon atoms in the Haworth projection), or β-isomer (-OH of the anomeric carbon above the plane in the Haworth projection). It can be used herein as a monosaccharide, disaccharide, polyol, or oligosaccharide containing 3 to 6 sugar units. As used herein, the term "antibody" refers to a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule containing an antigen-binding site that immunospecifically binds to an important target antigen or a portion thereof, and such targets include, but are not limited to, cancer cells or cell populations that produce autoantibodies associated with autoimmune diseases.

[0040] ​​​​​​It is not limited thereto. The immunoglobulins disclosed herein include any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Immunoglobulins are derived from any species. However, preferably, immunoglobulins are of human, mouse, or rabbit origin. Antibodies useful in the present invention are preferably monoclonal and include polyclonal, monoclonal, bispecific, human, humanized or chimeric antibodies, single-chain antibodies, Fv, Fab fragments , F(ab’) fragments, F(ab’)2 fragments, fragments generated by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDRs, and any of the above epitope-binding fragments that immunospecifically bind to cancer cell

[0041] antigens, viral antigens, or microbial antigens, but are not limited thereto. As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies that make up the population are identical except for naturally occurring mutations that may be present in trace amounts. Monoclonal antibodies act specifically on a single antigenic site and have high specificity. The

[0042] term "intact antibody" refers to an antigen-binding variable region and a light chain constant domain (C L ) and a heavy chain constant domain (CH1 , C H2 , C H3 , and C H4 consisting of antibodies . The constant domain may be the constant domain of the native sequence (e.g., the constant domain of the human native sequence of the constant domain) or an amino acid sequence variant thereof.

[0043] "Antibody fragment" is a part of an intact antibody and consists of its antigen-binding region or variable part. Examples of antibody fragments include Fab, Fab', F(ab')2, and F v fragments, diabodies, triabodies, tetra-bodies, linear antibodies, single-chain antibody molecules, scF v, scFv-FC, multi-specific antibody fragments formed from antibody fragments (s), fragments produced by Fab expression libraries , or any of the above epitope-binding fragments that immunospecifically bind to a target antigen (e.g., a cancer cell antigen, a viral antigen, or a microbial antigen). are mentioned.

[0044] "Antigen" refers to an entity to which an antibody specifically binds.

[0045] "Specific binding" and "specifically binds" mean that an antibody or antibody derivative binds highly selectively to the corresponding epitope of the target antigen and does not bind to many other antigens . Typically, an antibody or antibody derivative binds with an affinity of at least about 1×10 M, preferably 1 -7 0 0 -8 M to 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M and binds to the predetermined antigen with an affinity at least twice as great as the binding affinity to non-specific antigens (e.g., BSA, casein) other than the predetermined antigen or related antigens.

[0046] The same except that the left and right hands are opposite along a single axis (simply changing the direction does not make the hands appear identical.) In the same way, "optical isomers", also known as "mirror image isomers", are one of two stereoisomers that are non-superimposable (not identical) mirror images of each other. Due to a single chiral atom or similar structural feature within a compound, the compound has two non-superimposable structures, each of which is a mirror image of the other. When a particular compound has multiple chiral elements, the number of possible geometric forms increases, but there may be cases where there are perfect mirror image pairs. A pure enantiomeric compound refers to a sample with only one chirality within the detection limit. When present in a symmetric environment, enantiomers have the same chemical and physical properties except for the ability to rotate plane-polarized light (+ / -) by equal amounts in opposite directions (however, the polarized light can be considered an asymmetric medium). For this reason, they are sometimes called optical isomers. A mixture of equal parts of an optically active isomer and its mirror image is called a racemate, and the net rotation of plane-polarized light is zero. This is because the positive rotation of each (+) form is exactly canceled out by the negative rotation of the (-) form. Members of enantiomers often undergo different chemical reactions from other enantiomeric substances. Since many biomolecules are mirror image isomers, there can be significant differences in the effects of the two mirror image isomers on organisms. For example, in drugs, often only one of the enantiomers of the drug is involved in the desired physiological effect, and the other enantiomer may have low activity, be inactive, or in some cases, cause harmful effects. Due to this discovery, consisting of only one enantiomer ("pure enantiomer") ​​​​​​​​​​​​​​Develop drugs to enhance pharmacological effects and sometimes eliminate some side effects .

[0047] Isotopes are variants of a particular chemical element with different numbers of neutrons. All isotopes of a particular element have the same number of protons in each atom. Each atomic number identifies a particular element, but isotopes are not identified. Atoms of a given element may have a wide range of neutron numbers. The number of nucleons (both protons and neutrons) in the nucleus is the mass number of the atom, and each isotope of a particular element has a different mass number. For example, carbon-12, carbon-13, and carbon-14 are three isotopes of carbon with mass numbers 12, 13, and 14, respectively. The atomic number of carbon is 6. This means that all carbon atoms have 6 protons, so the neutron numbers of these isotopes are 6, 7, and 8, respectively. Hydrogen atoms have three isotopes: protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H ), where deuterium has twice the mass of protium and tritium has three times the mass of protium. By using isotope substitution, the mechanism of a chemical reaction can be determined or via the kinetic isotope effect. Isotope substitution can be used to study the metabolic changes of substances in the body (e.g., by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), as well as how the body is affected by specific xenobiotics / chemical substances through the mechanisms of absorption and distribution after administration, and to investigate the excretion pathways and effects of drug metabolites. This research is called pharmacokinetics (PK). Isotope substitution can be used to study the biochemical and physiological effects of drugs. The effects include those on animals (including humans), microorganisms (e.g., by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), not only the metabolic changes of substances in the body, but also how the body is affected by specific xenobiotics / chemical substances through the mechanisms of absorption and distribution after administration, and to investigate the excretion pathways and effects of drug metabolites. This research is called pharmacokinetics (PK). Isotope substitution can be used to study the biochemical and physiological effects of drugs. The effects include those on animals (including humans), microorganisms / chemical substances, as well as the excretion pathways and effects of drug metabolites. This research is called pharmacokinetics (PK). Isotope substitution can be used to study the biochemical and physiological effects of drugs. The effects include those on animals (including humans), microorganisms (including humans), and can be used to study the biochemical and physiological effects of drugs. The effects include those on animals (including humans), microorganisms This includes what appears in substances or combinations of organisms (such as infections). This research is called pharmacodynamics (PD ). The effects include what appears in animals (including humans), microorganisms, or combinations of organisms (such as infections ). Together, both affect drug administration, benefits, and adverse effects. Isotopes include stable (non-radioactive) or unstable elements. Isotope substitution of a drug may have a different therapeutic effect from the original drug. Labeling the compounds of the present disclosure with isotopes may be useful for tissue distribution assays of drugs and / or substrates. Tritium (< H) and carbon-14 (< C) labeled compounds are particularly preferred in terms of ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (2H) may result in certain therapeutic advantages arising from higher metabolic stability, for example, an increase in in vivo half-life or a decrease in required dose, and may therefore be preferred in certain situations. 3 H) and carbon-14 (< 14 C) labeled compounds are particularly preferred in terms of ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (2H) may result in certain therapeutic advantages arising from higher metabolic stability, for example, an increase in in vivo half-life or a decrease in required dose, and may therefore be preferred in certain situations. for example, an increase in in vivo half-life or a decrease in required dose, and may therefore be preferred in certain situations. Thus, it may be preferred under certain circumstances. The currently disclosed isotope-labeled compounds (including their pharmaceutically acceptable salts, esters, and prodrugs ) can be prepared by any means known in the art. Advantage may also be obtained by substituting the usually abundantly present 12 C with 13 C.

[0048] "Pharmaceutically" or "pharmaceutically acceptable" means that the corresponding compound or compound composition is not harmful and does not cause allergic or other adverse reactions when administered to animals or humans in an appropriate manner. "Pharmaceutically acceptable solvate" or "solvate" refers to a compound disclosed with one or more solvent molecules that does not cause allergic or other adverse reactions when administered to animals or humans in an appropriate manner.

[0049] "Pharmaceutically acceptable solvate" or "solvate" refers to a compound disclosed with one or more solvent molecules refers to the association with the resulting compound. Examples of solvents that form pharmaceutically acceptable solvates include water , isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and et thanolamine, but are not limited thereto.

[0050] Pharmaceutically acceptable auxiliary materials include all carriers, diluents, auxiliaries or molding agents, for example , preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, co ating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, the method of adding these auxiliary materials to the active drug component is a common method. Except when the auxiliary materials are incompatible with the drug active component, it is reasonable to add the auxiliary materials to the drug component . It can be said that it is reasonable to add active auxiliary materials to the drug component in order to obtain good results .

[0051] In the present invention, "pharmaceutically acceptable salts" refers to salt derivatives of the compounds of the present invention. By appropriate modification, the compounds according to the present invention can be formed into corresponding acid salts or alkali salts. Pharmaceutically acceptable salts include common non-toxic salts or quaternary ammonium, and these salts can be prepared by corresponding non-toxic inorganic acids or organic acids of the compounds according to the present invention . For example, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and organic acids include acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ben zenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulf onic acid, oxalic acid, fumaric acid, and lactic acid, etc. These acids can be used for pharmaceutically acceptable salts . Other salts include trometamol, meglumine, pyrrolidinoethanol​ ammonium salts such as ruthenium, and sodium, potassium, calcium, zinc, magnesium, etc. It contains metal salts of.

[0052] In the present invention, pharmaceutical salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods. Generally, these salts can be prepared in water, an organic solvent, or a mixture of both in a reaction with an appropriate salt base or acid in stoichiometric amounts in the free acid or free base form of these compounds. As a non-aqueous reaction solvent, generally, ether , ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is given in "Remington’s Pharmaceutical Sc iences", 17th edition. Mack Publishing Company, Eas ton, PA, 1985, page 1418, and the disclosure is incorporated by reference ton, PA, 1985, page 1418, and the disclosure is incorporated by reference . .

[0053] "Therapeutically effective amount" means an amount of a conjugate effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of the conjugate reduces the number of cancer cells; reduces the size of the tumor ; inhibits the invasion of cancer cells into peripheral organs (i.e., slows down, preferably stops, to some extent) ; inhibits tumor metastasis (i.e., slows down, preferably stops, to some extent); inhibits tumor growth to some extent ; and / or alleviates one or more symptoms associated with cancer to some extent. To the extent that it can inhibit growth and / or kill existing cancer cells, the agent may be cytostatic and / or cytotoxic. In the case of cancer treatment, effectiveness can be determined, for example, by evaluating the time to disease progression (TTP) and / or determining the response rate (RR). It can be measured.

[0054] "Pharmaceutically acceptable form" refers to a pharma- ceutically acceptable salt, ester, hydrate, solvate, or the like. This includes, but is not limited to, compounds, polymorphs, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, "a pharma- ceutically acceptable form" refers to any form of the disclosed compounds that is not limited to the above. " includes pharma- ceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, "a pharma- ceutically acceptable form" refers to a pharmaceutical The term "isotopically acceptable" includes all isomers and stereoisomers, prodrugs and isotopically labeled derivatives thereof. , but is not limited to these.

[0055] The terms "substantial" or "substantially" mean the majority of a population, mixture, or sample. Number, i.e., 50% or more of the population, preferably 50%, 55%, 60%, 65%, 7 0%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 9 This refers to 6%, 97%, 98%, or 99% or more.

[0056] Combinations of substituents and variables envisioned by this invention are those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that is capable of being manufactured. have sufficient stability and are suitable for the purposes detailed herein (e.g., for therapeutic or prophylactic administration to a subject); By this is meant a compound that maintains its compound integrity for a sufficient period of time to be useful.

[0057] Following their preparation, the compounds of the invention preferably have a purity of equal to or greater than 95%. by weight ("substantially pure"), which is is used or formulated as described herein. In certain embodiments, the invention compound has a purity of 99% or greater.

[0058] The term "cytotoxic activity" means the cell-killing effect of an agent, a camptothecin conjugate, or an intracellular metabolite of a camptothecin conjugate. Cytotoxic activity can be expressed as the concentration (molar or mass) per unit volume at which half of the cells survive, the IC 50 value.

[0059] The term "cytostatic activity" means the antiproliferative effect of an agent or a conjugate of a camptothecin analog, or an intracellular metabolite of a camptothecin conjugate. It means.

[0060] The term "cytotoxic agent" means a substance that has cytotoxic activity and causes destruction of cells. This term includes chemotherapeutic agents and toxins such as low molecular weight toxins or enzymatically active toxins derived from bacteria, fungi, plants, or animals (including their synthetic analogs and derivatives).

[0061] "Administering" or "administration" refers to any mode of transferring, delivering, introducing, or conveying a pharmaceutical or other agent to a subject. Such modes include oral administration, topical contact, intravenous, intraperitoneal, intramuscular, lesional, nasal, cavity, subcutaneous, or cavity administration. Also contemplated by the present invention is the use of a device or instrument for administering an agent. Such a device can utilize

[0062] In the context of cancer, the term "treating" includes any or all of the following: suppression of the growth of tumor cells or cancer cells, prevention of the replication of tumor cells or cancer cells, reduction of the overall burden of the tumor, and improvement of one or more symptoms associated with the disease. In the context of cancer, the term "treating" includes any or all of the following: suppression of the growth of tumor cells or cancer cells, prevention of the replication of tumor cells or cancer cells, reduction of the overall burden of the tumor, and improvement of one or more symptoms associated with the disease. In the context of cancer, the term "treating" includes any or all of the following: suppression of the growth of tumor cells or cancer cells, prevention of the replication of tumor cells or cancer cells, reduction of the overall burden of the tumor, and improvement of one or more symptoms associated with the disease.

[0063] In the context of an autoimmune disease, the term "treating" includes any or all of the following: prevention of the replication of cells associated with the pathophysiology of the autoimmune disease, including but not limited to cells capable of producing autoantibodies, reduction of the burden of autoantibodies, and improvement of one or more symptoms of the autoimmune disease. In the context of an autoimmune disease, the term "treating" includes any or all of the following: prevention of the replication of cells associated with the pathophysiology of the autoimmune disease, including but not limited to cells capable of producing autoantibodies, reduction of the burden of autoantibodies, and improvement of one or more symptoms of the autoimmune disease. In the context of an autoimmune disease, the term "treating" includes any or all of the following: prevention of the replication of cells associated with the pathophysiology of the autoimmune disease, including but not limited to cells capable of producing autoantibodies, reduction of the burden of autoantibodies, and improvement of one or more symptoms of the autoimmune disease. In the context of an autoimmune disease, the term "treating" includes any or all of the following: prevention of the replication of cells associated with the pathophysiology of the autoimmune disease, including but not limited to cells capable of producing autoantibodies, reduction of the burden of autoantibodies, and improvement of one or more symptoms of the autoimmune disease.

[0064] In the context of an infectious disease, the term "treating" includes any or all of the prevention of the growth, proliferation, or replication of the pathogen causing the infectious disease and improvement of one or more symptoms of the infectious disease. In the context of an infectious disease, the term "treating" includes any or all of the prevention of the growth, proliferation, or replication of the pathogen causing the infectious disease and improvement of one or more symptoms of the infectious disease. In the context of an infectious disease, the term "treating" includes any or all of the prevention of the growth, proliferation, or replication of the pathogen causing the infectious disease and improvement of one or more symptoms of the infectious disease.

[0065] The terms "Cancer" and "Cancerous" typically refer to or describe a mammalian physiological state or disorder characterized by uncontrolled cell growth. A "tumor" consists of one or more cancerous cells. The terms "Cancer" and "Cancerous" typically refer to or describe a mammalian physiological state or disorder characterized by uncontrolled cell growth. A "tumor" consists of one or more cancerous cells. The terms "Cancer" and "Cancerous" typically refer to or describe a mammalian physiological state or disorder characterized by uncontrolled cell growth. A "tumor" consists of one or more cancerous cells.

[0066] An "autoimmune disease" refers to a disease or disorder that arises from and is directed against an individual's own tissues or proteins. An "autoimmune disease" refers to a disease or disorder that arises from and is directed against an individual's own tissues or proteins.

[0067] "Patient" means the subject to whom the camptothecin conjugate of the present invention is administered. Patients include, but are not limited to, humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, patients are rats, mice, "Patient" means the subject to whom the camptothecin conjugate of the present invention is administered. Patients include, but are not limited to, humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, patients are rats, mice, "Patient" means the subject to whom the camptothecin conjugate of the present invention is administered. Patients include, but are not limited to, humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, patients are rats, mice, It is a dog, human, or non-human primate, more typically, a human.

[0068] Examples of "mammal" or "animal" include, but are not limited to, humans, rats, mice, guinea pigs, monkeys, pigs , goats, cows, horses, dogs, cats, birds, and poultry.

[0069] The term "treat" or "treatment" refers to therapeutic treatment and prevention aimed at suppressing or decelerating (mitigating) an undesirable physiological change or disorder, such as the occurrence or spread of cancer, unless otherwise indicated by the context. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction of the scope of the disease, stable (i.e., not worsening) state of the disease, delay or deceleration of the progression of the disease, improvement or alleviation of the disease state, and remission (partial or complete), whether detectable or undetectable. "Treatment" can also mean extending the survival period as compared to the expected survival period if not receiving treatment. Those in need of treatment include not only those who already have the condition or disorder, but also those who tend to have the condition or disorder. (i.e., not worsening), delay or deceleration of the progression of the disease, improvement or alleviation of the disease state, and remission (partial or complete), whether detectable or undetectable. "Treatment" can also mean extending the survival period as compared to the expected survival period if not receiving treatment. Those in need of treatment include not only those who already have the condition or disorder, but also those who tend to have the condition or disorder.

[0070] Drug-conjugate-binding ligand conjugate

[0071] As described above, the present invention provides a cell surface binding molecule-camptothecin analog conjugate represented by the following formula (I), or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or an isotope, optical isomer, racemate, diastereomer, or enantiomer thereof:

Chemical formula

[0072] wherein T is a cell-binding agent / molecule; L is a releasable linker; [Chemical formula] are independently linkages connecting to the atoms of L and the R within the parentheses 1 R 2 R 3 or R 5 respectively; n is from 1 to 30, and m is from 1 to 10; The inside of the parentheses is an effective camptothecin analog, wherein R R 1 and R 2 are independently H; straight-chain or branched C1-C6 alkyl, alkyl alcohol , alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), aminoalkyl, oxyalkyl, aminoalkylamino, oxyalkylamino, a minoalkyloxy, oxyalkyloxy, alkylcarboxylic acid, or carbonyl group; C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, aminosi cloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, aminoalkylca rbonyl, oxyalkylcarbonyl, alkyl ether, alkyl ester, alkyl amide, oxyalkylamide, aminoalkylamide, oxime; NH2, or OH respectively; R 3 is independently H, C(O)NH, C(O)O, SO2R 6 SO3R 6 PR 6 R 6’ POR 6 R 6’ CH2OP(O)(OR 6)2, C(O)OP(O)(OR 6 )2, PO(OR 6 )(OR 6’ )、P(O)(OR 6 )OP(O)(OR 6’ )2, C (O)R 6 、C(O)NHR 6 ; linear or branched C1-C6 alkyl, alkyl alcohol 、alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), or alkyl carboxylic acid; C2-C6 heteroalkyl, alkyl cycloalkyl, hetero cycloalkyl, cycloalkyl, heteroalkyl cycloalkyl, alkyl carbonyl 、alkyl ether, alkyl ester, alkyl amide, oxime; C5-C 12 gly coside, NH2, or OH; R 4 is halo (F, Cl, Br, or I), CN, NO2, SO3H, OR 6 、SR 6 、S(O2)R 6 、NHR 6 、N(R 6 )(R 6’ )、C(O)XR 6 、N + (R 6 )( R 6’ )(R 6’’ ); X is NH or O; R 5 is H, C(O)O, C(O)NH, R 6 C(O), linear or branched C1-C6 alkyl yl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), alkyl carboxylic acid; C2-C6 carbonate, carbamide, he teroalkyl, alkyl cycloalkyl, heterocycloalkyl, heterocycloalkyl , heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl ester, alkylamide, or amino acid; is; R 6 , R 6’ , and R 6’’ are independently H, C1-C6 alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), or alkylcarboxylic acid; C2-C6 heteroalkyl, alkylcycloalkyl, heterocyclic cycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl ester, alkylamide, or amino acid; or a pharmaceutically acceptable salt; Furthermore, R 1 , R 2 , R 3 , and R 6 can be independently absent, and R 2 , R 3 , X , C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle;

[0073] In one specific embodiment, the conjugate of the camptothecin analog has the structure of formula (II), or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers:

Chemical formula

[0074] wherein, T is a targeting or binding ligand; L is a releasable linker; n is from 1 to 30 , and m is from 1 to 10;​​ The inside of the parentheses is an effective camptothecin analog, and in the formula, R 1 is a straight-chain or branched C1-C6 alkyl, alkyloxy, alkylamino (including primary, secondary, tertiary amino, or quaternary ammonium), oxylcarbonyl, a minocarbonyl, aminoalkyl, oxylalkyl, aminoalkylamino, oxyl alkylamino, aminoalkyloxyl, oxyalkyloxyl, or alkylcarbo xy; C2-C6 heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, oxylcycloalkyl, aminocycloalkyl, heteroalkylcycloalkyl, al kylcarbonyl, aminoalkylcarbonyl, oxylalkylcarbonyl, alkyl e ther, alkyl ester, alkyl amide, oxylalkyl amide, aminoalkyl amide, oxime; NH, or O; R R 2 is H, straight-chain or branched C1-C6 alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), aminoalkyl a lcohol, aminoalkylamine, oxyalkyl alcohol, oxyalkylamine, aminoalkyl, oxyalkyl, alkyl carboxylic acid; C2-C6 heteroalkyl, a lkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloal kyl, alkylcarbonyl, alkyl ether, alkyl ester, alkyl am ide, oxime; NH2, or OH; R 3 is independently H, R 6 NHC(O), R 6 OC(O), SO2R 6 SO3R 6 or PR6 R 6’ 、 POR 6 R 6’ 、 CH2OP(O)(OR 6 )2、 C(O)OP(O)( OR 6 )2、 PO(OR 6 )(OR 6’ )、 P(O)(OR 6 )OP(O)(OR 6’ ) 2、 R 6 C(O)、 C(O)NR 6 R 6’ ; linear or branched C1-C6 alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium ), or alkylcarboxylic acid; C2-C6 heteroalkyl, alkylcycloalkyl l, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkyl carbonyl, alkyl ether, alkyl ester, alkyl amide, oxime; C5 -C 12 glycoside; R 4 is halo (F, Cl, Br, or I), CN, NO2, SO3H, OR 6 、 SR 6 、 S(O2)R 6 、 NHR 6 、 N(R 6 )(R 6’ )、 C(O)XR 6 、 N + (R 6 )( R 6’ )(R 6’’ ) is; X is NH or O; R 5 is H, C(O)OR 6 、 C(O)NHR 6 、 R 6 C(O), linear or branched C1- C6 alkyl, alkyl alcohol, alkylamine (primary, secondary, tertiary amines, or an alkyl carboxylic acid containing a quaternary ammonium; C2-C6 carbonate, car bamide, heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, cycloal kyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, al kyl ester, alkylamide, or an amino acid; R 6 、R 6’ 、and R 6’’ are independently H, C1-C6 alkyl, alkyl alcohol , alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), or an alkyl carboxylic acid; C2-C6 heteroalkyl, alkylcycloalkyl, heter ocycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbo nyl, alkyl ether, alkyl ester, alkylamide, or an amino acid; or a pharmaceutically acceptable salt; Furthermore, R 1 is absent, and C-7 and L can be directly linked, and R 2 、R 3 、X、 C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle; ;

[0075] The exemplary compounds shown within the parentheses of formula (II) have the following structures, or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystal structures of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers :

Chemical formula

[0076] In the formula, R 6 and R 6’ are defined in the same manner as above. [Chemical formula] is the linking site with the linker L of formula (II).

[0077] In another specific embodiment, the conjugate of the cell-binding molecule-camptothecin analog is of the formula (III), or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or is the polymorphic crystal structure of these compounds; or their isotopes, optical isomers, racemates, diastereo mers, or enantiomers: [Chemical formula]

[0078] In the formula, T is a targeting or binding ligand; L is a releasable linker; n is from 1 to 30 , and m is from 1 to 10; The inside of the parentheses is an effective camptothecin analog, and in the formula, R 1 is a linear or branched C1-C6 alkyl, alkyloxy, alkylamino (including primary, secondary, tertiary amino, or quaternary ammonium), oxycarbonyl, a mino carbonyl, aminoalkyl, oxyalkyl, aminoalkylamino, oxy alkylamino, etc. Alkylamino, aminoalkyloxyl, oxyalkyloxy, or alkylcarbo xy; C2-C6 heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, oxylcycloalkyl, aminocycloalkyl, heteroalkylcycloalkyl, al kylcarbonyl, aminoalkylcarbonyl, oxylalkylcarbonyl, alkyl e ther, alkyl ester, alkyl amide, oxylalkyl ether, aminoalky l ether, oxylalkyl ester, aminoalkyl ester, oxylalkyl a mide, aminoalkyl amide, oxime; NH, or O; R 2 is NH, NR 6 , N + R 6 R 6’ , O, S, straight or branched C1-C6 alkyl, alkyl alcohol, alkylamine (primary, secondary, tertiary amine, or quaternary an monium), aminoalkyl alcohol, aminoalkylamine, oxyalkyl alcohol, oxyalkylamine, aminoalkyl, oxyalkyl, alkylcarbo nic acid; C2-C6 heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl e ther, alkyl ester, alkyl amide, oxime; oxylalkyl ether, amino alkyl ether, oxylalkyl ester, oxylalkyl amide, aminoalkyl amide; R 3 is independently H, R 6 NHC(O), R 6 OC(O), SO2R 6 , SO3R 6 、 PR 6R 6’ , POR 6 R 6’ , CH2OP(O)(OR 6 )2, C(O)OP(O)( OR 6 )2, PO(OR 6 )(OR 6’ ), P(O)(OR 6 )OP(O)(OR 6’ ) 2, R 6 C(O), C(O)NR 6 R 6’ ; linear or branched C1-C6 alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium ), or alkyl carboxylic acid; C2-C6 heteroalkyl, alkyl cycloalkyl l, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkyl cycloalkyl, alkyl carbonyl, alkyl ether, alkyl ester, alkyl amide, oxime; C5 -C 12 glycoside; R 4 is halo (F, Cl, Br, or I), CN, NO2, SO3H, OR 6 , SR 6 , S(O2)R 6 , NHR 6 , N(R 6 )(R 6’ ), C(O)XR 6 , N + (R 6 )( R 6’ (R 6’’ ); X is NH or O; R 5 is H, C(O)OR 6 , C(O)NHR 6 , R 6 C(O), linear or branched C1- C6 alkyl, alkyl alcohol, alkylamine (primary, secondary, tertiary amines, or an alkyl carboxylic acid (including a quaternary ammonium); a C2-C6 carbonate, carb amide, heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, cycloal kyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, al kyl ester, alkylamide, or an amino acid; R 6 、R 6’ 、and R 6’’ are independently H, C1-C6 alkyl, alkyl alcohol (including primary, secondary, tertiary amines, or quaternary ammonium), or an alkyl carboxylic acid; C2-C6 heteroalkyl, alkylcycloalkyl, heter ocycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarb onyl, alkyl ether, alkyl ester, alkylamide, or an amino acid; or a pharmaceutically acceptable salt; Furthermore, R 2 is absent, and C-9 and L can be directly linked, and R 2 、R 3 、X, C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle.

[0079] The exemplary compounds shown within the parentheses of formula (III) have the following structures, or their pharmaceutically acceptable salts, hydrates, or hydrates of salts; or the polymorphic crystal structures of these compounds ; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers :

Chemical formula

[0080] wherein, R 6 and R 6’ are independently H, C1-C6 alkyl, alkyl alcohol, a lkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), or alkyl carboxylic acid; C2-C6 heteroalkyl, alkyl cycloalkyl, heterocyclic al kyl, heterocycle, cycloalkyl, heteroalkyl cycloalkyl, alkyl carbonyl, alkyl ether, alkyl ester, alkyl amide, or amino acid; or a pharmaceutically acceptable salt thereof;

[0081] In another specific embodiment, the conjugate of the cell-binding molecule-camptothecin analog has, or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or an isotope, optical isomer, racemate, diastereo mer, or enantiomer thereof:

Chemical formula

[0082] wherein, T is a targeting or binding ligand; L is a cleavable linker; n is from 1 to 30 and m is from 1 to 10; R 1 and R 2 are independently H, NR 6 R 6’ ,-N + R 6 R 6’R 6’’ 、 OH, SH 、 linear or branched C1 - C6 alkyl, alkyloxy, alkylamino (primary, secondary 、 tertiary amino, or quaternary ammonium (including)), oxylcarbonyl, aminocarbo nyl, aminoalkyl, oxylalkyl, aminoalkylamino, oxylalkylamino 、 aminoalkyloxyl, oxyalkyloxy, or alkylcarboxy; C2 - C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, oxylcyclo alkyl, aminocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl 、 aminoalkylcarbonyl, oxylalkylcarbonyl, alkyl ether, alkyl ester 、 alkyl amide, oxylalkyl ether, aminoalkyl ether 、 oxylalkyl ester, aminoalkyl ester, oxylalkyl amide, aminoalkyl amide 、 oxime; NH2, or OH; R 3 is independently, -NHC(O)-, -C(O)-, SO2-, SO2NH-, R 6 N HC(O), R 6 OC(O), SO2R 6 、 SO3R 6 、 PR 6 R 6’ 、 POR 6 R 6’ 、 CH2OP(O)(OR 6 )2, C(O)OP(O)(OR 6 )2, PO(OR 6 )( OR 6’ )、 P(O)(OR 6 )OP(O)(OR 6’ )2, R 6 C(O), C(O)N R 6 R 6’; linear or branched C1-C6 alkyl, alkyl alcohol, alkylamine ( including primary, secondary, tertiary amines, or quaternary ammonium), or alkylcarbo nic acid; C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether ester, alkylamide, oxime; R 4 is halo (F, Cl, Br, or I), CN, NO2, SO3H, OR 6 SR 6 S(O2)R 6 NHR 6 N(R 6 )(R 6’ )C(O)XR 6 N + (R 6 )( R 6’ )(R 6’’ ); X is NH or O; R 5 is H, C(O)OR 6 C(O)NHR 6 R 6 C(O), linear or branched C1- C6 alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), alkylcarboxylic acid; C2-C6 carbonate, car bamide, heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, cycloal kyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, al kyl ester, alkylamide, or amino acid; R 6 R 6’ and R 6’’ are independently H, C1-C6 alkyl, alkyl alcohol Ru, an alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), , or an alkyl carboxylic acid; C2-C6 heteroalkyl, alkyl cycloalkyl, hetero cycloalkyl, heterocycle, cycloalkyl, heteroalkyl cycloalkyl, alkyl carbo nyl, alkyl ether, alkyl ester, alkyl amide, or amino acid; or a pharmaceutically acceptable salt; Furthermore, R 3 is absent, and X and L at C-10 can be directly linked, and R 2 , R 3 , X, C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle thereby.

[0083] The exemplary compounds shown within the parentheses of formula (IV) have the following structures, or their pharmaceutically acceptable salts, hydrates, or hydrates salts; or the polymorphic crystal structures of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers are:

Chemical Structure

[0084] wherein,

Chemical Structure

[0085] In another specific embodiment, the conjugate of the cell-binding molecule-camptothecin analog has the formula (V), or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof; or a polymorphic crystal structure of these compounds; or an isotope, optical isomer, racemate, diastere omer, or enantiomer thereof:

Chemical formula

[0086] wherein, T is a targeting or binding ligand; L is a releasable linker; n is from 1 to 30 and m is from 1 to 10; The content inside the parentheses is an effective camptothecin analog, wherein, R 1 and R 2 are independently H, NR 6 R 6’ , -N + R 6 R 6’ R 6’’ , OH, SH , linear or branched C1-C6 alkyl, alkyloxy, alkylamino (including primary, secondary , tertiary amino, or quaternary ammonium), oxylcarbonyl, aminocarbo nyl, aminoalkyl, oxylalkyl, aminoalkylamino, oxylalkylamino , aminoalkyloxyl, oxyalkyloxyl, or alkylcarboxy; C2 -C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, oxylcyclo alkyl, aminocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl nyl, aminoalkylcarbonyl, oxylalkylcarbonyl, alkyl ether, a Lukyl ester, alkyl amide, oxyl alkyl ether, amino alkyl ether , oxyl alkyl ester, amino alkyl ester, oxyl alkyl amide, ami no alkyl amide, oxime; NH2, or OH; R 3 is independently R 6 NHC(O)-, R 6 C(O)-, R 6 SO2, -SO2NHR 6 , R 6 OC(O), R 6’ SO2R 6 -, SO3R 6 , PR 6 R 6’ , POR 6 R 6’ , CH2OP(O)(OR 6 )2, C(O)OP(O)(OR 6 )2, PO(OR 6 )( OR 6’ )、P(O)(OR 6 )OP(O)(OR 6’ )2, R 6 C(O), C(O)N R 6 R 6’ ; linear or branched C1-C6 alkyl, alkyl alcohol, alkyl amine( including primary, secondary, tertiary amines), or alkyl carboxylic acid; C2-C6 hetero alkyl, alkyl cycloalkyl, heterocyclic alkyl, heterocyclic ring, cycloalkyl, hetero alkyl cycloalkyl, alkyl carbonyl, alkyl ether, alkyl ester, a alkyl amide, oxime; R 4 is halo (F, Cl, Br, or I), CN, NO2, SO3H, OR 6 , SR 6 , S(O2)R 6 , NH(R 6 )S(O2)R6’ 、 N(R 6 )(R 6’ )、 C(O)X R 6 、 N + (R 6 )(R 6’ )(R 6’’ ) is; X is NH or O; R 5 is C(O)O, C(O)NH, R 6 C(O), linear or branched C1-C6 alkyl , alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary a mmonium), alkyl carboxylic acid; C2-C6 carbonate, carbamide, hete roalkyl, alkyl cycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, hete roalkyl cycloalkyl, alkyl carbonyl, alkyl ether, alkyl ester , alkyl amide, or amino acid; R 6 , R 6’ , and R 6’’ are independently H, C1-C6 alkyl, alkyl alcohol l, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium) , or alkyl carboxylic acid; C2-C6 heteroalkyl, alkyl cycloalkyl, heter ocyclic alkyl, heterocycle, cycloalkyl, heteroalkyl cycloalkyl, alkyl carb onyl, alkyl ether, alkyl ester, alkyl amide, or amino acid; or a pharmaceutically acceptable salt; Furthermore, R 5 does not exist, and O at C-20 and L can be directly linked, and R 2 , R 3 , X, C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle if possible.

[0087] The exemplary compounds shown within the parentheses of formula (V) have the following structures, or their pharmaceutically acceptable salts, hydrates, or hydrate salts; or the polymorphic crystal structures of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers are: [Chemical formula] TIFF2025108449000035.tif250170TIFF2025108449000036.tif250170TIFF2025108449000037.tif250170TIFF2025108449000038.tif244170TIFF2025108449000039.tif251170TIFF2025108449000040.tif251170TIFF2025108449000041.tif251170TIFF2025108449000042.tif251170TIFF2025108449000043.tif247170TIFF2025108449000044.tif93170

[0088] wherein, [Chemical formula] , R 6 and R 6’ are defined as above.

[0089] In another embodiment, the synthetic routes for producing the camptothecin analogs of the present invention and their conjugation to their cell surface receptor binding molecules are exemplified as shown in FIGS. 1 to 32, but are not limited thereto.

[0090] In another embodiment, the releasable linker (L) is an effective linker between the cell surface binding ligand (T) and A chain of atoms selected from C, N, O, S, Si, and P that covalently binds to the imptotesin analog. The linker may have a wide variety of lengths, such as in the range of about 2 to about 100 atoms. The atoms used to form the linker are alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, alkoxylamine, urethane, amino acid, acyloxyamine, or hydroxamic acid, or may be bonded in any chemically related way that forms many others. Furthermore, the atoms forming the releasable linker (L) may be either saturated or unsaturated, may be radicals, and may cyclize with each other to form a divalent cyclic structure in the linker containing cycloalkane, cyclic ether, cyclic amine, arylenes, heteroarylenes, etc. The term releasable linker refers to a linker containing at least one bond that can be cleaved under physiological conditions such as pH instability, acid instability, base instability, oxidative instability, metabolic instability, biochemical instability, or enzyme instability binding. It is understood that such physiological conditions that cause bond breakage do not necessarily include biological or metabolic processes, but rather may include standard chemical reactions such as hydrolysis or substitution reactions, for example, in endosomes having a pH lower than the cytoplasmic pH and / or disulfide bond exchange reactions with intracellular thiols such as abundant glutathione in malignant cells.

[0091]

[0092] The releasable linker L of the conjugate can have the formula -Ww-(Aa)r-Vv-. In the formula, -W- is an extension unit; w is 0 or 1; each -Aa- is independently an amino acid unit; r is independently an integer in the range from 0 to 12; -V- is a spacer unit ; and v is 0, 1, or 2.

[0093] When the extension unit (-W-) is present, the target binding molecule unit (T) may bind to the amino acid unit, or bind to T when Aa is absent. The extension unit W may independently contain a self-cleaving spacer, a peptide unit, a hydrazone bond, a disulfide bond, an ester bond, or a thioether bond. In this regard, the cell binding molecule (CBA) has a functional group capable of forming a bond with the functional group of the extension unit. Functional groups that can be present on the binding molecule naturally or through chemical manipulation include sulfhydryl (-SH), amino, hydroxy, carbonyl, oxyamino, alkynyl, heteroaromatic, anomeric hydroxy groups of carbohydrates , and carboxyl. Preferred functional groups are sulfhydryl, carboxyl, and amino. The sulfhydryl group can be generated by reduction of an intramolecular disulfide bond of a ligand (such as a protein or an antibody). Alternatively, the sulfhydryl group can be reacted with the amino group of the lysine moiety of the cell binding molecule using 2-iminothiolane (Traut's reagent), or by a thiolactone or another sulfhydryl generating reagent, for example, by modifying T with a disulfide, or by a thioall ester followed by reduction or hydrolysis respectively. The W bound to T can have, for example, the following structure:

[0094] ​​​​​​​ [Chemical formula] TIFF2025108449000047.tif217170

[0095] In the formula, R 20 and R 21 are C1-C9 alkylene, -C1-C7 carbocyclic ring, -O-(C 1-C8 alkyl)-, -arylene, -C1-C9 alkylene-arylene, -ary lene, -C1-C9 alkylene, -C1-C9 alkylene-(C1-C8 carbocyclic ring)-, - (C3-C7 carbocyclic ring)-C1-C9 alkylene-. -C3-C8 heterocycle-, -C1 ~C 10 alkylene-(C3-C8 heterocycle)-, -(C3-C8 heterocycle)- C1-C9 alkylene-, -(CH2CH2O) k -, -(CH(CH3)CH2O) k -, and -(CH2CH2O) k -CH2-; k is an integer from 1 to 20; R' and R'' are independently H or CH3;

[0096] In another embodiment, the covalent bond of W to T as exemplified above can be carried out via various chemical reactions, typical conjugation methods.

[0097] Examples of the formation of the amide bond of the conjugate are shown below: [Chemical formula]

[0098] In the formula, the extended unit contains a reactive site E capable of forming an amide bond with a primary or secondary amino group of the ligand. The reactive site E includes, for example, hydroxysuccinyl imide ​imidyl esters (NHS, sulfo-NHS, etc.), 4-nitrophenyl esters, pentaf Fluorophenyl esters, tetrafluorophenyl (sulfo-tetrafluorophenyl (including esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates) These include, but are not limited to, anates.

[0099] Examples of thiol ether or disulfide bond linkage of conjugates are shown below: [ka]

[0100] where the extender unit contains a sulfhydryl reactive site, which is capable of reacting with the binding ligand T or by reduction of the intramolecular disulfide bond of the bound ligand as shown above. Thiol groups and thiol ether or disulfide bonds generated by chemical modifications on T can be formed.

[0101] In yet another embodiment of the present invention, the reactive group of the extender unit is chemically modified on the binding molecule T. Reactive sites that react with aldehyde (-CHO) or ketone (-C(=O)R) groups For example, carbohydrates on the binding molecule T can be gently deoxyribonucleotideized using a reagent such as sodium periodate. It can be slightly oxidized to produce an aldehyde or ketone (-C(=O)R) group. Alternatively, in a buffer solution, Amines can be reacted with pyridoxal 5'-phosphate (PLP) to introduce a ketone group. (Scheck & Francis, ACS Chem. Biol. 2007,2,247-251). The resulting unit (-C =O) can condense with an extended unit containing a functional group such as hydrazide, oxime, primary or secondary amine, hydrazine, thiosemicarbazone, hydrazine carboxylate, aryl hydrazide, etc. and be condensed.

[0102] Examples of the conjugation of hydrazone, or oxime bond or imine bond are shown below: [Chemical formula]

[0103] In the formula, R 20 and R 21 are as defined above, and R 25 is an organic substituent of an amino acid.

[0104] In another aspect of the present invention, the extended unit (which may also contain spacer V and / or amino acid) can be linked to the binding molecule (T), and then an effective camptothecin analog can be conjugated to the binding molecule-extended unit moiety in an aqueous buffer solution. Examples of this two-step conjugation are shown below (the drug linked to R is omitted). -extended unit moiety. In the formula, E includes, but is not limited to, hydroxysuccinimidyl ester (NHS, sulfo-NHS, etc.), 16 4-nitrophenyl ester, pentafluorophenyl ester, tetrafluorophenyl (including sulfo-tetrafluorophenyl) ester, anhydride, acid chloride, sulfonyl chloride, [Chemical formula]

[0105] isocyanate, and isothiocyanate. 4-nitrophenyl ester, pentafluorophenyl ester, tetrafluorophenyl l (including sulfo-tetrafluorophenyl) ester, anhydride, acid chloride, sulfonyl chloride nil, isocyanate, and isothiocyanate are included, but not limited thereto. R’ and R’’ are independently H or CH3; R 20 , R16 and Ar are defined in various embodiments throughout this invention; R is independently H, or F, or NO2 26 ; J is independently F, Cl, Br, I, tosylate (TsO), or mesylate (MsO ); wherein, ) and, in the formula,

Chemical formula

Chemical formula

[0106] In another aspect of the present invention, the extension unit is first linked to an active camptothecin analog and then can be conjugated with a binding molecule (T) in an aqueous buffer solution having a pH of 3 to 10 (preferably pH 5 to 8) containing up to 50% of an organic co-solvent. An example of this type of two-step conjugation is shown below: :

Chemical formula

[0107] wherein, E includes, but is not limited to, hydroxysuccinimidyl esters (NHS, sulfo-NHS, etc.), 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl (including sulfo-tetrafluorophenyl) esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. R' and R'' are independently H or CH3; R 16 , R 20 , and Ar are throughout this invention ​Defined in various embodiments throughout; R 26 is independently H, or F, or NO2 ; J is independently F, Cl, Br, I, tosylate (TsO), or mesylate (MsO ), wherein

Chemical formula

[0108] When the amino acid unit (-Aa-) is present, if the spacer unit is present, the expansion unit is linked to the spacer unit, if the spacer unit is not present, the expansion unit is linked to the camptothecin analog unit, if neither the expansion unit nor the spacer unit is present, the linker molecule (T) unit is linked to the camptothecin analog unit. -(Aa) - is a sequence of the same or different amino acids of a dipeptide, tripeptide, tetrapeptide, pentapeptide, r hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit which are natural or non-natural amino acids, and r is an integer from 0 to 12. As used herein, the term amino acid generally refers to an aminoalkyl carboxylate optionally substituted with an alkyl radical such as alkyl, acyl, hydroxyalkyl, sulfhydrylalkyl, aminoalkyl, carboxyalkyl, etc. The structures of natural and non-natural amino acids and peptides are described in G. C. Barrett and D. T. Elmore, “Amino Acid and Peptide”, Cambridge Univ ersity Press, 1985, incorporated herein by reference. The structures of natural and non-natural amino acids and peptides generally refer to aminoalkyl carboxylates optionally substituted with alkyl radicals such as alkyl, acyl, hydroxyalkyl, sulfhydrylalkyl, aminoalkyl, carboxyalkyl, etc. The structures of natural and non-natural amino acids and peptides are described in G. C. Barrett and D. T. Elmore, “Amino Acid and Peptide”, Cambridge Univ ​The Amino Acids are described in the Society Press, 2004. oxymethyl, thiomethyl, carboxyl, carboxylmethyl, guanidinopropyl, etc. More preferably, it refers to an amino acid sequence of β, γ or longer length having an inner chain containing Amino acids are asparagine, aspartic acid, cysteine, glycine, glutamic acid, lysine The amino acid sequence is selected from among arginine, glutamine, arginine, serine, ornithine, threonine, and the like.

[0109] The amino acid units of the present invention are enzymatically modified by one or more enzymes, including tumor-associated proteases. The camptothecin analog can be selectively cleaved to release the camptothecin analog, and in one embodiment, upon release, It is protonated in vivo to provide the camptothecin analogue.

[0110] When a spacer unit (-V-) is present, the amino acid unit, if present, The amino acid unit is linked to a camptothecin analogue. If not, the spacer unit links the extender unit to the camptothecin analog. The spacer unit may also be used when both the amino acid unit and the extender unit are absent. In this case, the camptothecin analog is linked to a linking molecule (T). The water solubility, biological transport, preferential renal clearance, uptake, and It may also contain functional groups that substantially increase absorption, biodistribution, and / or bioavailability. There are two general types of spacer units: self-immolative and non-self-immolative. The non-self-immolative spacer unit may be a camptothecin analog-linker-binding molecule conjugate or After cleavage (especially enzymatically) of the amino acid unit from the camptothecin analog-linker compound, Part or all of the spacer unit remains bound to the camptothecin analog . The self-destructive unit is electronically similar to the para-aminobenzylcarbamoyl (PAB) group and includes aromatic compounds, 2-aminoimidazole-5-methanol derivatives, heterocyclic PAB analogs , β-glucuronide, ortho- or para-aminobenzyl acetal; or any of the following structures: [Chemical formula]

[0111] wherein the ( * ) atom is a binding point to an additional spacer or releasable linker unit, amino acid (A a) r , camptothecin analog, and / or binding molecule (T); X, Y, and Z 3 are independently NH, O, or S; Z 2 is independently H, NH, O, or S ; v is 0 or 1; Q is independently H, OH, C1-C6 alkyl, (OCH 2CH2) n , F, Cl, Br, I, OR 17 , or SR 17 , NR 17 R 18 , N=N R 17 , N=R 17 , NR 17 R 18 , NO2, SOR 17 R 18 , SO2R 17 , SO 3R 17 , OSO3R 17 , PR 17 R 18 , POR 17 R 18 , PO2R 17 R 18 , OPO(OR 17 ​)(OR 18 )、 or OCH2PO(OR 17 (OR 18 ) and here Here, R 17 、 R 18 are independently H, C1 - C8 alkyl; C2 - C8 alkenyl group, alkynyl, heteroalkyl; C3 - C8 aryl, heterocycle, carbocycle, cycloalkyl, heterocycloalkyl, heteroaralkyl group, alkylcarbonyl; or a drug cation salt ; v is an integer from 1 to 20.

[0112] Examples of the non - self - destructing spacer linker unit (-V-) are shown below:

Chemical formula

[0113] In the formula, “*” and

Chemical formula

[0114] The releasable component of the linker L, which is at least one bond in the linker L, is pH-labile, acid-labile, base-labile, oxidation-labile, metabolism-labile, biochemical-labile, or enzyme labile bond, etc., can be cleaved under physiological conditions and has any of the following structures: -(CR 15 R 16 ) m (Aa) r (CR 17 R 18 ) n (OCH2CH2) t -, -(CR 15 R 16 ) m (CR 17 R 18 )n (Aa) r (OCH2CH2) t -,-(Aa) r -( CR 15 R 16 ) m (CR 17 R 18 ) n (OCH2CH2) t -,-(CR 15 R 16 ) m (CR 17 R 18 ) n (OCH2CH2) r (Aa) t -,-(CR 15 R 16 ) m (CR 17 =R 18 )(CR 19 R 20 ) n (Aa) t (OCH2CH2) r -,-(C R 15 R 16 ) m (NR 11 CO)(Aa) t (CR 19 R 20 ) n (OCH2CH2) r -,-(CR 15 R 16 ) m (Aa) t (NR 21 CO)(CR 19 R 20 ) n (OC H2CH2) r -,-(CR 15 R 16 ) m (OCO)(Aa) t (CR 19 R 20 ) n (OCH2CH2) r-, -(CR 15 R 16 ) m (OCNR 17 )(Aa) t (CR1 9R 20 ) n (OCH2CH2) r -, -(CR 15 R 16 ) m (CO)(Aa) t -( CR 19 R 20 ) n (OCH2CH2) r -, -(CR 15 R 16 ) m (NR 21 CO) (Aa) t (CR 19 R 20 ) n (OCH2CH2) r -, -(CR 15 R 16 ) m (O CO)(Aa) t (CR 19 R 20 ) n -(OCH2CH2) r -, -(CR 15 R 16 ) m (OCNR 17 )(Aa) t (CR 19 R 20 ) n (OCH2CH2) r -, -(C R 15 R 16 ) m (CO)(Aa) t (CR 19 R 20 ) n (OCH2CH2) r -,- (CR 15 R 16 ) m -phenyl-(CO)(Aa)t (CR 17 R 18 ) n -,-(C R 15 R 16 ) m -frill-(CO)(Aa) t (CR 17 R 18 ) n -,-(CR 15 R 16 ) m -oxazolyl-(CO)(Aa) t (CR 17 R 18 ) n -,-(CR 15 R 16 ) m -thiazolyl-(CO)(Aa) t (CCR 17 R 18 ) n -,-(CR 15 R 16 ) t -thienyl-(CO)(CR 17 R 18 ) n -,-(CR 15 R 16 ) t -i midazolyl-(CO)(CR 17 R 18 ) n -,-(CR 15 R 16 ) t -morpholino- (CO)(Aa) t (CR 17 R 18 ) n -,-(CR 15 R 16 ) t -piperazino-( CO)(Aa) t (CR 17 R 18 ) n -,-(CR 15 R 16 ) t -N-methylpiper Zin-(CO)(Aa) t (CR 17 R 18 ) n -,-(CR 15 R 16 ) m -(Aa) t Phenyl-,-(CR 15 R 16 ) m -(Aa) t Furyl-,-(CR 15 R 16 ) m -Oxazolyl(Aa) t -,-(CR 15 R 16 ) m -Thiazolyl(Aa) t -,-( CR 15 R 16 ) m -Thienyl(Aa) t -,-(CR 15 R 16 ) m -Imidazolyl( Aa) t -,-(CR 15 R 16 ) m -Morpholino-(Aa) t -,-(CR 15 R 16 ) m -Piperazino-(Aa) t -,-(CR 15 R 16 ) m -N-Methylpiperazino-( Aa) t -,-K(CR 15 R 16 ) m (Aa) r (CR 17 R 18 ) n (OCH2CH 2) t -,-K(CR 15 R 16 ) m (CR 17R 18 ) n (Aa) r (OCH2CH2 ) t -, -K(Aa) r (CR 15 R 16 ) m (CR 17 R 18 ) n (OCH2CH2) t -, -K(CR 15 R 16 ) m (CR 17 R 18 ) n (OCH2CH2) r (Aa) t -, -K(CR 15 R 16 ) m (CR 17 =R 18 )(CR 19 R 20 ) n (Aa) t ( OCH2CH2) r -, -K(CR 15 R 16 ) m (NR 11 CO)(Aa) t (CR1 9R 20 ) n (OCH2CH2) r -, -K(CR5R6) m (Aa) t (NR 21 CO )(CR 19 R 20 ) n (OCH2CH2) r -, -K(CR 15 R 16 ) m (OCO) (Aa) t (CR 19 R 20 ) n (OCH2CH2) r -, -K(CR15 R 16 ) m ( OCNR 17 )(Aa) t (CR 19 R 20 ) n (OCH2CH2) r -, -K(CR1 5R 16 ) m (CO)(Aa) t (CR 19 R 20 ) n (OCH2CH2) r -, -K( CR 15 R 16 ) m (NR 21 CO)(Aa) t (CR 19 R 20 ) n (OCH2CH2 ) r -, -K(CR 15 R 16 ) m (OCO)(Aa) t (CR 19 R 20 ) n (OCH 2CH2) r -, -K(CR 15 R 16 ) m (OCNR 17 )(Aa) t (CR 19 R2 0) n (OCH2CH2) r -, -K(CR 15 R 16 ) m (CO)(Aa) t (CR1 9R 20 ) n (OCH2CH2) r -, -K(CR 15 R 16 ) m -phenyl-(CO) (Aa) t (CR17 R 18 ) n -, -K(CR 15 R 16 ) m -furyl-(CO)(A a) t (CR 17 R 18 ) n -, -K(CR 15 R 16 ) m -oxazolyl-(CO)( Aa) t (CR 17 R 18 ) n -, -K(CR 15 R 16 ) m -thiazolyl-(CO)( Aa) t (CR 17 R 18 ) n -, -K(CR 15 R 16 ) t -thienyl-(CO)(C R 17 R 18 ) n -, -K(CR 15 R 16 ) t -imidazolyl-(CO)(CR 17 R 18 ) n -, -K(CR 15 R 16 ) t -morpholino-(CO)(Aa) t (CR 17 R 18 ) n -, -K(CR 15 R 16 ) t -piperazino-(CO)(Aa) t (CR 17 R 18 ) n -, -K(CR 15 R 16 ) t-N-Methylpiperazine-(CO)(Aa) t ( CR 17 R 18 ) n -, -K(CR 15 R 16 ) m -(Aa) t Phenyl-, -K(CR 15 R 16 ) m -(Aa) t Furyl-, -K(CR 15 R 16 ) m -Oxazolyl(Aa ) t -, -K(CR 15 R 16 ) m -Thiazolyl(Aa) t -, -K(CR 15 R 16 ) m -Thienyl(Aa) t -, -K(CR 15 R 16 ) m -Imidazolyl(Aa) t -, - K(CR 15 R 16 ) m -Morpholino-(Aa) t -, -K(CR 15 R 16 ) m -Pip eridino-(Aa) t G-, -K(CR 15 R 16 ) m -N-Methylpiperazino-(Aa) t -; wherein the definitions of Aa, m, and n are as described above ; t and r are independently 0 to 100; R 13 , R 14 , R 15 , R1 6, R 17 , R 18 , R 19 , and R 20independently, H; halide; C1-C8 alkyl; C2-C8 aryl, alkenyl, alkynyl, ether, ester, amine, amide, or amide, C3-C8 aryl, or is optionally substituted with one or more halides, CN, NR1 2R 12’ CF3, OR 12 aryl, heterocycle, S(O)R 12 SO2R 12 - CO2H, -SO3H, -OR 12 -CO2R 12 -CONR 12 -PO2R 12 R 12 -PO3H, or P(O)R 12 R 12’ R 13 and is selected from; K is NH, NR 12 -SS-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C=N-NH-, -C(=O)NH-NH-, O, S, Se, B, Het(C3-C 12 heterocyclic or heteroaromatic ring), or a peptide containing 1 to 20 identical or different amino acids.

[0115] In yet another aspect of the present invention, the linker L preferably contains an amino group, sulfonamide, phospho famido, or amino acid group, and the side chain of formula (I-q) can be attached via said group, where the amino acid in the linker L is preferably selected from aspartic acid, glutamic acid, lysine, ornithine, or tyrosine, and where one or two of the functional groups of these amino groups, carboxyl group, or phenoxy group can be attached to the long side chain of formula (I-q).

Chemical formula

[0116] wherein, [Chem.] is a bond with a sulfonyl group, phosphate ester group, amino group, or carbonyl group in the linker, preferably a carbonyl, amino, or phenol group of an appropriate aspartic acid, glutamic acid, lysine, ornithine, or tyrosine in the linker; G1 is NH, NHNH, C(=O), NHNHC(O), C(=O)NH, C(=NH)NH, CH2, CH2C(O), C(O)O, NHC(O)NH, or (Aa) HNH, C(=O), NHNHC(O), C(=O)NH, C(=NH)NH, CH2, CH2C(O), C(O)O, NHC(O)NH, or (Aa) r , (r = 1 to 12) and there is; G2 is NH, NHNH, C(=O), NHNHC(O), C(=O)NH, C( =NH)NH, CH2, C(O)O, NHC(O)NH, O, S, B, P(O)(OH) , NHP(O)(OH), NHP(O)(OH)NH, CH2P(O)(OH)NH, O P(O)(OH)O, CH2P(O)(OH)O, NHS(O)2, NHS(O)2NH , CH2S(O)2NH, OS(O)2O, CH2S(O)2O, Ar, ArCH2, A rO, ArNH, ArS, ArNR1, (Aa) r , (r = 1 to 12); X1 and X2 are independently O, CH2, S, NH, N(R 12 ), + NH(R 12 ), + N(R1 2)(R 13 ), C(O), OC(O), OC(O)O, NHSO2NH, NHP(O) (NH)2, SO2NH, P(O)(NH)2, NHS(O)NH, NHP(O)(OH )(NH), OC(O)NH, NHC(O)NH; Y2 is O, NH, NR1, C H2, S, Ar; G3 is OH, SH, OR1, SR1, OC(O)R1, NHC (O)R 12 、C(O)R 12 、CH3, NH2, NR 12 、 + NH(R 12 )、 + N( R 12 )(R 13 )、C(O)OH, C(O)NH2, NHC(O)NH2, BH2, B R 12 R 13 、P(O)(OH)2, NHP(O)(OH)2, NHP(O)(NH2) 2, S(O)2(OH), (CH2) q1 C(O)OH, (CH2) q1 P(O)(OH )2, C(O)(CH2) q1 C(O)OH, OC(O)(CH2) q1 C(O)OH、 NHC(O)(CH2) q1 C(O)OH, CO(CH2) q1 P(O)(OH)2, N HC(O)O(CH2) q1 -C(O)OH, OC(O)NH-(CH2) q1 C(O) OH, NHCO(CH2) q1 P(O)(OH)2, NHC(O)(NH)(CH2) q 1C(O)OH, CONH(CH2) q1 -P(O)(OH)2, NHS(O)2(CH 2) q1 C(O)OH, CO(CH2) q1 S(O)2(OH), NHS(O)2NH- (CH2) q1 C(O)OH, OS(O)2NH(CH2) q1 C(O)OH, NHCO (CH2) q1S(O)2(OH), NHP(O)(OH)(NH)-(CH2) q1 C (O)OH, CONH(CH2) q1 S(O)(OH), OP(O)(OH)2, (CH 2) q1 P(O)(NH)2, NHS(O)2(OH), NHS(O)2NH2, CH2 S(O)2NH2, OS(O)2OH, OS(O)2OR1, CH2S(O)2OR1, Ar, ArR 12 , ArOH, ArNH2, ArSH, ArNHR 12 , or (Aa) q is 1; p1, p2, and p3 are independently 0 to 30, but not 0 simultaneously; q1 and q2 are independently 0 to 24; preferably, G3 is linear or branched, C2 - C 50 polycarboxylic acid or C2 - C 50 polyalkylamine; C6 - C 50 oligosaccharide or poly saccharide; C6 - C 50 zwitterionic betaine or zwitterionic poly(sulfobetaine) (PSB) containing a quaternary ammonium cation and a sulfonate anion; (poly(lactic / glycolic acid)) (PLGA), poly(acrylate), chitosan, copolymer of N-(2-hydroxypropyl ) methacrylamide, poly[2-(methacryloyloxy)ethyl phosphoryl choline] (PMPC), poly-L-glutamic acid, poly(lactide-co-glycolide )(PLG), poly(lactide-co-glycolide), poly(ethylene glycol)(PEG ), poly(propylene glycol)(PPG), poly(lactide-co-glycolide), poly(ethylene glycol)-modified peptide, poly(ethylene glycol) containing an amino acid or a peptide poly(ethylene glycol)-modified lipid, poly(ethylene glycol)-modified poly(ethylene glycol), Alkyl carboxylic acid, poly(ethylene glycol)-modified alkylamine, poly(lactide -co-glycolide, hyaluronic acid (HA) (glycosaminoglycan), heparin / hepar an sulfate (HSGAG), chondroitin sulfate / dermatan sulfate (CSGAG), poly(e thylene glycol)-modified alkyl sulfate, poly(ethylene glycol)-modified alkyl phosphate, or poly(ethylene glycol)-modified alkyl quaternary ammonium, and is a biodegradable polymer.

[0117] More preferably, formula (I-q) is specifically selected from the following:

Chemical formula

[0118] In the formula, G1, p1, p2, p3, Aa, r, X2, q1, and m1 are defined as above.

[0119] In yet another aspect of the present invention, the binding molecule (T) of the present invention binds to, complexes with, or reacts with a site of a cell population that requires a therapeutic or other biological modification, and can be any type of molecule known at present or that will become known. The binding molecule unit acts to deliver a camptothecin analog to a specific target cell population with which the binding molecule (T) reacts.

[0120] In yet another specific aspect of the present invention, the conjugate of a CPT analog to a cell-binding molecule has the formulas (IIq-1), (IIq-2), (IIq-3), (IIq-4) exemplified below, (IIq-5), (IIq-6), (IIq-7), (IIq-8): ​​​​​[Chemistry] TIFF2025108449000067.tif146170

[0121] In the formula, R’ and R’’ are independently H, Me, Et, i Pr, i Bu, Bz(CH2C6H5 ), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH 2, CH2CH2CH2CH2NH2, CH2CH2SCH3, CH2OH, CH2CH 2CH2NHC(=NH)NH2, CH(OH)CH3, CH2C6H4OH, or C H2C3N2H3; p1 and p2 are independently 0 to 24; q1 is 1 to 18 ; q3 is 0 to 6; q4 is 0 to 4; m’ and m’’ are independently 0 to 6 ; m’’’ is 0 or 1; and mAb is a cell-binding molecule, preferably an antibody; N H-Drug is the above compounds II-1 to II-61, III-1 to III-52, IV- 1 to IV-47, and V-1 to V-61; n is 1 to 20; and [Chemistry] is the site that binds to NH-Drug.

[0122] The conjugates of formula (IIq-1), (IIq-2), (IIq-3), (IIq-4), (IIq-5 ), (IIq-6), (IIq-7), (IIq-8) are cell-binding molecules containing thiol and the following formulas (IIq-9), (IIq-10), (IIq-11), (II q-12), (IIq-13), (IIq-14), (IIq-15), (IIq-16 ) can be prepared through reaction with:

Chem.

[0123] Wherein, R’ and R’’ are independently H, Me, Et, i Pr, i Bu, Bz(CH2C 6H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2C ONH2, CH2CH2CH2CH2NH2, CH2CH2SCH3, CH2OH, CH 2CH2CH2NHC(=NH)NH2, CH(OH)CH3, CH2C6H4OH, C H2C3N2H3; p1 and p2 are independently 0 to 24; q1 is 1 to 18; q 3 is 0 to 6; q4 is 0 to 4; m’ and m’’ are independently 0 to 6; m’ ’’ is 0 or 1; NH-Drug is the above compounds II-1 to II-61, III- 1 to III-51, IV-1 to IV-47, and V-1 to V-61; and

Chem.

[0124] Free thiols in proteins, especially in antibodies, in a buffer solution at pH 5.0 to 8.5, di thiothreitol (DTT), dithioerythritol (DTE), dithiobutylamine (DTBA), L-glutathione (GSH), tris(2-carboxyethyl)phosph ine (TCEP), 2-mercaptoethylamine (β-MEA), and / or β-mercap The interchain disulfide atoms of the protein can be reduced and generated by a reducing agent selected from thioethanol (β-ME, 2-ME). The reduction of two or more disulfide residues of the protein by TCEP can be carried out simultaneously with or before the conjugate reaction with formula (IIq-9), (IIq-10), (IIq-11), (IIq-12), (IIq-13), (IIq-14), (IIq-15), or (II q-16). Also, the thiols on the protein can be generated by the reaction of amino groups (lysine residues) with a trout reagent (2-iminothiolane) or γ-thiobutyrolactone. The conjugation of formula (IIq-9), (II q-10), (IIq-11), (IIq-12), (IIq-13), (IIq-1 4), (IIq-15), or (IIq-16) with the protein can be carried out in one pot (simultaneously) with a trout reagent (2-iminothiolane) or a γ-thiobrolactone compound. (IIq-10), (IIq-11), (IIq-12), (IIq-13), (IIq-1 4), (IIq-15), or (IIq-16) with the protein can be carried out in one pot (simultaneously) with a trout reagent (2-iminothiolane) or a γ-thiobrolactone compound.

[0125] The cell-binding agent T includes, but is not limited to, large molecular weight proteins such as whole antibodies ( polyclonal or monoclonal), dimers, multimers, multispecific antibodies (e.g., bispecific antibodies); single-chain antibodies; antibody fragments such as Fab, Fab’, F(ab’)2, F v [Parham, J. Immunol. 131, 2895-2902 (1983)], fragments obtained by a Fab expression library, anti-idiotype (anti-Id) antibodies , CDR’s, bispecific antibodies, trispecific antibodies, cancer cell antigens, viral antigens, microbial antigens, or any epitope-binding fragment of the above substances that can recognize, bind to, or express a desired biological activity and specifically bind immunologically to proteins generated in the immune system. ​; Interferons (e.g., Types I, II, III); peptides; lymphokines, such as , IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, GM-CSF, or interferon gamma (IFN-γ); hormones, such as insulin, TRH (thyrotropin releasing hormone), MSH (melanocyte-stimulating hormone), or steroid hormones such as androgens, estrogens or melanocyte-stimulating hormone (MSH); growth factors and colony-stimulating factors, such as epidermal growth factor (EFG), granulocyte macrophage colony - stimulating factor (GM-CSF); transforming growth factor (TGF), such as TGF α, TGFβ; insulin and insulin-like growth factors (IGF-I, IGF-II) G - CSF, M-CSF, and GM-CSF [Burgess, Immunology T oday, 5, 155 - 158 (1984)]; vaccine growth factor (VGF); fibroblast growth factor (FGF); small molecular weight proteins, polypeptides, peptides, and peptide hormones, such as bombesin, gastrin, and gastrin-releasing peptide; platelet-derived growth factor; interleukins and cytokines, such as interleukin-2 (IL-2 ), interleukin-6 (IL-6), leukemia inhibitory factor, granulocyte macrophage colony - stimulating factor (GM-CSF); vitamins such as folic acid; apoproteins and glycoproteins, such as transferrin [O’Keefe et al, J.Bio.Chem. 260 , 932 - 927 (1985)]; lectins and other carbohydrate-binding proteins or lipoproteins; cellular nutrient transport molecules; and small molecule inhibitors, such as inhibitors of prostate-specific membrane antigen (PSMA), small molecule tyrosine kinase inhibitors (TKIs), non-peptides, or other cell-binding molecules ; and small molecule inhibitors, such as inhibitors of prostate-specific membrane antigen (PSMA), small molecule tyrosine kinase inhibitors (TKIs), non-peptides, or other cell-binding molecules ; and small molecule inhibitors, such as inhibitors of prostate-specific membrane antigen (PSMA), small molecule tyrosine kinase inhibitors (TKIs), non-peptides, or other cell-binding molecules or a substance, such as a bioactive polymer (Dhar, et al, Proc. Natl. A cad. Sci. 2008, 105, 17356 - 61), a bioactive dendrimer (Le e, et al, Nat. Biotechnol. 2005, 23, 1517 - 26; A lmutairi, et al; Proc. Natl. Acad. Sci. 2009, 1 06, 685 - 90), nanoparticles (Liong, et al, ACS Nano, 200 8, 19, 1309 - 12; Medarova, et al, Nat. Med. 2007 , 13, 372 - 7; Javier, et al, Bioconjugate Chem . 2008, 19, 1309 - 12), liposomes (Medinai, et al, Cu rr. Pharm. Des. 2004, 10, 2981 - 9), virus capsids (Fle nniken, et al, Viruses Nanotechnol. 2009, 32 7, 71 - 93). Generally, if a suitable monoclonal antibody is available, mo noclonal antibodies are preferred as cell surface binding molecules.

[0126] Preferably, T is an antibody, a single - chain antibody; an antibody fragment that binds to a target cell; mo noclonal antibody; single - chain monoclonal antibody; monoclonal antibody fragment that binds to a target cell; chi meric antibody; chimeric antibody fragment that binds to a target cell; domain antibody; domain antibody fragment that binds to a target cell; an adnectin that mimics an antibody; DARPi ns; lymphokine; hormone; vitamin; growth factor; colony - stimulating factor; nutrient transport molecule (transferrin); and / or albumin, polymer, dendrimer, liposome, (transferrin); and / or albumin, polymer, dendrimer, liposome, Nanoparticles, vesicles, or small molecules, cell-binding peptides attached to (viral) capsids selected from the group consisting of, or proteins.

[0127] More preferably, the cell-binding agent / molecule T is a tumor cell, a virus-infected cell, a microorganism-infected cell cell, a parasite-infected cell, an autoimmune disease cell, an activated tumor cell, a bone marrow cell, an activated T cell, an affected B cell, a melanocyte, or any one of the following antigens or receptors conjugates according to claims 1 to 5, 10 or 12 that can target any cell expressing: CD1, CD1a, CD1b, CD1c, CD1d, CD1e, CD2, CD3, C D3d, CD3e, CD3g, CD4, CD5, CD6, CD7, CD8, CD8a, C D8b, CD9, CD10, CD11a, CD11b, CD11c, CD11d, CD1 2w, CD13, CD14, CD15, CD16, CD16a, CD16b, CDw17 、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25 , CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25 , CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD32 a, CD32b, CD33, CD34, CD35, CD36, CD37, CD38, CD 39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42 d, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD 49c, CD49c, CD49d, CD49f, CD50, CD51, CD52, CD5 3, CD54, CD55, CD56, CD57, CD58, CD59, CD60, CD6 0a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD 63, CD64, CD65, CD65s, CD66, CD66a, CD66b, CD66 c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD75, CD75s, CD76, CD77 , CD78, CD79, CD79a, CD79b, CD80, CD81, CD82, CD 83, CD84, CD85, CD85a, CD85b, CD85c, CD85d, CD8 5e, CD85f, CD85g, CD85i, CD85j, CD85k, CD85m, C D86, CD87, CD88, CD89, CD90, CD91, CD92, CD93, C D94, CD95, CD96, CD97, CD98, CD99, CD100, CD101 , CD102, CD103, CD104, CD105, CD106, CD107, CD1 07a, CD107b, CD108, CD109, CD110, CD111, CD112 , CD113, CD114, CD115, CD116, CD117, CD118, CD1 19, CD120, CD120a, CD120b, CD121, CD121a, CD12 1b, CD122, CD123, CD123a, CD124, CD125, CD126, CD127, CD128, CD129, CD130, CD131, CD132, CD13 3, CD134, CD135, CD136, CD137, CD138, CD139, CD 140, CD140a, CD140b, CD141, CD142, CD143, CD14 4, CD145, CDw145, CD146, CD147, CD148, CD149, C D150, CD151, CD152, CD153, CD154, CD155, CD156 , CD156a, CD156b, CD156c, CD156d, CD157, CD158 , CD158a, CD158b1, CD158b2, CD158c, CD158d, CD 158e1, CD158e2, CD158f2, CD158g, CD158h, CD15 8i, CD158j, CD158k, CD159, CD159a, CD159b, CD1 59c, CD160, CD161, CD162, CD163, CD164, CD165, CD166, CD167, CD167a, CD167b, CD168, CD169, CD 170, CD171, CD172, CD172a, CD172b, CD172g, CD1 73, CD174, CD175, CD175s, CD176, CD177, CD178, CD179, CD179a, CD179b, CD180, CD181, CD182, CD 183, CD184, CD185, CD186, CDw186, CD187, CD188 , CD189, CD190, CD191, CD192, CD193, CD194, CD1 95, CD196, CD197, CD198, CD199, CDw198, CDw199 , CD200, CD201, CD202, CD202(a,b), CD203, CD20 3c, CD204, CD205, CD206, CD207, CD208, CD209, C D210, CDw210a, CDw210b, CD211, CD212, CD213, C D213a1, CD213a2, CD214, CD215, CD216, CD217, C D218, CD218a, CD218, CD21b9, CD220, CD221, CD2 22, CD223, CD224, CD225, CD226, CD227, CD228, C D229, CD230, CD231, CD232, CD233, CD234, CD235 , CD235a, CD235b, CD236, CD237, CD238, CD239, C D240, CD240ce, CD240d, CD241, CD242, CD243, CD 244, CD245, CD246, CD247, CD248, CD249, CD250, CD251, CD252, CD253, CD254, CD255, CD256, CD25 7, CD258, CD259, CD260, CD261, CD262, CD263, CD 264, CD265, CD266, CD267, CD268, CD269, CD270, CD271, CD272, CD273, CD274, CD275, CD276, CD27 7, CD278, CD279, CD281, CD282, CD283, CD284, CD 285, CD286, CD287, CD288, CD289, CD290, CD291, CD292, CD293, CD294, CD295, CD296, CD297, CD29 8, CD299, CD300, CD300a, CD300b, CD300c, CD301 、CD302, CD303, CD304, CD305, CD306, CD307, CD3 07a, CD307b, CD307c, CD307d, CD307e, CD307f, C D308, CD309, CD310, CD311, CD312, CD313, CD314 、CD315, CD316, CD317, CD318, CD319, CD320, CD3 21, CD322, CD323, CD324, CD325, CD326, CD327, C D328, CD329, CD330, CD331, CD332, CD333, CD334 、CD335, CD336, CD337, CD338, CD339, CD340, CD3 41, CD342, CD343, CD344, CD345, CD346, CD347, C D348, CD349, CD350, CD351, CD352, CD353, CD354 , CD355, CD356, CD357, CD358, CD359, CD360, CD3 61, CD362, CD363, CD364, CD365, CD366, CD367, C D368, CD369, CD370, CD371, CD372, CD373, CD374 , CD375, CD376, CD377, CD378, CD379, CD381, CD3 82, CD383, CD384, CD385, CD386, CD387, CD388, C D389, CRIPTO, CR, CR1, CRGF, CXCR5, LY64, TDGF1 , 4-1BB, APO2, ASLG659, BMPR1B, 5AC, 5T4 (villus glycoprotein, TPBG, 5T4, Wnt activation inhibitor 1 or WAIF1), adenocarcinoma antigen, A GS-5, AGS-22M6, activin receptor-like kinase 1, AFP, AKAP-4, ALK, α-integrin, αvβ6, aminopeptidase N, amyloid β, androgen receptor, angiopoietin 2, angiopoietin 3, annexin A1, anthrax toxin defense antigen, anti-transferrin receptor, AOC3 (VAP-1), B7-H3, anthrax bacteria, BAFF (B-cell activating factor), BCMA, B-lymphocytes, bcr-abl, bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate antigen 125, MU C16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg, i nuIL31, carbonic anhydrase IX, cardiac myosin, CCL11 (C-C motif chemokine 11), CCR4 (CC chemokine receptor type 4), CCR5, CD3E (epsilon), CEA (carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD ( Factor D), Ch4D5, cholecystokinin 2 (CCK2R), CLDN18 (claudin-18), clamping factor A, cMet, CRIPTO, FCSF1R (colony stimulating factor 1 receptor), CSF2 (colony stimulating factor 2, granulocyte macrophage colony stimulating factor (GM-CSF)), CSP4, CTLA4 (cytotoxic T lymphocyte-associated protein 4), CTAA16.88 tumor antigen, CXCR4, CXC chemokine receptor type 4, cADPR ribohydrolase, cyclin B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, dabigatran, DLL4 (delta-like ligand 4), DPP4 (dipeptidyl peptidase 4), DR5 (death receptor 5), Escherichia coli Shiga toxin type 1, Escherichia coli Shiga toxin type 2, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, endoglin, endothelin B receptor, endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, epithin, ERBB2 (epidermal growth factor receptor 2), ERBB3, ERG (TMPRSS2-ETS fusion gene), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein α), FCGR1, α-fetoprotein, fibrin II, β-chain, fibronectin external domain B, FOLR (folate receptor), folate receptor α, folate hydrolase, Fos-related antigen 1F, RS virus F protein, Frizzled receptor, fucosyl GM1, GD2 ganglioside, G-28 (cell surface glycolipid antigen), GD3 idiotype, GloboH, glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor α-chain, growth differentiation factor 8 ​​​​​​​​​​​​​​​, GP100, GPNMB (transmembrane protein NMB), GUCY2C (guanylate cyclase 2C, guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor, heat-stable enterotoxin receptor (hSTAR)), heat shock protein, hemagglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2 / neu, HER3 (ERBB-3), IgG4, HGF / SF (stem cell growth factor / cell-dispersing factor), HHGFR, HIV-1, histone complex, HLA-DA (human leukocyte antigen), HLA-DR10, HLA-DRB, HM lase 2C, guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate late cyclase-C receptor, heat-stable enterotoxin receptor (hSTAR)), heat shock protein, hemagglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2 / neu, HER3 (ERBB-3), IgG 4, HGF / SF (stem cell growth factor / cell-dispersing factor), HHGFR, HIV-1, hist one complex, HLA-DA (human leukocyte antigen), HLA-DR10, HLA-DRB, HM WMAA, human chorionic gonadotropin, HNGF, human cell scattering factor receptor kinase, H PV E6 / E7, Hsp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idi otype, IGF1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, I FN-γ, influenza hemagglutinin, IgE, IgE Fc region, IGHE, inter leukin (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-6 R, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13 , IL-15, IL-17, IL-17A, IL-18, IL-19, IL-20, IL -21, IL-22, IL-23, IL-27, or IL-28), IL-31RA, I LGF2 (insulin-like growth factor 2), integrin (α4, α IIIb β3, αvβ3 , α4β7, α5β1, α6β4, α7β7, αIIβ3, α5β5, αvβ5), int erferon γ-induced protein, ITAGA2, ITGB2, KIR2D, LCK, Le , legumain, Lewis-Y antigen, LFA- 1 (Lymphocyte Function-Associated Antigen 1, CD11a), LHRH, LINGO-1, lipoteichoic acid , LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1 , MAGE-2, MAGE-3, MAGEA1, MAGEA3, MAGE4, MART1 , MCP-1, MIF (Macrophage Migration Inhibitory Factor or Glycosylation Inhibitory Factor (GIF )), MS4A1 (Membrane-Spanning 4-Domain Subfamily A Member 1), MSLN (Mesothe lin), MUC1 (Mucin 1, Cell Surface-Associated (MUC1) or Polymorphic Epithelial Mucin (PEM )), MUC1-KLH, MUC16 (CA125), MCP1 (Monocyte Chemotactic Protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1 (Membrane-Spanning Type 4 Dom in Subfamily A), MYCN, Myelin-Associated Glycoprotein, Myostatin, NA1 7, NARP-1, NCA-90 (Granulocyte Antigen), nectin-4 (ASG-22ME), NGF, Neuroapoptosis Regulatory Protease 1, NOGO-A, Notch Receptor, Nu creolin, Neu Oncogene Product, NY-BR-1, NY-ESO-1, OX-40, O xLDL (Oxidized Low-Density Lipoprotein), OY-TES1, P21, p53 Non-Mutant, P 97, Page4, PAP, Paratope Against (N-Glycolylneuraminic Acid), PAX3 , PAX5, PCSK9, PDCD1 (PD-1, Programmed Cell Death Protein 1 ), PDGF-Rα, (Platelet-Derived Growth Factor Receptor α), PDGFR-β, PDL-1, PLAC1, PLAP-Like Testicular Alkaline Phosphatase, Platelet-Derived Growth Factor Receptor β, Li um Sodium Cotransporter, PMEL17, Polysialic Acid, Protease 3 (PR1), Prostate cancer, PS (phosphatidylserine), prostate cancer cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI)), Rhesus factor, RANKL, PhoC, Ras variant , RG55, ROBO4, RS virus, RON, sarcoma metastasis breakpoint, SART 3, sclerostin, SLAMF7 (SLAM family member 7), selectin P, SDC1 (syndecan 1), sLe(a), somatomedin C, SIP (sphingosine- 1-phosphate), somatostatin, sperm protein 17, SSX2, STEAP1 ( prostate transmembrane epithelial antigen 1 of 6), STEAP2, STn, TAG-22 (tumor-associated glycoprotein 72), survivin, T cell receptor, T cell transmembrane protein, TEM1 (tumor epithelial marker 1), TENB2, tenascin C (TN-C), TGF-α, TGF-β ( transforming growth factor β), TGF-β1, TGF-β2 (transforming growth factor β2), Tie (CD202b), Tie2, TIM-1 (CDX-014) , TN, TNF, TNF-α, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor super family member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (tumor necrosis apoptosis-inducing ligand receptor 1), TRAILR2 (death receptor 5 (D R5)), major associated calcium signal transducer 2, tumor-specific glycosylation of MUC1 , TWEAK receptor, TYRP1 (glycoprotein 75), TRP-2, tyrosine nase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VE GFR2, or vimentin, WT1, XAGE1, or any insulin growth factor receptor a cell expressing, or any epidermal growth factor receptor.

[0128] In another particular embodiment, the cell binding molecule is a ligand or receptor a gonist that may be selected from: folic acid derivatives (binding to the folic acid receptor, a protein overexpressed in ovarian cancer and other malignancies) (Low, P. S. et al 2008, Acc. Chem. Res. 41, 120-129); glu tamate urea derivatives (binding to prostate specific membrane antigen, a surface marker of prostate cancer cells) (Hi llier, S. M.et al, 2009, Cancer Res. 69, 6932-6940); somatostatin (growth horm one inhibitory hormone (GHIH), somatotropin release inhibiting factor (SRIF), or somatot ropin release inhibiting hormone, also known as) and their derivatives, such as octre otide (sandostatin) and lanreotide (somatuline) (especially neuroendocrine tumors, GH producing pituitary adenomas, paragangliomas, hypofunctional pituitary adenomas, pheochromocytomas) (Ginj, M., et al, 2006, Proc. Natl. Acad. Sci. U.S.A. 103, 16436-16441); somatostatin receptor subtypes (sst1, sst2, sst3, sst4, and sst5) in GH secreting pituitary adenomas (Reubi JC, Landolt, AM 1984 J. Clin. Endocrinol Metab 59:1148-51; Re ubi JC, Landolt AM 1987 J Clin Endocrinol Metab 65:65-73; Moyse E, et al, J Cli n Endocrinol Metab 79:2201-2206); and bombesin (gastrin releasing peptide, GRP), and its receptor subtype BB2 (gastrin releasing peptide receptor, GRPR) (especially small cell lung cancer) (Kubota Y, et al, 2001, Cancer Res. 61:3532-3538); n Endocrinol Metab 61:98 - 103), gastrointestinal and pancreatic tumors (Reubi JC, et al, 1987 J Clin Endocr inol Metab 65:1127 - 34; Reubi, J.C., et al al, 1990 Cancer Res 50:5969 - 77), brown chromaffin cells (Epel -baum J, et al 1995 J Clin Endocrinol Metab 80:1837 - 44; Reubi JC , et al, 1992 J Clin Endocrinol Metab 74:1082 - 9), neuroblastoma (Prevost G, 199 6 Neuroendocrinology 63:188 - 197; Moertel, C.L., et al 1994 Am J Clin Path 102: 752 - 756), medullary thyroid cancer (Reubi, J.C., et al 1991 Lab Invest 64:567 - 573) small cell lung cancer (Sagman U, et al, 1990 Cancer 66:2129 - 2133), meningioma, medulloblastoma, or glioma (Reubi JC, et al 1986 J Clin Endocrinol Metab 63:433 - 8; Reubi JC, et al 1987 Cancer Res 47:5758 - 64; Fruhwald, M.C., et al 1999 Pediatr Res 45:697 - 708), breast cancer (Reubi JC, et al al 1990 Int J Cancer 46:416 - 20; Srkalovic G, et al 1990 J Clin Endocrinol Metab 70:661 - 669), lymphoma (Reubi JC, et al 1992, Int J Canc er50:895 - 900), renal cell carcinoma (Reubi JC, et al 1992, Cancer Res 52:6074 - 6078), mesenchymal Leaf tumors (Reubi JC, et al 1996 Cancer Res 56:1922-31), prostate (Reubi JC, et al 1995, J. Clin. Endocrinol Metab 80:2806-14; et al 1989, Prostate 14:191-208; Halmos G, et al J. Clin. Endo-crinol Metab 85:2564-71), ovary (Halmos, G, et a l, 2000 J Clin Endocrinol Metab 85:3509-12; Reubi JC, et al 1991 Am J Pathol 13 8:1267-72), stomach (Reubi JC, et al 1999, Int J Cancer 81: 376-86; Miller, G. V, 1992 Br J Cancer 66:391-95), hepatocytes (Kouroumalis E, et al 1998 Gut 42:442-7; Reubi JC, et al 1999 Gut 45:66-774) and nasopharyngeal cancer (Loh K. S, et al, 2002 Virch ows Arch 441:444-8; carbonic anhydrase IX (a marker for hypoxia and renal cell carcinoma) specific to a specific aromatic sulfonamide (Neri, D., et al, Nat. Rev. Drug Discov. 2011, 10, 767-777); pituitary adenylate cyclase activating peptide (PACAP) (PAC1) for pheochromocytoma and paraganglioma; vasoactive intestinal peptide (VIP / PACAP) and its receptor subtypes (VPAC1, VCAP2); α-melanocyte stimulating hormone ( α-MSH) receptor; cholecystokinin (CCK) / gastrin receptor and its receptor sub types (CCK1 (formerly CCK-A) and CCK2; bombesin (Pyr-Gln-Arg-Leu-Gl y-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) / Gastrin-releasing peptide (GRP)( BB1, GRP receptor subtype (BB2), BB3, and BB4) (Ohlsson, B., et al, 1999, Scand. J. Gastroenterology 34 (12): 1224-9; Weber, H. C., 2009, Cur. Opin. Endocri. Diab. Obesity 16(1): 66-71, Gonzalez N, et al, 2008, Cur. Opin. E ndocri. Diab. Obesity 15(1), 58-64); Neurotensin receptor and its receptor subtypes (NTR1, NTR2, NTR3); Substance P receptor and its receptor subtypes( NK1 receptor of glioma, etc.), Hennig I.M. et al, 1995 Int. J. Cancer 61, 786-792 ); Neuropeptide Y (NPY) receptor and its receptor subtypes (Y1-Y6); R GD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimers and multimeric cyclic RGD peptides( such as, cRGDfV) (Laakkonen P, Vuorinen K. 2010, Integr Biol (Camb). 2(7-8 ): 326-337; Chen K, Chen X. 2011, Theranostics. 1:189-200; Garanger E, et al, An ti-Cancer Agents Med Chem. 7 (5): 552-558; Kerr, J. S. et al, Anticancer Researc h, 19(2A), 959-968; Thumshirn, G, et al, 2003 Chem. Eur. J. 9, 2717- 2725), and along with TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteogly can NG2 receptor) and F3 peptide (a 31 amino acid peptide that binds to cell surface-expressed nucleolin receptor) (Zitzmann, S., 2002 Cancer Res., 62, 18, pp. 5139-5143, Temmi nga, K., 2005, Drug Resistance Updates, 8, 381-402; P. Laakkonen and K. Vuorine n, 2010 Integrative Biol, 2(7-8), 326-337; M. A. Burg, 1999 Cancer Res., 59(12), 2869-2874; K. Porkka, et al 2002, Proc. Nat. Acad. Sci. USA 99(11), 7444-9) homing peptides containing; cell-penetrating peptides (CPP) (Nakase I, et al, 2012, J. Control Release. 159(2),181-188); peptide hormones, such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the same way as testosterone production luteinizing hormone-releasing hormone (LHRH) agonists and antagonists that act by targeting, and gonadotropin-releasing hormone (GnRH) agonists, such as buserelin (Pyr-Hi s-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), gonadorelin (Pyr-His-Trp-Ser-Tyr- Gly-Leu-Arg-Pro-Gly-NH2), goserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-P ro-AzGly-NH2), histrelin (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NH Et), leuprorelin (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), nafarelin ( Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2), tryptorelin (Pyr-His-Trp-Ser- Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2), nafarelin, deslorelin, abarelix (Ac- D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro -DAla-NH2), cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Ty r-D-Cit-Leu-Arg-Pro-D-Ala-NH2), degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3- pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carba-moyl)-Leu-isopropyl Lys-Pro-D-Ala-NH2), and ganirelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl) Ala-Ser-Tyr-D-(N9, N10-diethyl)-homoArg-Leu-(N9, N10-diethyl)-homoArg-Pro-D-Ala- NH2)(Thundimadathil, J., J. Amino Acids, 2012, 967347, doi:10.1155 / 2012 / 96734 7; Boccon-Gibod, L.; et al, 2011, Therapeutic Advances in Urology 3 (3): 127-140 ; Debruyne, F., 2006, Future Oncology, 2(6), 677-696; Schally A. V; Nagy, A. 199 9 Eur J Endocrinol 141:1-14; Koppan M, et al 1999 Prostate 38:151-158); and for example, from small molecules (imiquimod, guanidine, and adenosine analogs), to lipopolysaccharide (LPS), nucleic acids (CpG DNA, poly I:C), and lipopeptides (Pam3CSK4) (Kasturi, S. P., et al, 2011, Nature 470, 543-547; Lane, T., 2001, J. R. Soc. Med. 94, 316; Hotz, C., and Bourquin, C., 2012, Oncoimmunology 1, 227-228; Dudek , A. Z., et al, 2007, Clin. Cancer Res. 13, 7119-7125) such as large and complex biological macromolecules, pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), C-type lectins, and Nod1 like receptors (NLRs) (Fukata, M., et al, 2009, Semin. Immunol. 21, 242-253; Maisonneuve, C., et al, 2014, Proc. Natl. Acad. Sci. U. S. A. 111, 1-6; Botos, I., et al, 2011, Structure 19, 447-459; Means, T. K., et al, 2000, Life Sci. 68, 241-258), etc. Calcitonin receptor, a 32-amino acid neuropeptide mainly involved in the regulation of calcium levels through its effects on osteoclasts and the kidney ​Body (Zaidi M, et al, 1990 Crit Rev Clin Lab Sci 28, 109-174; Gorn, AH, et al 1995 J Clin Invest 95:2680-91); Integrin receptors that generally play an important role in angiogenesis and their receptor subtypes (α V β1, α V β3, α V β5, α V β6, α6β4, α7β1, α L β2 、α IIb β3, etc.) are expressed on the surface of various cells, particularly osteoclasts, endothelial cells, and tumor cells (Ruoslahti, E. et al, 1994 Cell 77, 477-8; Albelda, SM et al, 1990 Cancer Res. 、50, 6757-64). Short-chain peptides, GRGDSPK, and cyclic (RGDfV) (L1), etc. Cyclic RGD pentapeptides and their derivatives [cyclo(-N(Me)R-GDfV), cyclo (R-Sar-DfV), cyclo(RG-N(Me)D-fV), cyclo(RGD-N( Me)fV), cyclo(RGDf-N(Me)V-)(cilengitide)] showed high binding affinity for integrin receptors (Dechantsreiter, MA et al, 1999 J. Med.Chem.42 、3033-40, Goodman S.L. et al,2002 J. Med.Chem.45, 1045-51).

[0129] Cell-binding molecules / ligands or cell receptor agonists can be Ig-based and non-Ig-based protein scaffold molecules. The Ig-based scaffold is not limited to, but is a derivative of nanobody (VHH (camelid Ig)) (Muyldermans S., 2013 Annu Re v Biochem. 82, 775-797); domain antibodies (dAb, derivatives of VH or VL domains)( Holt, L. J, et al, 2003, Trends Biotechnol. 21, 484-490); bispecific T cell en gagers (BiTE, bispecific dimers)(Baeuerle, P. A, et al, 2009, Curr. Opin. M ol. Ther. 11, 22-30); dual affinity retargeting (DART, bispecific dimers)(Moore P . A. P, et al. 2011, Blood 117(17), 4542-4551); tetravalent tandem antibodies (TandAb , bispecific dimers)(Cochlovius, B, et al. 2000, Cancer Res. 60(16):4336-4341) can be selected from. Non-Ig scaffolds include, but are not limited to, anticalin( derivatives of lipocalins)(Skerra A. 2008, FEBS J., 275(11): 2677-2683; Beste G, et al, 1999 Proc. Nat. Acad. USA. 96(5):1898-1903; Skerra, A. 2000 Biochim Biophys Acta, 1482(1-2):337-350; Skerra, A. 2007, Curr Opin Biotechnol. 18(4):295-304; Skerra, A. 2008, FEBS J. 275(11):2677-2683); adnectins (10th FN3 (fib ronectin))(Koide, A, et al, 1998 J. Mol. Biol., 284(4):1141-1151; Batori V, 2002, Protein Eng. 15(12): 1015-1020; Tolcher, A. W, 2011, Clin. Cancer Re s. 17(2):363-371; Hackel, B. J, 2010, Protein Eng. Des. Sel. 23(4):211-219); etc. Engineered ankyrin repeat proteins (DARPins) (derivatives of ankyrin repeat (AR ) proteins) (Boersma, Y.L, et al, 2011 Curr Opin Biotechnol. 22(6): 8 49-857), e.g., DARPinC9, DARPinEc4, and DARPinE69_ LZ3_E01 (Winkler J, et al, 2009 Mol Cancer Ther. 8(9), 2674-2683; Patrici a M-K. M., et al, Clin Cancer Res. 2011;17(1):100-110; Boersma Y. L, et al, 2011 J. Biol. Chem. 286(48),41273-41285); Avimer (domain A / low density lipoprotein (LDL) receptor) (Boersma Y. L, 2011 J. Biol. Chem. 286(48): 41273-41285; Silverman J, et al, 2005 Nat. Biotechnol., 23(12):1556-1561) can be selected from.

[0130] Examples of the structures of the small molecules of the cell-binding molecule / ligand or cell receptor agonist of the present application are as follows : LB01 (folic acid), LB02 (PMSA ligand), LB03 (PMSA li gand), LB04 (PMSA ligand), LB05 (somatostatin), LB06 (so matostatin), LB07 (octreotide, somatostatin analog), LB08 (lama reotide, somatostatin analog), LB09 (bapreotide (samba), somatostatin Chin analogs), LB10 (CAIX ligand), LB11 (CAIX ligand), LB1 2 (gastrin-releasing peptide receptor (GRPr), MBA), LB13 (luteinizing hormone releasing hormone (LH-RH) ligand and GnRH), LB14 (luteinizing hormone release hormone (LH-RH) and GnRH ligand), LB15 (GnRH antagonist , abarelix), LB16 (cobalamin, vitamin B12 analog), LB17 (coba lamin, vitamin B12 analog), LB18 (α v β3 integrin receptor for, cyclic RGD pentapeptide), LB19 (heterobivalent peptide ligand for VEGF receptor ), LB20 (neuromedin B), LB21 (bombesin for G protein-coupled receptor ), LB22 (TLR2 for toll-like receptor), LB23 (for androgen receptor ), LB24 (α v integrin receptor for cilengitide (Cilen gitide) / cyclo(-RGDfV-), LB23 (fludrocortisone), LB2 5 (rifabutin analog), LB26 (rifabutin analog), LB27 (rifabutin analog), LB28 (fludrocortisone), LB29 (dexamethasone), LB30 ( fluticasone propionate), LB31 (beclomethasone dipropionate), LB32 ( triamcinolone acetonide), LB33 (prednisone), LB34 (prednisolone ), LB35 (methylprednisolone), LB36 (betamethasone), LB37 (irin otecan analog), LB38 (crizotinib analog), LB39 (bortezomib analog) car filzomib analog), LB40 (carfilzomib analog), LB41 (carfil Zomib analogs), LB42 (Leuprolide analogs), LB43 (Triptorelin analogs ), LB44 (Clindamycin), LB45 (Lixisenatide analogs), LB46 (Sema Glucotide analogs), LB47 (Retapamulin analogs), LB48 (Indibulin analogs) , LB49 (Vinblastine analogs), LB50 (Lixisenatide analogs), LB51( Osimertinib analogs), LB52 (Nucleoside analogs), LB53 (Erlotinib analogs ), or LB54 (Lapatinib analogs); their structures are shown below.

Chemical formula

[0131] In the formula,

Chemical formula

[0132] Preparation of the conjugate

[0133] In another aspect of the present invention, the camptothecin analog is easily reactive with the cell-binding molecule T or the modified cell -binding molecule T to form conjugates of formulas (I), (II), (III), (IV), and (V) respectively, and is preferably synthesized to include a linker L and a reactive group Lv represented by formulas (VI), (VII), (VIII), (IX), and (X).

Chemical formula

[0134] Wherein, R1, R2, R3, R4, R5, L, X, and m have the same definition as in formula (I) above ;

[0135] Lv is a reactive group that can react with a thiol, amine, carboxylic acid, selenol, phenol, or hydroxyl group on the cell-binding molecule. The reactive group is, but not limited to, halides (e.g., fluoride, chloride, bromide, iodide), maleimide, methanes ulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethylsulfonyl( Triflate), trifluoromethylsulfonate, nitrophenoxy, N-succinyl imidazoloxy (NHS), phenoxyl; dinitrophenoxyl, pentafluoropheno noxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluoropheno xyl, monofluorophenoxyl, pentachlorophenoxyl, 1H-imidazole- 1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetra rachlorophenoxyl, N-(benzotriazol-yl)oxyl, 2-ethyl-5- phenylisoxazolium-3'-sulfonyl, phenyloxadiazole-sulfonyl (-sulfonate-ODA), oxadiazol-yl, unsaturated carbon (carbon-carbon, carbon -nitrogen, carbon-sulfur, carbon-phosphorus, sulfur-nitrogen, phosphorus-nitrogen, oxygen-nitrogen, or carbon-oxy gen double or triple bonds), or an intermediate molecule generated by a condensing reagent for the Mitsunobu reaction selected from; examples of said condensing reagent include EDC (N-(3-dimethylaminop ropyl)-N'-ethylcarbodiimide), DCC (dicyclohexyl-carbodiimide ), N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl-N'- (2-morpholinoethyl)carbodiimide meso-p-toluenesulfonate (CMC, or CME-CDI), 1,1'-carbonyldiimidazole (CDI), TBTU (O- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetra fluoroborate), N,N,N',N'-tetramethyl-O-(1H-benzotri zol-1-yl)uronium hexafluorophosphate (HBTU), (benzotri azol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophos Fert (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEP C), chloro-N,N,N’,N’-tetramethylformamidinium hexafluoro phosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo [4,5-b]pyridin-1-ium-3-oxide hexafluorophosphate (HD MA), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyCl oP), fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium he xafluorophosphate (BTFFH), N,N,N’,N’-tetramethyl-S-( 1-oxide-2-pyridyl)thiuronium hexafluorophosphate, O-(2-o xido-1(2H)pyridyl)-N,N,N’,N’-tetramethylthiuronium tetra fluoroborate (TPTU), S-(1-oxide-2-pyridyl)-N,N,N’,N ’-tetramethylthiuronium tetrafluoroborate, O-[(ethoxycarbonyl) cyanomethyleneamino]-N,N,N’,N’-tetramethyluronium hexafluoro phosphate (HOTU), (1-cyano-2-ethoxy-2-oxoethylideneamino oxy)dimethylamino-morpholino-carbene hexafluorophosphate (CO MU), O-(benzotriazol-1-yl)-N,N,N’,N’-bis(tetrame thylen)uronium hexafluorophosphate (HBPyU), N-benzyl-N’- cyclohexylcarbodiimide (with or without polymer bound), dipyrrolidino(N -succinimidyloxy)-carbenium hexafluorophosphate (HSPyU) , chlorodipyrrolidinocarbenium hexafluorophosphate (PyCIU), 2-ch loro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), (benzo (triazol-1-yloxy)dipiperidinocarbenium hexafluorophosphate (HBPipU), O-(6-chlorobenzotriazol-1-yl)-N,N,N’, N’-tetramethyluronium tetrafluoroborate (TCTU), bromotris(di methylamino)phosphonium hexafluorophosphate (BroP), propylphospho nic anhydride (PPACA, T3P®), 2-morpholinoethyl isocyanide( MEI), N,N,N’,N’-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), 2-bromo-1-ethyl-pyridinium te trafluoroborate (BEP), O-[(ethoxycarbonyl)cyanomethyleneamino -N,N,N’,N’-tetramethyluronium tetrafluoroborate (TOTU) , 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpho linium chloride (MMTM, DMTMM), N,N,N’,N’-tetramethyl-O- (N-succinimidyl)uronium tetrafluoroborate (TSTU), O-(3, 4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’ , N’-tetramethyluronium tetrafluoroborate (TDBTU), 1,1’-( (azodicarbonyl)dipiperidine (ADD), di-(4-chlorobenzyl)azodicarbo xylate (DCAD), di-tert-butyl azodicarboxylate (DBAD), diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD); furthermore, Lv may be an anhydride formed by the acid itself or by another C1-C8 anhydride;

[0136] More preferably, Lv is a halide (e.g., fluoride, chloride, bromide, iodide ), maleimide, methanesulfonyl (mesyl), toluenesulfonyl (tosyl), tri fluoromethylsulfonyl (triflate), trifluoromethylsulfonate, nitro phenoxyl, N-succinimidyldioxyl (NHS), phenoxyl; dinitro phenoxyl, pentafluorophenoxyl, tetrafluorophenoxyl, trifluoro phenoxyl, difluorophenoxyl, monofluorophenoxyl, pentachloropheno xyl, 1H-imidazol-1-yl, chlorophenoxyl, dichlorophenoxyl , trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-1 yl)oxyl, 2-ethyl-5-phenylisoxazolium-3’-sulfonyl, pheny loxadiazole-sulfonyl (-sulfonate-ODA), oxadiazol-yl , an unsaturated carbon (double or triple bond between carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphorus, sulfur-nitrogen, phosphorus- nitrogen, oxygen-nitrogen, or carbon-oxygen), or selected from one of the following structures;

Chemical formula

[0137] In the formula, X1’ is F, Cl, Br, I, or Lv3; X2’ is O, NH, N( R1), or CH2; R3 is H, an aromatic group, a heteroaromatic group, or an aromatic group in which one or several H atoms are independently substituted with -R1, -halogen, -OR1, -SR1, -NR1R2, - NO2, -S(O)R1, -S(O)2R1, or -COOR1, where R1 and R2 are as defined above; Lv3 is F, Cl, Br, I , nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitro phenol; pentafluorophenol; tetrafluorophenol; difluoropheno l; monofluorophenol; pentachlorophenol; triflate; imidazole ; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfone ate, an anhydride formed by itself or formed together with another anhydride, such as acetic anhydride or formic anhydride ; or an intermediate molecule generated by a condensing reagent for the Mitsunobu reaction from which is selected as the leaving group.

[0138] In the conjugation process, prior to conjugation with the camptothecin analog of the present invention, the cell-binding molecule is conjugated to a more specific peptide, protein, or drug, or other functional molecule, for example, amine-nonselective (succinimidyl (NHS)-diazirin (SDA), NHS ester L / azide), amine-sulfhydryl (NHS ester / maleimide, NHS ester / pyridyldithiol, NHS ester / haloacetyl), sulfhydryl-carbohydrate( maleimide / hydrazide, pyridyldithiol / hydrazide), hydroxyl-sulfhydryl (isocyanate / maleimide), amine-DNA (NHS ester / psoralen ), amine-carboxyl (carbodiimide) conjugates, etc., heterobifunctional crosslinkers can be attached and modified.

[0139] In SDA bond modification, in a buffer solution with pH 6 - 9, the NHS ester of the SDA conjugate reacts with the primary amine of the binding molecular backbone, and a stable amide bond is formed with the elimination of NHS. Next, when diazirine is photoactivated with long - wavelength ultraviolet light (330 - 370 nm), it can react with the amine groups of more specific peptides, proteins, or other functional molecules to generate a reactive carbene intermediate. The order of these two steps, where the amine group of the functional molecule first reacts with the SDA conjugate and then the binding molecule undergoes a photoactive reaction with long - wavelength ultraviolet light (330 - 370 nm), can be changed. The SDA conjugate can be cleavable (such as an SDA - D conjugate that has an internal disulfide bond).

[0140]

Chemical formula

[0141] In NHS ester / azide bond modification, in a buffer solution with pH 6 - 9, the NHS ester of the conjugate reacts with the primary amine of the binding molecular backbone to form a stable amide. Next, more specific ​​​​​​An alkynyl group on a peptide, protein, or other functional molecule reacts with an azide on the opposite side of the linker via an azide-alkynyl Huisgen cycloaddition reaction to form a 1,2,3-triazole bond (click chemistry). Also, in a buffer solution with a pH of 6 to 9, the NHS ester of the linker reacts with the primary amine of the functional molecule to form a stable amide. Thus, the alkynyl group linked to the binding molecule reacts with the azide on the opposite side of the linker via a 5-azido-alkyl Huisgen cycloaddition reaction to form a 1,2,3-triazole bond.

[0142]

Chemical formula

[0143] In amine-sulfhydryl bond modification, in a buffer solution with a pH of 6 to 9, the NHS ester of the linker reacts with the primary amine of the binding molecule skeleton to form a stable amide bond. Next, at a pH of 4.5 to 8.5, the sulfhydryl of a more specific peptide, protein, or other functional molecule reacts with maleimide, pyridyldithiol, or haloacetyl on the opposite side of the amine-sulfhydryl linker to form a thioether or disulfide bond. Conjugation with the amine-sulfhydryl linker can be carried out in a different order. For example, first, the amine group of the functional molecule can be reacted with the linker to form an amide bond, and then it can be reacted with the sulfhydryl group on the binding molecule. Also, first, the sulfhydryl group of the functional molecule can be reacted with the linker at a pH of 4.5 to 7 to form a thioether bond or a disulfide bond, and then it can be reacted with the amine group on the binding molecule at a pH of 6 to 9 to form an amide bond. ​​​​​​​​​​​​​​​

[0144] [Chemical formula]

[0145] In the sulfhydryl-carbohydrate bond modification, first, at pH 4.5 to 8, the sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, the carbonyl (aldehyde / ketone) group of the functional molecule and hydrazide are reacted to form a hydrazone bond. Also, first, at pH 4.5 to 8, the sulfhydryl group on the functional molecule is reacted with the linker to form a thioether or disulfide bond, and then, by reacting with the carbonyl (aldehyde / ketone) group on the carbohydrate, oxidized carbohydrate, or binding molecule, a hydrazone bond can be formed. The sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, the carbonyl (aldehyde / ketone) group of the functional molecule and hydrazide are reacted to form a hydrazone bond. In the sulfhydryl-carbohydrate bond modification, first, at pH 4.5 to 8, the sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, the carbonyl (aldehyde / ketone) group of the functional molecule and hydrazide are reacted to form a hydrazone bond. Also, first, at pH 4.5 to 8, the sulfhydryl group on the functional molecule is reacted with the linker to form a thioether or disulfide bond, and then, by reacting with the carbonyl (aldehyde / ketone) group on the carbohydrate, oxidized carbohydrate, or binding molecule, a hydrazone bond can be formed. ton) group and hydrazide are reacted to form a hydrazone bond. Also, first, at pH 4 .5 to 8, the sulfhydryl group on the functional molecule is reacted with the linker to form a thioether or disulfide bond, and then, by reacting with the carbonyl (aldehyde / ketone) group on the carbohydrate, oxidized carbohydrate, or binding molecule, a hydrazone bond can be formed. The sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, the carbonyl (aldehyde / ketone) group of the functional molecule and hydrazide are reacted to form a hydrazone bond. This can be achieved.

[0146] [Chemical formula]

[0147] In the hydroxyl-sulfhydryl bond modification, first, at pH 6 to 8, the sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the functional molecule and the isocyanate on the linker are reacted to form a carbamate bond. Also, first, at pH 6 to 8, the sulfhydryl group on the functional molecule is reacted with the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the binding molecule is reacted with the linker. The sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the functional molecule and the isocyanate on the linker are reacted to form a carbamate bond. In the hydroxyl-sulfhydryl bond modification, first, at pH 6 to 8, the sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the functional molecule and the isocyanate on the linker are reacted to form a carbamate bond. The sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the functional molecule and the isocyanate on the linker are reacted to form a carbamate bond. In the hydroxyl-sulfhydryl bond modification, first, at pH 6 to 8, the sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the functional molecule and the isocyanate on the linker are reacted to form a carbamate bond. The sulfhydryl group of the binding molecule is reacted with maleimide or pyridyldithiol on the linker to form a thioether or disulfide bond, and then, at pH 8 to 9, the hydroxyl group on the binding molecule is reacted with the linker. It can also be made to form a carbamate bond.

[0148] [Chemical formula]

[0149] The production of the antibodies used in the present invention includes in vivo or in vitro production processes or combinations thereof. Method for preparing anti-receptor peptide polyclonal antibodies is well known, for example, as shown in U.S. Patent No. 4,493,795 (Nestor et al.). A typical method for preparing monoclonal antibodies is a method of fusing mouse spleen cells isolated from a mouse immunized with a specific antigen with myeloma cells (Kohler , G; Milstein, C. 1975. Nature 256:495 - 497). Regarding the detailed operation method, it is described in antibodies - A Laboratory Manual, Harlow and Lane, eds., cold spring harbor laboratory press, new York (1988), and the content of this document is incorporated herein by reference as part of this specification. In particular, monoclonal antibodies can be obtained by immunizing mice, rats, hamsters, or other mammals with the target antigen, and examples of the target antigen include intact target cells, antigens isolated from target cells, whole viruses, attenuated whole viruses, and virus stamp proteins. PEG6000 is used to fuse spleen cells and myeloma cells. For the hybridomas obtained after fusion, HAT (hypoxanthine - aminopterin - thymine idine) is used. It is described in r laboratory press, new York (1988), and the content of this document is incorporated herein by reference as part of this specification. In particular, monoclonal antibodies can be obtained by immunizing mice, rats, hamsters, or other mammals with the target antigen, and examples of the target antigen include intact target cells, antigens isolated from target cells, whole viruses, attenuated whole viruses, and virus stamp proteins. PEG6000 is used to fuse spleen cells and myeloma cells. For the hybridomas obtained after fusion, HAT (hypoxanthine - aminopterin - thymine idine) is used. can be used, and examples of the target antigen include intact target cells, antigens isolated from target cells, whole viruses, attenuated whole viruses, and virus stamp proteins. PEG6000 is used to fuse spleen cells and myeloma cells. For the hybridomas obtained after fusion, HAT (hypoxanthine - aminopterin - thymine idine) Screening is carried out by utilizing the sensitivity to (the relevant substance). Monoclonal antibodies useful for the implementation of the present invention Hybridomas that produce are identified by performing an immune reaction with a specific target cell receptor or suppressing receptor activity .

[0150] The monoclonal antibodies used in the present invention can be obtained by starting the culture of monoclonal hybridoma cells in a nutrient medium containing hybridoma cells that secrete antibodies having appropriate antigen specificity . In this culture, it is necessary to maintain conditions and time sufficient for the hybridoma cells to secrete antibodies into the culture medium. After collecting the antibody-containing culture supernatant , the antibodies can be isolated by well-known techniques such as protein A affinity chromatography; anion exchange chromatography, cation exchange chromatography, hydrophobic interaction chromatography , and molecular sieve chromatography (in particular, affinity chromatography and molecular sieve chromatography using antigen-crosslinked protein A); centrifugation, precipitation methods, or other standard methods for purifying proteins . Chromatography, and molecular sieve chromatography); centrifugation, precipitation methods, or other standard methods for purifying proteins . Chromatography and molecular sieve chromatography); centrifugation, precipitation methods, or other standard methods for purifying proteins .

[0151] Media useful for the preparation of these compositions are well-known in the art and commercially available , and include synthetic media. An exemplary synthetic medium is Dulbecco's Minimum Essential Medium (D MEM; Dulbecco et al., Virol. 8:396 (1959)) supplemented with 4.5 g / L glucose, 20 mM glutamine, 20% fetal bovine serum, and an antifoaming agent (e.g., , polyoxyethylene-polyoxypropylene block copolymer).

[0152] Furthermore, antibody-producing cell lines can be obtained by direct transformation of B lymphocytes with oncogenic DNA ​​- sion, or oncogenic viruses, such as Epstein - Barr virus (EBV, human herpesvirus 4 (HHV - 4) also known as), or Kaposi's sarcoma - related virus (KSHV) can also be produced by techniques other than cell fusion techniques, such as transfection (see U.S. Patent Nos. 4,341,761; 4,399,121; 4,427,783 ; 4,444,887; 4,451,570; 4,466,917; 4,472,500 ; 4,491,632; 4,493,890). Monoclonal antibodies can be prepared by known methods based on anti - receptor peptides or peptides containing a terminal carboxyl group (see in detail Niman et al. Proc. Natl. Acad. Sci. US A, 80:4949 - 4953 (1983); Geysen et al. Proc. Natl. Ac ad. Sci. USA, 82:178 - 182 (1985); Lei et al. Biochem istry 34(20):6675 - 6688 (1995)). Usually, anti - receptor poly peptides or polypeptide analogs can be used alone or conjugated to a cross - linked immunogenic carrier as an immunogen for preparing the anti - receptor polypeptide of a monoclonal antibody.

[0153] There are also many other well - known production methods for producing monoclonal antibodies as the binding molecules of the present invention. Among them, the method for producing fully human antibodies is particularly noteworthy. Phage display technology can obtain fully human antibodies that specifically bind to known antigens from a fully human antibody library by affinity selection. There are detailed descriptions in the literature about phage display technology itself, the construction of vectors, and the screening of libraries. In detail ​ See Dente et al., Gene 148(1):7-13 (1994); Little et al. Biotechnol Adv. 12(3):539-55 (1994); Clacks on et al., Nature 352:264-628 (1991); Huse et al., Scien ce 246:1275-1281 (1989).

[0154] Monoclonal antibodies obtained from species other than humans (e.g., mice) using hybridoma technology can be humanized to avoid human anti-mouse antibodies when administered to humans. Among them, well-known methods for humanizing antibodies are transplantation and remodeling of complementarity-determining regions. For details, see U.S. Patent Nos. 5,859,205 and 6 ,797,492; Liu et al., Immunol Rev. 222:9-27 (2008 ); Almagro et al., Front Biosci. 1;13:1619-33 (200 8); Lazar et al., Mol Immunol. 44(8):1986-98 (2007 ); Li et al., Proc. Natl. Acad. Sci. USA. 103(10):355 7-62 (2006). The disclosures of the above documents are incorporated by reference. Fully human antibodies can be prepared by immunizing transgenic mice, goats, monkeys and other mammals that possess most of the human immunoglobulin light and heavy chains with an antigen. Examples of such mice include Xenomouse (Abgenix, Inc.), HuM ab-Mouse (Medarex / BMS), VelociMouse (Regene ron). For details, see U.S. Patent Nos. 6,596,541, 6,207,418, U.S. Patent Nos. 6,150,584, 6,111,166, 6,075,181, 5,922,5 45, 5,661,016, 5,545,806, 5,436,149, and 5 569,825 are incorporated by reference. During the course of human treatment, the immunogenicity produced in the human body by chimeric antibodies constructed by integrating mouse antibody variable region genes and human antibody constant region genes is much lower than that of mouse antibodies (Kipriyanov et al., Mol Biotechnol nol. 26:39 - 60 (2004); Houdebine, Curr Opin B iotechnol. 13:625 - 9 (2002)). The disclosures of the above - mentioned documents are incorporated by reference. Furthermore, by site - specific mutagenesis of the antibody variable region, the antibody affinity and specificity can be improved (Brannigan et al., Nat Rev M ol Cell Biol. 3:964 - 70 (2002); Adams et al., J.Imm unol Methods. 231:249 - 60 (1999)). By partially replacing the constant region of the antibody and effectively promoting the affinity with immune effector cells, the cytotoxic effect can be enhanced. Immunologically specific antibodies against malignant cell antigens can be obtained by commercial routes or several common technical methods, such as chemical synthesis or recombinant expression techniques. Similarly, nucleotide sequences encoding immunologically specific antibodies against malignant cell antigens can be obtained from commercial routes such as the GenBank database or other similar databases, known literature, or routine cloning and

[0155] sequencing. In addition to antibodies, polypeptides or proteins can also be used as binding molecules to target cell surface antigens. Similar to antibodies, polypeptides or proteins can also be used as binding molecules to target cell surface antigens.

[0156] antigens. bind to the corresponding receptor or epitope, block, attack or otherwise interact with it. As long as these peptides or proteins can specifically bind to the epitope or its corresponding receptor, they do not necessarily belong to the immunoglobulin family. These polypeptides can also be isolated by techniques similar to those for phage display antibodies (Szardenings, J Recept Signal Transduct Res. 2003;23(4):307-49). Peptide fragments obtained from random peptide libraries are similar in application to antibodies and antibody fragments. A polypeptide or protein molecule maintains its antigen-binding specificity by connecting to several macromolecules or media through a binding molecule. These macromolecules include, but are not limited to,

[0157] albumin, polymers, liposomes, nanoparticles, or dendrimers. Antibodies used in conjugates of the camptothecin analogs of the present invention for treating cancer, autoimmune diseases, and / or infectious diseases include, but are not limited to, for example: 3F8 (anti-GD2 antibody), abagovomab (anti-CA-125 antibody), abciximab (anti-CD41 antibody (integrin α-IIb)), adalimumab (anti-TNF-α antibody), adecatumumab (anti-EpCAM antibody, CD326), afelimomab (anti-TNF-α); afutuzumab (anti-CD20 antibody), alacizumab pegol (anti-VEGF R2 antibody), ALD518 (anti-IL-6 antibody), alemtuzumab ag-72 antibody), anrukinzumab (IMA-638, anti-IL-13 antibody), apolizumab (anti-HLA-DR antibody), arcitumomab (anti-CEA antibody), aselizumab (anti-L -selectin (CD62L) antibody), atorizumab (Atlizumab) (alias: tocilizumab , Actemra, RoActemra, anti-IL-6 receptor antibody), atorolimumab (Atorolimum ab) (anti-rhesus factor antibody), bapineuzumab (anti-β-amyloid antibody), basiliximab (Simulect, anti-CD25 (IL-2 receptor α chain) antibody), bavituximab (Bavitu ximab) (anti-phosphatidylserine antibody), bectumomab (Bectumomab) (alias: LymphoS can, anti-CD22 antibody), belimumab (alias: BENLYSTA, LymphoStat-B, anti-BAFF antibody ), benralizumab (anti-CD125 antibody), beltilimumab (anti-CCL 11 (eotaxin-1) antibody), besilesomab (alias: Scintimun, anti-CEA-related antigen antibody), bevacizumab (alias: Avastin, anti-VEGF antibody), bisiromab (alias: Fibr iScint, anti-fibrin IIβ chain antibody), bivatuzumab (anti-CD44v6 antibody), blinatumomab (blinatumomab) (alias: BiTE, anti-CD19 antibody), brentuximab (Bren tuximab) (cAC10, anti-CD30 TNFRSF8 antibody), briakinumab (Briakin umab) (anti-IL-12, IL-23 antibody), canakinumab (alias: Ilaris, anti-IL -1 antibody), canzumab (alias: C242, anti-CanAg antibody), capromab (Caprom ab), catumaxomab (alias: removab, anti-EpCAM, anti-CD3 antibody), CC49 (anti TAG-72 antibody), Cedelizumab (anti-CD4 antibody), Certolizumab Pegol (also known as CIMZIA, anti-TNF-α antibody), Cetuximab (also known as Erbitux, IM C-C225, anti-EGFR antibody), Sitaxizumab (anti-EpCAM antibody), Cixutumumab (anti-IGF-1 antibody), Clenoliximab (anti-CD4 antibody), Clivatuzumab (anti-MUC1 antibody), Conatumumab (anti-TRA IL-R2 antibody), CR6261 (anti-influenza A hemagglutinin antibody), Dacetuzumab (anti-CD40 antibody), Daclizumab (also known as Zenapax, anti-CD25C (α-chain of IL-2 receptor) antibody), Daratumumab (anti-CD38 (cyclic ADP ribose hydrolase) antibody), Denosumab (also known as Prolia, anti-RANKL antibody), Detumomab (anti-B-lymphocyte antibody), Dolimumab, Dorlizumab (Dorlizumab), Ecromeximab (anti-GD3 ganglioside antibody), Eculizumab (also known as Soliris, anti-C5 antibody), Edobacomab (anti-endotoxin antibody), E drecolomab (also known as Panorex, MAb17-A1, anti-EpCAM antibody), Efalizumab (also known as Raptiva, anti-LFA-1 (CD11a) antibody), Efungumab (also known as Mycograb, anti-Hsp90 antibody), Elotuzumab (anti-SLAMF7 antibody), Elsilmomab (anti-IL-6 antibody), Enlimomab Pegol (anti ICAM-1 (CD54) antibody), Epitumomab (anti-epithin antibody) , epratuzumab (anti-CD22 antibody), erlizumab (anti-ITGB2 (C D18) antibody), ertumaxomab (alias: Rexomun, anti-HER2 / ne u, CD3 antibody), etaracizumab (alias: Abegrin, anti-integrin αvβ3), eck sibuvirumab (anti-hepatitis B surface antigen antibody (HBs antibody)), fanolesomab (Fanolesoma b) (alias: NeutroSpec, anti-CD15 antibody), faralimomab antibody (faralimomab) (anti-in terferon receptor antibody), farletuzumab (Farletuzumab) (anti-folate receptor 1 antibody ), felvizumab (antibody against RS virus), fezakinumab (Fe zakinumab) (anti-IL-22 antibody), figitumumab (Figitumumab) (anti-IGF-1 receptor antibody), fontolizumab (anti-IFN-γ antibody), foravirumab (Forav irumab) (antibody against rabies virus glycoprotein), fresolimumab (Fresolimumab) (anti-T GF-β antibody), galiximab (anti-CD80 antibody), gantenerumab (Ganten erumab) (anti-β-amyloid antibody), gavilimomab (Gavilimomab) (anti-CD147 (basigin ) antibody), gemtuzumab (anti-CD33 antibody), girentuximab (anti-carbon ic anhydrase 9 antibody), glembatumumab (alias: CR011, anti-GPNMB antibody), golimumab (alias: Simponi, anti-TNF-α antibody), gomiliximab (Gomilixim ab) (anti-CD23C (IgE receptor) antibody), ibalizumab (Ibalizumab) (anti-CD 4 antibody), Ibritumomab (anti-CD20 antibody), Igovomab )(also known as Indimacis-125, anti-CA-125 antibody), Imciromab (also known as Myoscint, anti-myocardial myosin antibody), Infliximab (also known as Remicade, anti-TNF-α antibody ), Intetumumab (anti-CD51 antibody), Inolimomab (anti-CD25 (IL-2 receptor α chain) antibody), Inotuzumab (anti-CD22 antibody ), Ipilimumab (anti-CD152 antibody), Iratumumab (anti-CD30 (T NFRSF8) antibody), Keliximab (anti-CD4 antibody), Labelizumab (also known as CEA-Cide, anti-CEA antibody), Lebrikizumab (anti-IL-13 antibody ), Lemalesomab (anti-NCA-90 (granulocyte antigen) antibody), Lerdelimumab (anti-TGFβ-2 antibody), Lexatumumab (anti-T RAIL-R2 antibody), Libivirumab (anti-hepatitis B surface antigen antibody), Lintuzumab (anti-CD33 antibody), Lucatumumab (anti-CD 40 antibody), Lumiliximab (anti-CD23 (IgE receptor) antibody ), Mapatumumab (anti-TRAIL-R1 antibody), Maslimomab (anti-T cell receptor antibody ), Matuzumab (anti-EGFR antibody), Mepolizumab (also known as Bosat ria, anti-IL-5 antibody), Metelimumab (anti-TGFβ-1 antibody), Miratumumab Milatuzumab (anti-CD74 antibody), Minretumomab (anti-TA G-72 antibody), Mitumomab (alias: BEC-2, anti-ganglioside antibody -GD3), Morolimumab (anti-monkey factor antibody), Motavizumab (Mo alias: Numax, anti-RSV antibody), Muromonab-CD3( alias: Orthoclone OKT3, anti-CD3 antibody), Nacolomab (anti-C242 antibody) 、Naptumomab (anti-5T4 antibody), Natalizumab (alias: Tysabri, anti-integrin α4 antibody), Nebacumab (anti-endotoxin antibody), Necitumumab (anti-EGFR antibody), Nerelimomab (anti-TNF-α antibody), Nimotuzumab (alias: Theracim, Theraloc, anti-EGFR antibody), Nofetumomab (Nofetumomab), Ofatumumab (anti-CD20 antibody), Odelimumab (alias: Afolimo mab, anti-LFA-1 (CD11a) antibody), Ofatumumab (alias: Arzerra, anti-CD20 antibody), Olaratumab (anti-PDGF-Rα antibody), Omalizumab (Omaliz umuba)(alias: Xolair, anti-IgE Fc region antibody), Oportuzumab ( anti-EpCAM antibody), Oregovomab (alias: OvaRex, anti-CA-125 antibody ), Otelixizumab (anti-CD3 antibody), Pagibaximab (Pagibaxima b)(anti-LTA antibody), Palivizumab (alias: Synagis, Abbosynagis, anti-RSV antibody body), panitumumab (alias: Vectibix, ABX-EGF, anti-EGFR antibody), panobacumab (Panobacumab) (anti-Pseudomonas aeruginosa antibody), pascolizumab (anti-IL-4 anti body), pemtumomab (alias: Theragyn, anti-MUC1 antibody), pertuzumab (alias: Omnitarg, 2C4, anti-HER2 / neu antibody), pexelizumab (anti-C5 antibody), pintumomab (anti-adenocarcinoma antigen antibody), priliximab ( Priliximab) (anti-CD4 antibody), pritumumab (anti-vimentin antibody), P RO140 (anti-CCR5 antibody), racotumomab (alias: 1E10, anti( N-glycolylneuraminic acid (NeuGc, NGNA)-ganglioside (GM3) antibody ), rafivirumab (anti-rabies virus glycoprotein antibody), ramucirumab (Ramucirumab) (anti-VEGFR2 antibody), ranibizumab (alias: Lucentis, anti-VEGF- A antibody), raxibacumab (anti-anthrax toxin, protective antigen antibody), regavir umab (anti-CMV glycoprotein B antibody), reslizumab ( anti-IL-5 antibody), rilotumumab (anti-HGF antibody), rituximab (alias : MabThera, Rituxanmab, anti-CD20 antibody), robatumumab (anti-IG F-1 receptor antibody), rontalizumab (anti-IFN-α antibody), rovelizumab (alias: LeukArrest, anti-CD11, CD18 antibody), ruprizumab (Ruplizumab) (alias: Antova, anti-CD154 (CD40L) antibody), Satsumomab (anti-TAG-72 antibody), Sevirumab (anti-CMV antibody), Sibrotuzumab (anti-FAP antibody), Sifalimumab (anti-IFN-α antibody), Siltuximab (anti-IL-6 antibody), Cipilizumab (anti-CD2 antibody), (Smart) MI95 (anti-CD33 antibody), Solanezumab (anti-β-amyloid antibody), Sonepcizumab (anti-sphingosine-1-phosphate antibody), Sontuzumab (anti-epicerin antibody), Stamulumab (anti-myostatin antibody), Sulesomab (alias: LeukoScan, (anti-NCA-90 (granulocyte antigen) antibody))), Tacatuzumab (anti-α-fetoprotein antibody), Tadocizumab (anti-integrin αIIbβ3 antibody), Talizumab (anti-IgE antibody), Tanezumab (anti-NGF antibody), Taplitumomab (anti-CD19 antibody), Tefibazumab (alias: Aurexis, anti-clumping factor A antibody), Telimomab, Tenatumomab (anti-tenascin C antibody), Teneliximab (anti-CD40 antibody), Teplizumab (anti-CD3 antibody), TGN1412 (anti-CD28 antibody), Tisilimumab (alias: Tremelimumab, anti-CTLA-4 antibody), Tigatuzumab (anti-TRAIL- antibody), R2 antibody), TNX-650 (anti-IL-13 antibody), tocilizumab (also known as Atlizumab, Act emra, RoActemra, (anti-IL-6 receptor antibody), toralizumab (anti-CD1 54 (CD40L) antibody), tositumomab (anti-CD20 antibody), trastuzumab (also known as: Herceptin, anti-HER2 / neu antibody), tremelimumab (anti-CTLA -4 antibody), tucotuzumab celmoleukin (anti-EpCAM antibody), tuvirumab (anti-hepatitis B antibody), urtoxazumab ( anti-E. coli antibody), ustekinumab ( also known as: Stelara, anti-IL-12, IL-23 antibody), vapaliximab (anti-A OC3 (VAP-1) antibody), vedolizumab, (anti-integrin α4β 7 antibody), belimumab (anti-CD20 antibody), vepalimomab (anti-AOC 3 (VAP-1)) antibody), bisirilizumab (also known as Nuvion, anti-CD3 antibody), vitaxin (anti-angiogenic integrin avb3 antibody), volociximab (anti-inte grin α5β1), votumumab (also known as HumaSPECT, anti-tumor antigen CTAA1 6.88 antibody), zalutumumab (also known as HuMax-EGFr, (anti-EGFR antibody), zanolimumab (also known as HuMax-CD4, anti-CD4 antibody), ziralimumab (anti-CD147 (basic immunoglobulin) antibody), zolimomab (anti-CD5 antibody), etanercept (anti-CD5 antibody), etanercept (Registered Trademark "Enbrel"), alefacept (Alefacept) (Registered Trademark "Amevive"), abatacept (Registered Trademark "Orencia"), rilonacept (Rilonacept) (Arcalyst), 14F 7[Anti-IRP-2 (Iron Regulatory Protein 2) Antibody], 14G2a (Anti-Ganglioside GD2 Antibody for Melanoma and Solid Tumors from Nat. Cancer Inst.), J591 (Anti-PSMA Antibody for Treating Prostate Cancer from Weill Cornell Medical School), 225.28S[Anti-HMW-MAA (High Molecular Weight Melanoma-Associated Antigen) Antibody for Melanoma, Sorin Radiofarmaci S.R.L. (Milan, Italy)] COL-1 (Anti-CEACAM3 Antibody for Colorectal and Gastric Cancers from Nat. Cancer Inst., CGM1), CYT-356 (Registered Trademark "Oncoltad", Prostate Cancer), HNK20 (For RS Virus from Ora Vax Inc.), ImmuRAIT (For Non-Hodgkin Lymphoma from IM MUNOMEDICS), Lym-1 (Anti-HLA-DR10 Antibody, from Peregrine Pharm for Tumors) MAK-195F [Anti-TNF (Tumor Necrosis Factor; TNFA, TNF-α; TNFSF2) Antibody for Sepsis, Toxic Shock from Abbott / Knoll] MEDI-500 [Also Known As: T10B9, Anti-CD3 Antibody for Graft-versus-Host Disease from MedImmune Inc, TRαβ (T Cell Receptor α / β)] RING SCAN [Anti-TAG72 (Tumor-Associated Glycoprotein 72) Antibody for Breast Cancer, Colorectal Cancer, and Colorectal Cancer from Neoprobe Corp.] Avicidin (Anti-EPCAM (Epithelial Cell Adhesion Molecule) Antibody), Anti-TACSTD1 (Tumor-Associated Calcium Signal Transducer 1) Antibody, Anti-GA733-2 (Gastrointestinal Tumor) ​​​​​​​​​​ Antibodies against tumor-related protein 2), anti-EGP-2 (epithelial glycoprotein 2) antibody; anti-KSA antibody; KS1 / 4 antigen; M4S; tumor antigen 17-1A; CD326 for colon cancer, ovarian cancer, prostate cancer, and non-Hodgkin lymphoma from NeoRx Corp.; LYMPHOCIDE (IMMUNOMEDI CS, NJ), Smart ID10 (Protein Design Labs), Oncolym (Techniclone Inc, CA), Allomune (BioTransplant, CA), anti-VEGF antibody (Genentech, CA) ; CEAcide (Immunomedics, NJ), IMC-1C11 (ImClone Systems, NJ ), and cetuximab (ImClone, NJ).

[0158] Other antibodies as binding ligands include, but are not limited to, antibodies against the following antigens: aminopeptidase N (CD13), annexin A1, B7-H3 (CD27 6, various cancers), CA125 (ovary), CA15-3 (cancer), CA19-9 (cancer), L6 (cancer), Lewis Y (cancer), Lewis X (cancer), alpha-fetoprotein (cancer), CA242 (colorectal), placental alkaline phosphatase (cancer), prostate-specific antigen (prostate gland), prostate acid phosphatase (prostate gland), epidermal growth factor (cancer), CD2 (Hodgkin disease, NHL lymphoma, multiple myeloma), CD3ε (T cell lymphoma, lung cancer, breast cancer, gastric cancer, ovarian cancer, autoimmune disease, malignant ascites), CD19 (B cell malignancy), CD20 (non-Hodgkin lymphoma), CD22 (leukemia, lymphoma, multiple myeloma, systemic lupus erythematosus) , CD30 (Hodgkin lymphoma), CD33 (leukemia, autoimmune disease), CD38 (multiple myeloma), etc. Multiple myeloma), CD40 (lymphoma, multiple myeloma, leukemia (CLL)), CD51 (metastatic melanoma, sarcoma), CD52 (leukemia), CD56 (small cell lung cancer, ovarian cancer, Merkel cell carcinoma and liquid tumors, multiple myeloma), CD66e (cancer), CD70 (metastatic renal cell carcinoma and non- Hodgkin lymphoma), CD74 (multiple myeloma), CD80 (lymphoma), CD98 (cancer ), mucin (carcinoma), CD221 (solid tumor), CD227 (breast cancer, ovarian cancer), CD26 2 (non-small cell lung cancer and other cancers), CD309 (ovarian cancer), CD326 (solid tumor), CE ACAM3 (colorectal cancer, gastric cancer), CEACAM5 (carcinoembryonic antigen; CEA, CD66e )(breast cancer, colorectal cancer and lung cancer), DLL4 (Δ-like-4), EGFR (epidermal growth factor receptor, various cancers), CTLA4 (melanoma), CXCR4 (CD184, hemangioma, solid tumor), endoglin (CD105, solid tumor), EPCAM (epithelial cell adhesion molecule, bladder, head, neck, colon cancer, NHL prostate cancer, and ovarian cancer), ERBB2 (epidermal growth factor receptor 2; lung cancer, breast cancer, prostate cancer), FCGR1 (autoimmune disease), FOLR (folate receptor body, ovarian cancer), GD2 ganglioside (cancer), G-28G (cell surface antigen glycolipid, melanoma ), GD3 idiotype (cancer), heat shock protein (cancer), HER1 (lung cancer, gastric cancer ), HER2 (breast cancer, lung cancer and ovarian cancer), HLA-DR10 (NHL), HLA-DRB (NHL, B cell leukemia), human chorionic gonadotropin (carcinoma), IGF1R (insuli n-like growth factor-1 receptor, solid tumor, blood cancer), IL-2 receptor (interleukin-2 receptor, T cell leukemia and lymphoma), IL-6R (interleukin 6 receptor, multiple myeloma, RA, Castleman disease, IL6-dependent tumors), integrin (for various cancers αVβ3, α5β1, α6β4, αIIβ3, α5β5, αVβ5), MAGE-1( cancer), MAGE-2 (cancer), MAGE-3 (cancer), MAGE-4 (cancer), anti-transferrin receptor (cancer), p97 (melanoma), MS4A1 (membrane-spanning 4-domain family A member 1, non-Hodgkin B-cell lymphoma, leukemia), MUC1 or MUC1-K LH (breast cancer, ovarian cancer, cervical cancer, bronchial and gastrointestinal cancer), MUC16 (CA125) (ovarian cancer), CEA (colon), gp100 (melanoma), MART1 (melanoma), MPG (melanoma ), MS4A1 (membrane-spanning 4-domain family A member 1, small cell lung cancer, NHL), nucleolin, neuro-oncogene product (cancer), P21 (cancer), anti-(N-glycolylneuraminic acid paratope) (breast cancer, melanoma cancer), PLAP-like testicular alkaline phosphatase (ovarian cancer, testicular cancer), PSMA (prostate cancer), PSA (prostate), ROBO4, TAG72( tumor-associated glycoprotein 72, leukemia (AML), gastric cancer, colorectal cancer, ovarian cancer), T-cell membrane-spanning protein (cancer), Tie (CD202b), TNFRSF10B (tumor necrosis receptor superfamily member 10B, cancer), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B, multiple myeloma, NHL, other cancers, RA and SLE ), TPBG (trophoblast glycoprotein, renal cell carcinoma), TRAIL-R1 (TNF-related apoptosis ligand receptor 1, lymphoma, NHL, colorectal cancer, lung cancer), VCAM-1 (CD106 , melanoma), VEGF, VEGF-A, VEGF-2 (CD309) (various cancers ). Other tumor-associated antigens recognized by antibodies have already been reported (Gerber, et al, mAbs 1:3, 247-253 (2009); Novellino et al, cancer immunol immunother. 54 (3 ), 187-207 (2005)Franke et al, cancer biother radiopharm. 2000, 15,459-76). Examples of these antigens for antibodies are as follows: Many other clusters of differentiation (CD4 , CD5, CD6, CD7, CD8, CD9, CD10, CD11a, CD11b, CD 11c, CD12w, CD14, CD15, CD16, CDw17, CD18, CD21 , CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD31 , CD32, CD34, CD35, CD36, CD37, CD41, CD42, CD43 , CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD 53, CD54, CD55, CD58, CD59, CD61, CD62E, CD62L, CD62P, CD63, CD68, CD69, CD71, CD72, CD79, CD81 , CD82, CD83, CD86, CD87, CD88, CD89, CD90, CD91 , CD95, CD96, CD100, CD103, CD105, CD106, CD109 , CD117, CD120, CD127, CD133, CD134, CD135, CD1 38, CD141, CD142, CD143, CD144, CD147, CD151, C D152, CD154, CD156, CD158, CD163, CD166, CD168 , CD184, CDw186, CD195, CD202(a,b), CD209, CD2 35a, CD271, CD303, CD304), annexin A1, nucleolin, en Doglin (CD105), ROBO4, aminopeptidase N, Δ-like-4 (DL L4), VEGFR-2 (CD309), CXCR49CD184), Tie2, B7- H3, WT1, MUC1, LMP2, HPV E6 E7, EGFRvIII, HER- 2 / neu, Idiotype, MAGE A3, p53 non-mutant, NY-ESO-1, GD2, CEA, MelanA / MART1, Ras mutant, gp1 00, p53 mutant, Proteinase 3 (PR1), bcr-abl, Tyrosinase, Sa vibin, hTERT, Sarcoma metastasis breakpoint, EphA2, PAP, ML-IAP , AFP, EpCAM, ERG (TMPRSS2 ETS fusion gene), NA17, PA X3, ALK, Androgen receptor, Cyclin B1, Polysialic acid, MYCN, Rho C, TRP-2, GD3, Fucosyl GM1, Mesothelin, PSCA, MAGE A1, s Le(a), CYP1B1, PLAC1, GM3, BORIS, Tn, GloboH, E TV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES1, Sperm protein 17, LCK, HMWMAA, AKAP-4 , SSX2, XAGE 1, B7H3, Legumain, Tie2, Page4, VEGFR 2, MAD-CT-1, FAP, PDGFR-β, MAD-CT-2, Fos-related antigen 1 .

[0159] In another specific embodiment, the camptothecin analog-binding molecule conjugate of the present invention is used for the treatment of cancer in accordance with the compositions and methods of the present invention. The cancer to be targeted is not limited to these, but includes adrenal cortical cancer, anal cancer, bladder cancer, brain tumor (adult, brain ), but is not limited thereto, and includes adrenal cortical cancer, anal cancer, bladder cancer, brain tumor (adult, brain Glioblastoma, children, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, primitive neuro ectodermal and pineal tumors, visual pathway and hypothalamic gliomas), breast cancer, carcinoid tumors, stomach intestine, cancer of unknown primary origin, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's family tumors (PNET), extracranial malignant germ cell tumors, eye cancer, intraocular melanoma , gallbladder cancer, gastric cancer (stomach), germ cell tumors, extragonadal, gestational trophoblastic tumors, head and neck cancer, lower pharyngeal cancer, pancreatic islet cell cancer types, kidney cancer (renal cell cancer), laryngeal cancer, leukemia (acute lymphoblastic , acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cancer, liver cancer, lung cancer (non-small cell, small cell, lymphoma (AIDS-related, central nervous system, cutaneous T cell , Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic squamous neck cancer of unknown primary origin , multiple myeloma and other plasma cell tumors, fungating polyps, myelodysplastic syndromes , myeloproliferative syndromes, nasopharyngeal cancer, neuroblastoma, oral cancer, pharyngeal cancer, osteosarcoma, ovarian cancer (epithelial, germ cell tumors, low malignant potential tumors), pancreatic cancer (exocrine gland, pancreatic islet cell cancer), paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasmacytoma , prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell cancer (kidney cancer), renal pelvis and ureter( transitional cell), salivary gland cancer, Sézary syndrome, skin cancer, skin cancer (cutaneous T cell lymphoma , Kaposi's sarcoma, melanoma), small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymoma (malignant) , thyroid cancer, urethral cancer, uterine cancer (sarcoma), abnormal cancer in children, vaginal cancer, vulvar cancer, Wilms tumor is included.

[0160] In another specific embodiment, the camptothecin analog-binding molecule conjugate of the present invention is For the treatment or prevention of autoimmune diseases, it is used according to the compositions and methods of the present invention. Auto Autoimmune diseases include, but are not limited to, autoimmune achlorhydria, chronic active hepatitis, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, anti-GMB / TBM nephritis, antiphospholipid syndrome, anti-synthetase syndrome, arthritis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune myocarditis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral nervous system disease, autoimmune pancreatitis, multiple autoimmune endocrine disorders type I, II, III, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune uveitis, Behçet's disease / Behçet's concentric sclerosis, Behçet's disease, Berger's disease, Bickerstaff encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, Chagas disease, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, chronic Lyme disease, chronic obstructive pulmonary disease, allergic granulomatous angiitis, cicatricial pemphigoid, celiac disease, Cogan's syndrome, cold agglutinin disease, complement component C2 deficiency, cranial arteritis, CREST syndrome, Crohn's disease ( idiopathic inflammatory bowel disease), Cushing's syndrome, cutaneous leukocytoclastic vasculitis, malignant atrophic papulosis, painful fat syndrome, dermatitis herpetiformis, dermatomyositis, type 1 diabetes, diffuse cutaneous scleroderma, myocardial infarction, discoid lupus erythematosus, eczema, endometriosis, adhesive arthritis-related arthritis, eosinophilic fasciitis, acquired epidermal blistering disease, erythema nodosum, idiopathic mixed cryoglobulinemia, Evans syndrome, progressive osseous fibroplasia imperfecta, fibromyalgia, fibromyositis, fibrosing alveolitis, gastritis, gastrointestinal pemphigoid , giant cell arteritis, glomerulonephritis, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura, gestational herpes, suppurative hidradenitis, Hughes syndrome (antiphospholipid antibody syndrome), hypogammaglobulinemia, idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (autoimmune thrombocytopenic purpura), IgA nephropathy (Berger's disease), inclusion body myositis, inflammatory demyelinating polyneuropathy, interstitial cystitis, irritable bowel syndrome, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, cutaneous mucous membrane lymph node syndrome, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease (LAD), Lou Gehrig's disease (amyotrophic lateral sclerosis), lupus-like hepatitis, systemic lupus erythematosus, Blau syndrome, Ménière's disease, microscopic polyangiitis, Miller Fisher syndrome, mixed connective tissue disease, scleroderma, Creutzfeldt-Jakob disease, McCune-Albright syndrome, multiple myeloma, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, optic neuromyelitis (Devic's disease), neuromyelitis optica, oculocutaneous cicatricial pemphigoid, opsoclonus-myoclonus syndrome, autoimmune thyroiditis, relapsing polychondritis, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, Personage-Gilliat syndrome, pars planitis, pemphigus, pemphigus vulgaris, pernicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen encephalitis, Raynaud's disease, Relapsing polychondritis, Reiter's syndrome, restless legs syndrome, retroperitoneal fibrosis, rheumatoid arthritis Rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler's syndrome syndrome, scleritis, scleroderma, Sjogren's syndrome, spondyloarthropathy, sticky blood syndrome, Still's disease , stiff-man syndrome, subacute bacterial endocarditis, Susac syndrome, acute febrile neutrophilic Skin disease, Sydenham's chorea, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (giant cell arteritis), Rosa Hunt syndrome, transverse myelitis, ulcerative colitis (a type of idiopathic inflammatory bowel disease), undifferentiated Diffuse connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener's granulomatosis, Wilson's syndrome group, and Westcott-Aldrich syndrome.

[0161] In another particular embodiment, the conjugates are used for the treatment or prevention of autoimmune diseases. Binding molecules that can be used include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; Anti-basement membrane type IV collagen protein antibody; Antinuclear antibody; Anti-double-stranded DNA antibody, Anti-single stranded DNA antibody Anti-DNA antibodies, anti-cardiolipin antibodies IgM, IgG; anti-celiac antibodies; anti-phospholipid antibodies body IgK, IgG; anti-SM antibodies; anti-mitochondrial antibodies; thyroid antibodies; microparticle antibodies, T cells thyroglobulin antibody, anti-scleroderma-70 antibody (AntiSCL-70); anti-joint antibody Antibody (Anti-Jo), anti-U1RNP antibody (Anti-U1RNP); anti-La / SSB Antibody; Anti-SSA antibody; Anti-SSB antibody; Anti-parietal cell antibody; Anti-histone antibody; Anti-RNP antibody; C -ANCA; P-ANCA; anti-centromere antibody; anti-fibrin antibody, anti-GBM antibody, anti Ganglioside antibodies; Anti-Desmosomal Glycoprotein 3 Core Antibody (anti-Desmog ein3); anti-p62 antibody; anti-sp100 antibody; anti-mitochondria (M2) antibody; rheumatoid factor antibody; anti-MCV antibody; anti-topoisomerase antibody; anti-neutrophil cytoplasmic (cANCA) antibody is included.

[0162] In certain preferred embodiments, the binding molecule used in the conjugate of the present invention binds to both a receptor and a receptor complex expressed by activated lymphocytes associated with autoimmune diseases. The receptor or receptor complex can be, for example, a member of the immunoglobulin gene superfamily (e.g., CD2, CD3, CD4, CD8, CD19, CD20, CD22, CD28, CD30, CD33, CD37, CD38, CD56, CD70, CD79, CD90, CD125, CD147, CD152 / CTLA-4, PD-1, or ICOS), TNF receptor superfamily (e.g., CD27, CD40, CD9 5 / Fas, CD134 / OX40, CD137 / 4-1BB, INF-R1, TNFR -2, RANK, TACI, BCMA, osteoprotegerin, Apo2 / TRAIL- R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and APO-3), integrin, cytokine receptor, chemokine receptor, major histocompatibility protein, lectin (C-type, S-type, or I-type), or complement regulatory protein. In another specific embodiment, a useful binding ligand having immunological specificity for a viral antigen or a bacterial antigen is a humanized or human monoclonal antibody. As used herein, the term "viral antigen" includes any viral peptide, poly peptide that can induce an immune response.

[0163] In another specific embodiment, a useful binding ligand having immunological specificity for a viral antigen or a bacterial antigen is a humanized or human monoclonal antibody. As used herein, the term "viral antigen" includes any viral peptide, poly peptide that can induce an immune response. Peptide proteins (e.g., HIV gp120, HIV nef, RSV F glycoprotein, influenza virus neuraminidase, influenza virus hemagglutinin, HTLV tax, herpes simplex virus glycoproteins (e.g., gB, gC, gD, and gE), and hepatitis B surface antigen) are included, but not limited to these. The term "bacterial antigen" as used herein includes any microbial peptide, polypeptide, protein, carbohydrate, polysaccharide, or lipid molecule (e.g., bacteria, fungi, pathogenic protozoa, yeast polypeptides (e.g., LPS and 5 / 8)) that can induce an immune response, but is not limited to these. Type I antibodies useful for the treatment of viral or bacterial infections include palivizumab (a humanized anti-respiratory syncytial virus monoclonal antibody used for the treatment of RSV infection), PRO542 (a CD4 fusion antibody used for the treatment of HIV infection), Ostavir (a human antibody used for the treatment of hepatitis B virus), PROTVIR (a humanized antibody IgG1 used for the treatment of cytomegalovirus), and anti-LPS antibodies, but are not limited to these. The cell-binding molecule-camptothecin analog conjugate of the present invention can be used for the treatment of infectious diseases. The infectious diseases include Acinetobacter infections, actinomycosis, African sleeping sickness (Trypanosoma brucei gambiense), AIDS (acquired immunodeficiency syndrome), amebiasis, Anaplasma, anthrax, bacterial tuberculosis infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterial vaginitis, Bacteroides infection, Balantidium coli infection, Baylisascaris procyonis infection, BK virus infection, black piedra, but are not limited to these.

[0164] ​​​​​​​​​​​​​Sarcocystis hominis infection, Blastomyces, Bolivian hemorrhagic fever, Borrelia infection, Botulinum poisoning (and infant botulism), Brazilian hemorrhagic fever, Brucellosis, Burkholderia infection , Buruli ulcer, Calicivirus infection (Norovirus, Sapovirus), Campylobacter infection, Candida infection (Candidiasis, Thrush), Cat scratch disease, Cellulitis , Chagas disease (American trypanosomiasis), Chancroid, Chickenpox, Chlamydia, Chlamydia pneumoniae infection , Cholera, Chromoblastomycosis, Clonorchiasis, Clostridium difficile infection, Coccidioidomycosis , Colorado tick fever, Cold (Acute viral nasopharyngitis, Acute rhinitis), Creutzfeldt -Jakob disease, Crimean-Congo hemorrhagic fever, Cryptococcus, Cryptosporidium, Cutaneous larva migrans, Cyclospora infection, Cysticercosis, Cytomegalovirus infection, Dengue fever, Entamoeba histolytica , Diphtheria, Diphyllobothriasis, Dracunculiasis, Ebola hemorrhagic fever, Echinococcosis, Ehrlichiosis , Enterobiasis (Pinworm infection), Enterococcal infection, Enterovirus infection, Exanthematous typhus, Infectious erythema (Fifth disease), Infantile acute exanthema, Fasciolopsis buski, Fascioliasis, Fatal familial insomnia, Filariasis , Food poisoning caused by Vibrio welchii, Non-parasitic ameba infection, Fusobacterium infection , Gas gangrene (Clostridial myonecrosis), Geotrichosis, Gerstmann-Straussler-Scheinker syndrome, Giardiasis , Glanders, Gnathostomiasis, Gonorrhea, Granuloma inguinale (Donovanosis), Group A streptococcal infection, Group B streptococcal infection, Influenza virus infection, Hand, foot and mouth disease (HFMD), Hantavirus pulmonary syndrome, Helicobacter pylori infection , Hemolytic uremic syndrome, Hemorrhagic fever with renal syndrome, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Herpes simplex, Histoplasmosis, Hookworm infection, Human Balkan virus infection, Human immunodeficiency virus (HIV) infection, Infectious mononucleosis, Japanese encephalitis, Leishmaniasis, Leprosy, Listeriosis Ehrlichiosis, human granulocytic anaplasmosis, human metapneumovirus infection , human monocytic ehrlichiosis, human papillomavirus infection, human parainfluenza virus infection, dwarf tapeworm disease, influenza, isosporiasis, Kawasaki disease, mononucleosis, Kingella infection, Q fever, Lassa fever, Legionnaires' disease (Pontiac fever), leishmaniasis, Hansen's disease, leptospirosis, listeriosis, Lyme disease (Lyme borrelia), lymphatic filariasis (elephantiasis), lymphocytic choriomeningitis, malaria, Marburg hemorrhagic fever, measles, melioidosis (Whitmore's disease), meningitis, meningococcal disease, metagonimiasis, microsporidiosis, molluscum contagiosum, mumps, endemic typhus (endemic typhus), mycoplasma pneumonia, mycetoma, fly disease, neonatal conjunctivitis (neonatal ophthalmia), Creutzfeldt-Jakob disease (vCJD, nvCJD), nocardiosis, onchocerciasis (blinding filariasis), paracoccidioidomycosis (South American blastomyces), paragonimiasis, pasteurellosis, body lice (body lice), body louse disease (body lice), crab louse disease (crab lice, Crabb ice), pelvic inflammatory disease, pertussis (Whooping cough ), plague, pneumococcal infection, Pneumocystis pneumonia, pneumonia, polio, Prevotella infection, PAME, progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies, rat bite fever, respiratory syncytial virus infection, rhinovirus infection, rickettsial infection, rickettsia, Rift Valley fever, Rocky Mountain spotted fever, rotavirus infection, rubella, salmonellosis, SARS (severe acute respiratory syndrome group), scabies, schistosomiasis, sepsis, diarrhea (dysentery), shingles (Herpes zoster ) ​​​r), smallpox, Sporothrix, staphylococcal food poisoning, staphylococcal infection, nematodes, syphilis, tapeworms disease, tetanus (lockjaw), Barber's itch, tinea manus, black dermatophytosis, tinea pedis, onychomycosis, vitiligo, Toxocara (ocular larva migrans), Toxocara (internal visceral larva migrans), toxoplasmosis, Trichinella, Trichomonas, cryptobiotic (whipworm infection), pulmonary tuberculosis, rabbit fever, ureaplasma urealyticum infection, Venezuelan encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, white piedra, pseudotuberculosis , Yersinia, yellow fever, zygomycosis, including but not limited to these.

[0165] The binding molecules to pathogenic strains described in this patent, the provided antibodies include Acinetobacter baumannii, Actinomyces israelii, Actinomyces odontolyticus Gerencseria, Propionibacterium propionicum, Trypanosoma brucei gambiense, HIV (human immunodeficiency virus), Entamoeba histolytica, Anaplasma, Bacillus anthracis, Arcanobacterium haemolyticum ), Funin virus, Ascaris lumbricoides, Aspergillus, Astroviridae, Babesia, Serratia bacteria genus, multiple bacteria, Bacteroides genus, Balantidium coli, Bailey Ascaris nematode genus, BK virus, Piedraia hortae , Blastocystis hominis, blastomycosis, Macpo virus, Borrelia, Bortella linus bacteria, Sabia, Brucella genus, usually Burkholderia cepacia and other Burkholderia species, Mycobacterium ulcerans, Caliciviridae family, Campylobacter Kutah bacteria, Candida albicans and other Candida species, Bartonella henselae( English: Bartonella henselae), Group A streptococcus and staphylococcus, Kru zotripanosoma, Haemophilus ducreyi, varicella-zoster virus (VZV), Chlamydia tra chomatis, Chlamydia pneumoniae, Vibrio cholerae, Fonsecaea pedrosoi, liver fluke disease, Clostridium difficile, Coccidioides immitis, Coccidioides posadasii, Colorado tick fever virus, rhinovirus, coronavirus, Creutzfeld t-Jakob disease prion, Crimean-Congo hemorrhagic fever virus, Cryptococcus neo formans, Cryptosporidium, cat hookworm, co-parasite, Cyclospora, Taenia solium, sa imtomavirus, dengue virus (DEN-1, DEN-2, DEN-3 and DE N-4)-Flavivirus, Entamoeba coli, Corynebacterium diphtheriae, Diphyllobothrium genus, Dracunculus medinensis, Ebola virus, echi nococcus genus, Ehrlichia genus, pinworm, Enterococcus genus, Enterovirus genus, exanthema t phus Rickettsia, parvovirus B19, human herpesvirus 6, human herpesvirus 7, Fasciolopsis buski, liver fluke and Fasciola gigantica, FFI prion, Filarioidea, u ersinia, Fusobacterium, Clostridium other genera, Geotrichum candida, GSS prion, Giardia lamblia, Burkholderia mallei, Gnathostoma spinigerum, Gnathostoma hispidum, Neisseria gonorrhoeae, granuloma bacteria, Streptococcus pyogenes, s treptococcus agalactiae, Haemophilus influenzae, enterovirus, most coc sackie A virus, enterovirus 71, Sindbis virus, Helicobacter Helicobacter pylori, Escherichia coli O158:H7, Bunyaviridae, hepatitis A virus, hepatitis B virus , hepatitis C virus, hepatitis D virus, hepatitis E virus, herpes simplex virus type 1 , herpes simplex virus type 2, Histoplasma capsulatum, Ancylostoma duodenale, Ascaris lumbricoides, Haemophilus influenzae, bocavirus, Ehrlichia ewingii , Anaplasma phagocytophilum, human metapneumovirus, Ehrlichia chaffeensis , human papillomavirus, human parainfluenza virus , Hymenolepis nana, Hymenolepis diminuta, Epstein - Barr virus, Orthomyxoviridae , Isospora belli, Kingella kingae, Klebsiella pneumoniae, Klebsiella ozaenae , Klebsiella rhinoscleromotis , kuru prion, Lassa fever virus, Legionella pneumophila, Legionella pneumophila , Leishmania, Mycobacterium lepromatosis, Leptospira, Listeria , Borrelia burgdorferi and other Borrelia species, Wuchereria bancrofti and Brugia malayi, lymphocytic choriomeningitis virus (LCMV), Plasmodium genus , Marburg virus, measles virus, Burkholderia pseudomallei, Neisseria meningitidis , Schistosoma yokogawai, Microsporidia, molluscum contagiosum virus (MCV) , mumps virus, Rickettsia typhi, Mycoplasma pneumoniae, species , etc. Various bacteria (actinomycetoma) and fungi (fungal mycetoma), larvae of parasitic flies of the Diptera, C Chlamydia trachomatis, Neisseria gonorrhoeae, vCJD prion, Nocardia asteroides and other Nocardia species, Spirometra mansoni, Blastomyces brasiliensis, Paragonimus westermani and other Paragonimus species , Pasteurella species, Pediculus humanus, Pthirus pubis, Bordetella pertussis, Yersinia pestis, Streptococcus pneumoniae, Pneumocystis carinii, Poliovirus , Prevotella species, Naegleria ameba, JC virus, Chlamydia psittaci, Coxiella burnetti, Rabies virus, Streptobacillus moniliformis and Spirillum minus of rat-bite fever, Respiratory syncytial virus, Rhinosporidium seeberi, Rhinovirus, Rickettsia species, Rickettsia conorii, Rift Valley fever virus, Rocky Mountain spotted fever Rickettsia, Rotavirus , Rubella virus, Salmonella species, SARS coronavirus, Sarcoptes scabiei, Schistosoma species, Shigella dysenteriae, Varicella zoster virus, Smallpox or Variola major, Sporothrix schenckii, , Staphylococcus species, Staphylococcus aureus, Streptococcus pyogenes, Strongyloides stercoralis, Treponema pallidum, Taenia species, Corynebacterium diphtheriae, Tinea corporis, Trichophyton tonsurans, Tinea capitis, Epidermophyton floccosum , Trichophyton rubrum and Trichophyton mentagrophytes, Trichophyton rubrum, Hortaea werneckii, Tinea versicolor, Malassezia species, Toxocara canis and Toxocara cati, Toxoplasma gondii, Trichinella spiralis, Trichomonas vaginalis, Trichuris trichiura, Mycobacterium tuberculosis, , Francisella tularensis, Ureaplasma urealyticum, Venezuelan equine encephalitis virus, Vibrio cholerae, Guanarito virus, West Nile virus, Trichosporon beigelii, Mycobacterium avium, Yersinia enterocolitica, Yellow fever virus, Zygomycetes (Mucormycosis) and Entomophthorales (Entomophthoramycosis), Pseudomonas aeruginosa, Campylobacter fetus (Vibrio), Aeromonas bacteria, E scherichia coli, and other bacteria, viruses, fungi, protozoa, and parasites that can cause infectious diseases in humans and animals. scherichia coli, and other bacteria, viruses, fungi, protozoa, and parasites that can cause infectious diseases in humans and animals. Genus Dworshiella, Tarda, Pestis, Shigella dysenteriae, Dysentery bacillus, Shigella sonnei, Salmonella typhimurium Bacteria, Treponema pertenue, Treponema carateum, Finsemblegdorfi Rie, Borrelia burgdorferi, Leptospira icterohaemorrhagiae, Pneumocystis carinii, Brucella abortus, Brucella suis, Brucella melitensis, Mycoplasma genus, Rickettsia typhus exanthematicus, Rickettsia tsutsugamushi, Chlamydia genus, Pathogenic fungi (Aspergillus fumigatus, Candida albicans, Histoplasma capsulatum); Protozoa (Entamoeba histolytica, Trichomonas vaginalis Trichomonas hominis, Trichomonas vaginalis, Trypanosoma gambiense, Trypanosoma rhodesiense, Leishmania donovani, Leishmania tropica, Leishmania braziliensis, Pneumocystis carinii pneumonia, Plasmodium malariae, Plasmodium falciparum, Plasmodium vivax); or Helminths( Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium and hookworms), but not limited to these.

[0166] Other antibodies as binding ligands for the treatment of viral diseases in the present invention include, for example but not limited to these, antibodies against antigens of pathogenic viruses such as the following Poxviridae, Herpesviridae, Adenoviridae, Papovaviridae, Enteroviridae, Picornaviridae, Parvoviridae, Reoviridae, Retroviridae, Influenza virus, Parainfluenza virus, Mumps, Measles, Respiratory syncytial virus, Rubella, Arbovirus, Rabies virus, Arenaviridae, Non-A / Non-B hepatitis virus, Rhinovirus, Coronavirus, Rotavirus, Tumor virus [e.g., HBV (hepatocellular carcinoma), HPV ​​ (Cervical cancer, anal cancer), Kaposi's sarcoma-associated herpesvirus (Kaposi's sarcoma), Epstein-Barr virus (Nasopharyngeal carcinoma, Burkitt lymphoma, primary central nervous system lymphoma), MCPyV (Merkel cell carcinoma), SV40 (Simian virus 40), HCV (Hepatocellular carcinoma), HTLV-I (Adult T-cell leukemia / lymphoma)]; Immune diseases caused by viruses: [For example, Human immunodeficiency virus (AIDS)], CNS viruses: [For example, JCV (Progressive multifocal leukoencephalopathy), MeV (Subacute sclerosing panencephalitis), LCV (Lymphocytic choriomeningitis), Al boviral encephalitis, Orthomyxoviridae (presumed) (Encephalitis lethargica), RV (Rabies disease), Vesicular stomatitis, Herpesviral meningitis, Ramsay Hunt syndrome type II; Poli ovirus (Acute poliomyelitis, Post-polio syndrome), HTLV-I (Tropical spastic paraparesis)]; Sa limonavirus (CMV retinitis, HSV (Herpetic keratitis)); Cardiovascular viruses [For example, CBV (Pericarditis, Myocarditis)]; Respiratory system / Acute nasopharyngitis / Viral pneumonia: [E BV (EBV infection / Infectious mononucleosis), Cytomegalovirus, SARS coronavirus (Severe acute respiratory syndrome), Orthomyxoviridae: Influenza virus A / B / C (Influenza / Avian influenza), Paramyxovirus: H uman parainfluenza virus (Parainfluenza), RSV (Human respiratory syncytial virus rus), hMPV]; Digestive system viruses [MuV (Mumps), Cytomegalovirus (CMV esophagitis); Adenovirus (Adenovirus infection); Rotavirus, Norovirus , Astrovirus, Coronavirus, HBV (Hepatitis B virus), CBV, H AV (hepatitis A virus), HCV (hepatitis C virus), HDV (hepatitis D virus) , HEV (hepatitis E virus), HGV (hepatitis G virus); urogenital viruses [For example, BK virus, MuV (mumps)] are included.

[0167] For a further object, the present invention provides a conjugate of the present invention and a pharmaceutically acceptable carrier, diluent, or excipient, together with a pharmaceutical composition for treating cancer, infectious diseases, or autoimmune diseases. Methods for treating cancer, infectious diseases, and autoimmune diseases can be carried out in vitro ( in vitro), in vivo or ex vivo . Examples of in vitro therapy include cell culture treatments for killing all cells other than desired variants that do not express the target antigen, or for killing variants that express undesired antigens. Examples of ex vivo therapy include treating hematopoietic stem cells (HSC) prior to the performance of transplantation (HSCT) and returning the same to the body of the same patient to kill diseased or malignant cells. For example, prior to autologous transplantation in the treatment of cancer and autoimmune diseases, for removing cancer cells or lymphocyte cells from the bone marrow, or for preventing graft-versus-host disease, clinical ex vivo treatments for removing T cells and other lymphocytes from allogeneic bone marrow or tissue prior to transplantation can be carried out as follows. After obtaining bone marrow cells from a patient or other individual, culturing in a serum-containing medium supplemented with the conjugate of the present invention at a concentration range of about 1 pM to 0.1 mM at 37°C for 15 minutes to about 48 hours. The exact concentration conditions and culture time (= dose) can be readily determined by an experienced clinician. After the culture is completed, Subsequently, the bone marrow cells are washed with a serum-containing medium and returned to the human body by a known method such as intravenous injection. During the acquisition and reinfusion treatment of bone marrow cells, if the patient is undergoing other treatments (e.g., ablation chemotherapy or total body irradiation), the processed bone marrow cells are cryopreserved by liquid nitrogen using standard medical devices.

[0168] For in vivo clinical application, the conjugate of the present invention can be provided in the form of a solution or a lyophilized solid that can be redissolved in sterile water for injection. Examples of suitable methods of administering the conjugate are as follows. The conjugate is administered by intravenous bolus daily, weekly, every two weeks, every three weeks, every four weeks, or once a month over a period of 8 to 54 weeks. The bolus dose is dissolved in 50 to 10 00 mL of physiological saline, and human serum albumin can optionally be added to the physiological saline (e.g., 0.5 to 1 ml of concentrated human serum albumin solution at 100 mg / ml) The drug dosage is about 50 μg to 20 mg / kg body weight per week and is by intravenous injection (the injection volume per time is in the range of 10 μg to 200 mg / kg). After the treatment for 4 to 54 weeks is completed, the patient can receive a second course of treatment. The detailed treatment method, including the administration route, excipient, diluent, dosage, and treatment period, can be determined by an experienced surgeon.

[0169] Examples of treating diseases by selectively killing cell populations by in vivo or ex vivo methods include any type of cancer, autoimmune diseases, transplant rejection, and infectious diseases (including viruses, bacteria, or parasites).

[0170] The amount of conjugate required to achieve the desired biological effect depends on the chemical properties of the conjugate. ​​​​​​, effectiveness and bioavailability, disease type, patient ethnicity, patient pathological condition, route of administration, and all factors determining the required dose, including many factors such as the delivery and regimen administered vary according to.

[0171] Generally speaking, the conjugate via the linker of the present invention may be a formulation for parenteral administration dissolved in a physiological buffer so as to contain the conjugate at a concentration of 0.1 to 10% w / v. The typical dosage range is 1 μg / kg body weight to 0.1 g / kg body weight per day, per week, every two weeks, every three weeks, or per month, and the preferred dosage range is 0.01 mg / kg body weight to 20 mg / kg body weight per week, every two weeks, every three weeks, or per month. The preferred drug dosage depends appropriately on variables such as, for example, the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic properties of the drug in the selected mode of administration, and the rate of administration (single injection or continuous infusion) and the administration schedule (frequency of administration within a certain time). There are cases.

[0172] The conjugate of the present invention can also be administered in unit dose, where "unit dose" means a single dose administered to a patient, can be used for simplicity and convenience of packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical total dose range per day / week / every two weeks / every month is 0.01 to 100 mg / kg. As a general guideline , the unit dose for humans is per day, or per week, every two weeks (biwee k), or per month. ​​​​​​kly), in the range of 1 to 3000 mg per 3 weeks, or per month. Preferably, The unit dosage range is 1 mg to 500 mg administered 1 to 4 times a month, more preferably 1 mg to 100 mg once a week, or once every 2 weeks, or once every 3 weeks. Here The conjugate given can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose of the drug can be, for oral administration, tablets, simple capsules or soft capsules; for nasal administration, powders, nasal drops, or aerosols ; or for skin administration, for example, as ointments, creams, lotions, gels or sprays or skin patches. The composition can conveniently be administered in unit dosage form and can be prepared by any method known in the art of pharmacy , for example, reference can be made to the methods described in "Remington: The Science and Practice of Pharmacy, 21th ed.; Lippincot t Williams & Wilkins: Philadelphia, PA, 2005".

[0173] Preferred formulations include pharmaceutical compositions in which the compounds of the present invention are formulated for oral or parenteral administration. For example, oral administration formulations such as tablets, pills, powders, capsules, lozenges, etc. can contain one or more of the following raw materials or other compounds having similar properties : binders such as microcrystalline cellulose or tragacanth gum; diluents such as starch or lactose ; dispersants such as starch and cellulose derivatives; lubricants such as magnesium stearate ; lubricants such as colloidal silica; sweeteners such as sucrose or saccharin; peppermint or ; or Flavoring agents such as methyl salicylate. The capsules are obtained in hard or soft form by mixing gelatin, or optionally by mixing with a plasticizer, and starch capsules can also be obtained. Furthermore, the dosage unit can include various different materials, for example, sugar coating, shellac or enteric solvents, etc., in order to modify its physical form. Other oral dosage forms such as syrups or elixirs can include sweetening agents, preservatives, pigments, coloring agents and flavoring agents. Furthermore, the active compound can be manufactured into fast-dissolving dosage forms, sustained-release or controlled-release dosage forms with other treatments and formulations, and such sustained-release formulations are preferably in a dual mode. Preferred tablet formulations contain a mixture of lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc or combinations thereof. Liquid formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Liquid medicaments may contain binders, buffers, preservatives, chelating agents, sweetening agents, flavoring agents and coloring agents, etc. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic acid esters such as ethyl oleate. Aqueous carriers include mixtures of water and ethanol, buffers and physiological saline. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene / polyoxypropylene copolymers can be used as raw materials for controlling the release of the active compound. Media for intravenous administration include fluids, nutritional supplements and electrolyte supplements based on Ringer’s dextrose.

[0174] It contains liquids, etc. Other possible parenteral delivery systems for these active compounds include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes are included.

[0175] Other alternative administration methods include inhalants, which include dry powders, aerosols, and drops . The inhalant may be administered, for example, in the form of an aqueous solution containing polyoxyethylene-9-lauryl ether, glycolate, deoxycholate, or an oily solution for administration as nasal drops or a gel for intranasal application . Formulations for oral administration, such as tablets or troches may contain flavoring agents such as sucrose or gum arabic and other additives such as glycolic acid . Formulations suitable for rectal administration are preferably given as unit-dose suppositories containing, for example, a solid base such as cocoa butter and may contain salicylic acid. Formulations for topical skin use are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. The base includes petrolatum, lanolin, polyethylene glycol and alcohols and mixtures thereof. Formulations suitable for transdermal administration can be given as separate patches and can also be in the form of a lipophilic emulsion or buffered aqueous solution dissolved or dispersed in a polymer or adhesive .

[0176] In certain embodiments, the conjugate of the present invention is administered simultaneously with other known or yet-to-be-known drugs , such as chemotherapeutic agents, radiation therapy, immunotherapeutic agents, drugs for treating autoimmune diseases, anti-infective drugs, or other antibody-drug conjugates to achieve a synergistic effect. In another specific embodiment , the synergistic drug or radiation therapy is administered prior to or subsequent to the administration of the conjugate of the present invention It can be administered or administered, and in some cases, for at least 1 hour, 12 hours, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, and even several months, prior to or subsequent to the conjugate of the present invention is administered.

[0177] In other embodiments, the synergistic drugs include, but are not limited to, the following:

[0178] (1) a) Alkylating agents selected from the following: nitrogen mustard: chlorambucil sil, chloronaphazine, cyclophosphamide, dacarbazine, estramustine, ifos famid, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobu ronitol, melphalan, mitolactol, pipobroman, nobenbitin, phenest rine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1 065 and synthetic analogs of adzelesin, carzelesin and bizelesin; duocarmycin sin and its synthetic analogs KW-2189 and CBI-TMI; benzodiazepine dimers or pyrrolobenzodiazepine (PBD) dimers, tomamycin dimers, indoli novobenzodiazepine dimers, imidazobenzothiadiazepine dimers, or oxazolidino benzodiazepine dimers; nitrosourea compounds including carmustine, lomustine, chlorozotocin, fotemustine , nimustine, ranimustine; alkyl sulfonates including busulfan, treosulfan ne, imiprosulfan, and piposulfan; triazene or dacarbazine; platinum-containing compounds including carboplatin, cisplatin, and oxaliplatin aziridines, benzodopa, carbquone, metsuredopa, and uredopa; ethyl Renimines, as well as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, methylmelamines including trimethylolmelamine; b) Plant alkaloids selected from the group consisting of: vincristine, vinblastine, vindesine, vinorelbine, navelbine-containing vinca alkaloids; paclitaxel and docetaxel-containing taxoids and their analogs; DM1, DM2, DM 3, DM4, DM5, DM6, DM7, maytansine, ansamitocin-containing maytans inoids and their analogs; cryptophycins including the group of cryptophycin 1 and cryptophycin 8; epothilones, erythrobins, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; sarcodictyin; spongistatin; c) DNA topoisomerase inhibitors selected from: 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acid (retinols), teniposide, topotecan, 9-nitrocamptothecin or epipodophyllins including RFS 2000; and mitomycins, and their analogs; d) Antimetabolites: {[Antifolates: (DHFR inhibitors: methotrexate, trimethoprim, denopterin, pteropterin, aminopterin (4-aminopteroylglutamic acid), or other folate analogs included.); IMP dehydrogenase inhibitors (mycophenolic acid, thiazofurin, ribavirin, EICAR included.); Ribonucleotide reductase inhibitors​​ (including hydroxyurea, deferoxamine)]; [Pyrimidine analogues: uracils Antibiotics (ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, Cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-fluorouracil Cytosine analogues: (Cytarabine , cytosine arabinoside, fludarabine; Purine analogs: (azathioprine, Fludarabine, mercaptopurine, thiamiprine, thioguanine); folic acid supplementation agents, fluoronic acid}; e) Hormonal therapy agents: Receptor antagonists: [Anti-estrogens: (megestrol, raloxidine including tamoxifen; LHRH agonists: (goserelin, leuprorelin acetate) loride); Antiandrogens: (bicalutamide, flutamide, calsterone, propionamide, Dromostanolone onate, epithiostanol, goserelin, leuprolide, mepitiostanol androgen blockers such as stan, nilutamide, testolactone, trilostane, and other similar androgen blockers Retinoids / deltoid: [Vitamin D3 analogs: (CB1093, EB 1089, KH1060, cholecalciferol, ergocalciferol); light Radiodynamic therapy agents: (verteporfin, phthalocyanine, photosensitizer Pc4, demethoxyhyd Cytokines: (interferon alpha, interferon gamma, tumor necrosis factor (TNF), including TNF domain-containing human proteins) r; f) Kinase inhibitors: BIBW2992 (anti-EGFR / Erb2), imatinib, Fentanib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, Rotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VE GFR2), mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, bismodegib, iniparib, luxorutinib, CYT387, axitinib, tibozanib , sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitum umab, ispinesib, selected from the group consisting of; g) Olaparib, niraparib, iniparib, talazoparib, veliparib, CEP97 22 (Cephalon), E7016 (Eisai), BGB-290 (BeiGene), or 3 -aminobenzamide, selected from the group consisting of poly(ADP-ribose) polymerase (PARP) inhibitors; h) Enediyne antibiotics (calicheamicins, calicheamicin γ1, δ1, α 1, or β1; dynemicin A and dynemicin including deoxydynemicin; esper micin, kedarcidin, C-1027, mazlopeptin, or neocarzinostatin chromo phore and related pigment protein enediyne antibiotic chromophore selected. ), aclacinomycins, actinomycin, anthramycin (authramyc in), azaserine, bleomycins, cactinomycin (cactinomycin ), carabicin, calminomycin, cardinophilin; chromo mycins, daunorubicin, daunomycin, detorubicin, 6-diazo-5-oxo -L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino -doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epi Rubicin, eribulin, esorubicin, idarubicin, marcellomycin, mitomycin s (nitomycins), mycophenolic acid, nogalamycin, olivomycins , peplomycin, potfiromycin, puromycin, querramycin, rhodrubicin , streptomycin (streptonigrin), streptozocin, tubericidin , ubenimex, dinostatin, zorubicin; an antibiotic selected from i) polyketides (acetogenins), bratasin and bratasinone; gemcitabine, epothilones and carfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zibotentan, PLX4032, STA-909 0, Stimuvax, alovectin-7, zygeva, probenecid, elbo, isoprenylation inhibitors and lovastatin, dopaminergic neurotoxins and 1-me thyl-4-phenylpyridinium ion, cell cycle inhibitors (including staurosporine.), a ctinomycins (including actinomycin D, dactinomycin.), amanitins, bleomycins (including bleomycin A2, bleomycin B2, peplomycin. ), anthracyclines (including daunorubicin, doxorubicin (adriamycin), i darubicin, epirubicin, pirarubicin, zorubicin.), mitoxantrone, MDR inhibitors or verapamil, Ca 2+ ATP inhibitors or thapsigargin, histone de acetylating enzyme inhibitors (vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat (MGCD0103), belinostat, PCI-24781, entinostat, stat, SB939, resminostat, givinostat, AR-42, CUDC- 101, including sulforaphane and trichostatin A); thapsigargin, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A, anti-adrenal drugs (selected from the group consisting of aminoglutethimide, mitotane, trilostane)); aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine (a msacrine); arabinoside, bestrabucil; bisantrene; edatrexate ; defofamine; demeclocycline; diacozone; eflornithine (DFMO), elf ornithine; ellipticine acetate; etoclucid, gallium nitrate, gastrocine, hydroxy urea; ibandronate, lentinan; lonidamine; mitoguazone; mopidamol; nitro lacin; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethyl hydrazide; procarbazine; PSK (registered trademark); razoxane; lysosyme; schizofi ran; spirogermanium; tenuazonic acid; triazone; 2,2’,2’’-trichloro lortriethylamine; trichothecenes (including T2 toxin, verrucarin A, roridin A, and anguidine); urethane, siRNA, antisense pharmaceuticals;

[0179] 2) Anti-autoimmune disease drugs: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, cor ticosteroids (amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone danazol, dexamethasone, triamcinolone acetonide, di ); danazol; It contains beclomethasone propionate.), DHEA, etanercept, hydroxychloro quine, infliximab, meloxicam, methotrexate, mofetil, mycopheno lic acid, prednisone, sirolimus, tacrolimus;

[0180] 3) Anti-infective drugs: a) Aminoglycosides: amikacin, astromicin, gentamicin (netilmicin, sisomicin, isepamicin), hygromycin B, kanamycin (amikacin, albekacin, bekanamycin, dibekacin, tobramycin), neomycin (framycetin, paromomycin, ribostamycin), netilmicin, spectinomycin, streptomycin, tobramycin, verdamycin; b) Amphenicols: azidamfenicol, chloramphenicol, florfenicol, thiamphenicol; c) Ansamycins: geldanamycin, herbimycin; d) Carbapenems: biapenem, doripenem, ertapenem, imipenem, cilastatin, meropenem, panipenem; e) Cephems: carbacephems (loracarbef), cefacetrile, cefaclor, cefradine, cefadroxil, cephalonium, cephaloridine, cephalothin or cephalothin, cephalexin, cephaloglycin, cefamandole, cefapirin, cefatriaxone, cefazafur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefuroxime, ceftezole, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone ​ Lazone, ceforanide, cefotaxime, cefothiam, cefozopran, cephalexin n, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cef quinome, cefurosine, ceftazidime, cefteram, cefibuten, cefthiolen, cef tizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefzonam, cefama ycin (including cefoxitin, cefotetan, cefmetazole.); Oxacephems ( flomoxef, latamoxef); f) Glycopeptides: Bleomycin, vancomycin (including oritavancin, telavancin.); Teicoplanin (dalbavancin), ramoplanin; n, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cef g) Glycylcyclines: Tigecycline; h) β-Lactamase inhibitors: Penams (sulbactam, tazobactam), clavams ( clavulanic acid); i) Lincomycins: Clindamycin, lincomycin; j) Lipopeptides: Daptomycin, A54145, calcium-dependent antibiotics ( CDA); k) Macrolides: Azithromycin, cethromycin, clarithromycin, di risromycin, erythromycin, flurithromycin, josamycin, ketolide (telithromycin, cethromycin), midecamycin, miocamycin, oleand amycin, rifamycin (rifampicin, rifampin, rifabutin, rifapentine ), rokitamycin, roxithromycin, spectinomycin, spiramycin , tacrolimus (FK506), troleandomycin, telithromycin; l) Monobactams: Aztreonam, tigemonam; m) Oxazolidinones: Linezolid; n) Penicillins: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, azidocillin, azlocillin, ben zylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicill in, chrometocillin, procaine benzylpenicillin, carbenicillin (carindacillin ), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mesylinam (pivmecillinam), mezlocillin, methicillin, nafcillin, oxacillin, penameci llin, penicillin, phenethicillin, phenoxymethylpenicillin, piperacillin, pro picillin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin , floxacin, galenoxacin, gatifloxacin, gemifloxacin, grepaf loxacin, canofloxacin, levofloxacin, lomefloxacin, marbof loxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin , ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trova floxacin; q) Streptogramins: pristinamycin, quinupristin / dalfopristin ; r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfame thiazole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethop Rim, trimethoprim-sulfamethoxazole (co-trimoxazole); s) Steroid antibacterial agents: selected from fusidic acid; t) Tetracyclines: doxycycline, chlortetracycline, chromocycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, glycylcycline (including tigecycline); u) Other antibiotics: annonacin, arsphenamine, bacteriophage inhibitor (bacitracin), DADAL / AR inhibitor (cycloserine), dactinomycin, desisocoumarin, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laurimolide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitor (fosfomycin), nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampicin (rifampin), tazobactam tinidazole, uvaricin; (4) Antiviral drugs: a) Entry / fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41 ( enfuvirtide), PRO140, CD4 (ibalizumab); b) Integrase inhibitors: raltegravir, elvitegravir, globoidnan A ;

[0181] (4) Antiviral drugs: a) Entry / fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41 ( enfuvirtide), PRO140, CD4 (ibalizumab); b) Integrase inhibitors: raltegravir, elvitegravir, globoidnan A ; c) Maturation inhibitors: bevirimat, vivicon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides and nucleotides: abacavir, acyclovir, adefovir, a Mudoxivir, apricitabine, brequinar, cidofovir, clevudine, dexelbusib Tavabine, didanosine (DDI), elvucitabine, emtricitabine (FTC), entecavir Cavir, famciclovir, fluorouracil (5-FU), 3'-fluoro-substituted 2', 3'-deoxynucleoside analogs (3'-fluoro-2',3'-dideoxythymidine (FLT) and 3'-fluoro-2',3'-dideoxyguanosine (FLG) consisting of Group. ) Homibilsen, ganciclovir, idoxuridine, lamivudine (3TC) , L-nucleosides (group consisting of β-L-thymidine and β-L-2'-deoxycytidine Including. ), Penciclovir, lasivir, ribavirin, stamipidine, stavudine set (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluridine Baracyclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT ); f) Non-nucleosides: amantadine, ataviridine, capravirine, diarylpyrimidine Midazine (etravirine, rilpivirine), delavirdine, docosanol, emivirine, e Favirenz, foscarnet (phosphonoformic acid), imiquimod, interferon α, Lobivudide, rodenosine, methylthiazone, nevirapine, NOV-205, pegylated interferon α, podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848) , tromantadine; g) Protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir , fosamprenavir, indinavir, lopinavir, nelfinavir, precona ril, ritonavir, saquinavir, telaprevir (VX-950), tipranavir; h) Other types of antiviral drugs: abzymes, arbidol, calanolide a, celagnin, cyanoviolin-n, diarylpyrimidine, epigallocatechin gallate (EGCG )、phosphonoformate, griffithsin, taribavirin (viramidine), hydroxycarb mid, KP-1461, miltefosine, pre-conazole, portmanteau inhibitors, ribav rin, seliciclib;

[0182] 5) Radioisotopes for radiotherapy. Examples of radioisotopes (radionuclides) include 3 H, 11 C, 14 C, 18 F, 32 P, 35 S, 64 Cu, 68 Ga, 86 Y, 99 Tc, 1 11 In, 123 I, 124 I, 125 I, 131 I, 133 Xe, 177 Lu, 211 At, and 213 Bi. Radioisotope-labeled antibodies are very useful in receptor-target imaging experiments or, for example, can be used directly for relative target therapy, such as in the invention of antibody-drug conjugates (Wu et al (2005) Nature Biotechnology 23(9):1137-1146). Cell-binding molecules, such as antibodies, can be labeled by binding, chelating, or forming other complex radioisotope-metal bonds with the cross-linking conjugates of the present application as described above, and this labeling technique is described in Current Protocols in Immunology, Volumes 1 and 2, Coligen et al, Ed. ​ It is described in Wiley-Interscience, New York, N.Y., Pubs. (1991). Chelating agents capable of generating complex metal complexes include DOTA, DOTP, DOTMA, DTPA, and TE TA (Macrocyclics, Dallas, Tex. USA).

[0183] 6) Other cell-binding molecule-drug conjugates as synergistic therapies. Preferred synergistic conjugates are tubulysin analogs, maytansinoid analogs, taxanoid analogs (taxanes), C C-1065 analogs, daunorubicin and doxorubicin compounds, amatoxin analogs, benzodiazepine dimers (e.g., pyrrolobenzodiazepine (PBD), tomamycin , anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepine, or oxazolidinobenzodiazepine dimers), calicheamicin and enediyne antibiotics, actinomycin, azaserines, bleomycins, epirubicin, eribulin, tamoxifen, idarubicin, dolastatin, auristatin (e.g., monomethyl auristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, auristatin 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP ) and their analogs), duocarmycin, geldanamycin, methotrexate, thiotepa, vindesine, vincristine, hemiasterlin, nazumamide, microginin, radiosumin, alterobactin, microsclerodermin (alterobactins), microsclerodermycins​​​ odermins), theonellamides, esperamicins, PNU-159682; and conjugates containing cytotoxic agents of their analogs and derivatives can be used.

[0184] 7) Other immunotherapeutic drugs: For example, imiquimod, interferon (e.g., α, β), granulocyte colony-stimulating factor, cytokines, interleukins (IL-1 to IL-35), antibodies (e.g., trastuzumab, pertuzumab, bevacizumab, cetuximab, panitumumab, infliximab, adalimumab, basiliximab, daclizumab, omalizumab , PD-1, or PD-L1), protein binders (e.g., abraxane), calicheamicin derivatives, maytansine derivatives (DM1 and DM4), CC-1065, SN-3 8, exatecan, topotecan, topoisomerase I inhibitors, duocarmycin, PB D or IGN minor groove binders, effective taxol derivatives, doxorubicin, auristatin-based mitotic inhibitors (e.g., trastuzumab-DM1, trastuzumab deruxtecan ( DS-8201a), inotuzumab ozogamicin, brentuximab vedotin, s acituzumab govitecan, glembatumumab vedotin, lorvotuzumab mertansine , AN-152LMB2, TP-38, VB4-845, canertinib mertansine, AVE9633, SAR3419, CAT-8015 (anti-CD22), IMGN388, mirvetuximab soravtansine (IMGN853), enfortumab vedotin, miratuzumab-doxorubicin, SGN-75 (anti-CD70), anti-Her3-exateca ​N, anti-Trop2-exatecan, anti-CD79b-MMAE, anti-Her2-MMAE, anti- Trop2-MMAE, anti-Her2-MMAF, anti-Trop2-MMAF, anti-CD22- calicheamicin derivative, anti-CD22-MMAE, anti-Her2-aureastatin derivative, anti-Muc1-aureastatin derivative, anti-cMet-aureastatin derivative, or anti-Cla udin18.2-aureastatin derivative)) conjugated with an antibody selected from the group consisting of:

[0185] 8) A pharmaceutically acceptable salt, acid, or derivative of any of the above drugs.

[0186] In another synergistic immunotherapy, a checkpoint inhibitor, TCR (T cell receptor) T cells, or CAR (chimeric antigen receptor) T cells, or B cell receptor (BCR), natural killer - (NK) cells, or cytotoxic antibody cells, or anti-CD3, CD4, CD8, CD16( FcγRIII), CD27, CD40, CD40L, CD45RA, CD45RO, C D56, CD57, CD57 bright , TNFβ, Fas ligand, MHC class I molecules (HLA-A, B, C), or NKR-P1 are preferably used together with the conjugate according to the present invention for synergistic therapy. body for synergistic therapy.

[0187] In yet another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a conjugate of formula (I)-(VII) or any conjugate described through this patent is capable of being co-administered with other therapeutic agents such as chemotherapeutic agents, radiation therapy, immunotherapeutic agents, autoimmune disease agents, anti-infective agents, or other conjugates for synergistically effective treatment or prevention of cancer, autoimmune diseases, or infectious diseases. The synergistic agents are more preferably selected from one or more of the following agents: abatace an, Put, Avemaciclib, Abiraterone Acetate, Abraxane, Acetaminophen / Hydro Codon, Acalabrutinib, Aducanumab, Adalimumab, ADXS31-142, A DXS-HER2, Afatinib Dimaleate, Aldesleukin, Alectinib, Ale Mutsumab, Alitretinoin, Ad-Trastuzumab Emtansine, Amphetamine / Dextroamphetamine, Anastrozole, Aripiprazole, Anthracycline Aripiprazole, Atazanavir, Atezolizumab, Atorvastatin, Avelumab, Axicabtageneciloleucel, Axitinib, Belinostat, Live B CG, Bevacizumab, Bexarotene, Blinatumomab, Bortezomib, Bosutinib, Bre ntuximab Vedotin, Brigatinib, Budesonide, Budesonide / Formoterol, Bup renorphine, Cabazitaxel, Cabozantinib, Capmatinib, Capecitabine, Calfi lucib, Chimeric Antigen Receptor Engineered T (CAR-T) Cells, Celecoxib, Seriti nib, Cetuximab, Kidamide, Cyclosporine, Cinacalcet, Crizotinib, Cobi metinib, Cosentyx, Crizotinib, Tisagenlecleucel, CTL019, Dabigatran, Dabrafenib, Dacarbazine, Daclizumab, Dacomoti nib, Daptomycin, Daratumumab, Darbepoetin Alfa, Darunavir, Dasatinib, De nilukin Diphtheria Toxin, Denosumab, Depakote, Dexlansop razole, Dexmethylphenidate, Dexamethasone, DigniCap Cool ing System, Dinutuximab, Doxycline, Duloxetine, Duveli sib, Durvalumab, Elotuzumab, Emtricitabine / Rilpivirine / Tenofovir, F Disoproxil Fumarate, Emtricitabine / Tenofovir / FTC, Enoxaparin Enzalutamide, Epoetin Alfa, Erlotinib, Esomeprazole Eszopiclone, Etanercept, Everolimus, Exemestane, Everolimus, E Xenical ER, Ezetimibe, Ezetimibe / Simvastatin, Fenofibrate, Fi lgrastim, Fingolimod, Fluticasone Propionate, Fluticasone / Salmeter ol, Fulvestrant, Gazyva, Gefitinib, Glatiramer, Acetic Acid Goserelin, Icotinib, Imatinib, Ibritumomab Tiuxetan, Ibrutinib, I delalisib, Ifosfamide, Infliximab, Imiquimod, ImmuCyst, I mmunoBCG, Iniparib, Insulin Aspart, Insulin Detemir, Insli ngargin, Insulin Lispro, Interferon Alfa, Interferon Alfa-1b, Interferon Alfa-2a, Interferon Alfa-2b, Interferon Beta, Inter feron Beta1a, Interferon Beta1b, Interferon Gamma-1a, Lapatinib, I pilimumab, Ipratropium Bromide / Salbutamol, Ixazomib, Canuma(Kanu ma), Lanreotide Acetate, Lenalidomide, Lenaridomide, Lenvatinib Mesylate, Ret olozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, LN-144, Lorlatinib, Memantine, Methylphenidate Metoprolol, Mekinist, Mericitabine / Rilpivirine / Tenofovir, Modafinil Nesitumumab, Neratinib, Nilotinib, Nira Pabriv, nivolumab, ofatumumab, obinutuzumab, olaparib, olmesartan, Olmesartan / hydrochlorothiazide, omalizumab, omega-3 fatty acid ethyl ester, o ncoline, oseltamivir, osimertinib, oxycodone, palbociclib, parvizumab , panitumumab, panobinostat, pazopanib, pembrolizumab, PD-1 antibody , PD-L1 antibody, pemetrexed, pertuzumab, pneumococcal conjugate vaccine, pomalidomide , pregabalin, ProscaVax, propranolol, quetiapine, rabeprazole , radium-223 chloride, raloxifene, raltegravir, ramucirumab, ranibizumab , regorafenib, ribociclib, rituximab, rivaroxaban, romidepsin , rosuvastatin, loxicitinib phosphate, salbutamol, savolitinib, semaglutide , sevelamer, sildenafil, siltuximab, sipuleucel-T, sitagliptin , sitagliptin / metformin, solifenacin, sonidegib, sorafenib, sunitinib , tacrolimus, temsirolimus, tenofovir / emtricitabine, tenofovir disoproxil fumarate , Tafinlar, Talimogen laherparepvec , tarazoparib, teraprevir, tarazoparib, temozolomide , temsirolimus, tenofovir / emtricitabine, tenofovir disoproxil fumarate , testosterone gel, thalidomide, TICE BCG, tiotropium bromide , tisagenlecleucel, toremifene, trametinib, trastuzumab, trabectedin (ecteinascidin 743), t , rametinib, tremelimumab, trifluridine / tipiracil, Uro-BCG, ustekinumab , rametinib, tremelimumab, trifluridine / tipiracil, Uro-BCG, ustekinumab Numab, valsartan, belinostat, vandetanib, bemrafenib, venetoclax , vorinostat, ziv-aflibercept, and zosetaxel, and analogs thereof, derivatives, pharmaceutically acceptable salts, carriers, diluents or excipients therefor, or combinations thereof.

[0188] For a further object, the present invention also relates to a process for preparing the conjugate of the present invention. The compounds and processes of the present invention can be prepared by many methods well known to those skilled in the art. The camptothecin analogs used in the conjugate can be synthesized, for example, by the application or adaptation of the methods described below, or by modifications thereof as understood by those skilled in the art. Appropriate modifications and substitutions are readily apparent to those skilled in the art, well-known or readily obtainable by those skilled in the art from the scientific literature. In particular, such methods can be found in R. C. Larock, Comprehensive Organic Transformations, 2 nd Edition, Wiley-VCH Publishers, 1999. In the synthetic reaction of the cytotoxic agent of the present invention, the desired reactive functional groups in the final product, for example, hydroxy, amino, imino, thio, or carboxy groups, can be protected as necessary to avoid unwanted participation during the reaction. Conventional protecting groups can be used according to standard practice, for example, see P. G. Wuts, T. W. Greene Greene’s Protective Groups in Organic Synthesis, Wiley-Interscience; 4th edition (2006). nd Edition, Wiley-VCH Publishers, 1999.

[0189] In the synthetic reaction of the cytotoxic agent of the present invention, the desired reactive functional groups in the final product, for example, hydroxy, amino, imino, thio, or carboxy groups, can be protected as necessary to avoid unwanted participation during the reaction. Conventional protecting groups can be used according to standard practice, for example, see P. G. Wuts, T. W. Greene Greene’s Protective Groups in Organic Synthesis, Wiley-Interscience; 4th edition (2006). in Organic Synthesis, Wiley-Interscience; 4th edition (2006). in Organic Synthesis, Wiley-Interscience; 4th edition (2006). It can be carried out. Depending on the reaction, it can be carried out in the presence of a base or an acid, or in a suitable solvent. There are no particular restrictions on the nature of the base, acid, or solvent used in this reaction. As long as it does not have an adverse effect on other parts of the molecule, the bases, acids, and solvents conventionally used in this type of reaction can be used similarly. This reaction can be carried out over a wide temperature range. Generally, it is considered preferable to carry out the reaction at a temperature of -80 °C to 150 °C (more preferably about room temperature to 100 °C). The time required for the reaction also depends on many factors, especially the reaction temperature and the nature of the reagents, and can vary greatly. However, as long as the reaction is effective under the above-preferred conditions, usually a period of 3 hours to 20 hours is sufficient.

[0190] The post-treatment of the reaction can be carried out by ordinary methods. For example, the reaction product can be recovered by distilling the solvent from the reaction mixture, or, if necessary, after distilling the solvent from the reaction mixture, pour the residue into water, and then extract with an organic solvent immiscible with water, and the solvent can be evaporated from the extract. Furthermore, if necessary, the product can be further purified by various known techniques such as recrystallization, reprecipitation, or various chromatography techniques, especially column chromatography or thin-layer chromatography. The synthesis of the camptothecin analogs and their conjugates of the present invention is shown in FIGS. 1 to 32.

[0191] The conjugate of the binding molecule and the effective camptothecin analog will be further described, but it is not limited by the description of the following examples.

Examples

[0192] The conjugate of the effective camptothecin analog and the binding molecule will be further described in the following examples. These will be described, but the description of these examples is not intended to limit the conjugate.

[0193] The present invention will be further described by the following examples, which are not intended to limit the scope of the present application. The cell lines described in the following examples were maintained in culture medium based on conditions specified by the American Type Culture Collection (ATCC), the German Microbial Cell Culture Collection (DMSZ) in Braunschweig, Germany, or the Shanghai Institute of Cell Biology, Chinese Academy of Sciences, unless otherwise specified. Unless otherwise specified, all cell culture reagents were provided by Invitrogen. Amino acids and their derivatives and proload resins were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). Some linkers, NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD The following examples are not intended to limit the scope of the present application. The cell lines described in the following examples were maintained in culture medium based on conditions specified by the American Type Culture Collection (ATCC), the German Microbial Cell Culture Collection (DMSZ) in Braunschweig, Germany, or the Shanghai Institute of Cell Biology, Chinese Academy of Sciences, unless otherwise specified. Unless otherwise specified, all cell culture reagents were provided by Invitrogen. Amino acids and their derivatives and proload resins were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). Some linkers, NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). Some linkers, NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). ), were obtained from Merck Chemicals International Co, Synthetech Co, Peptides International Inc, Chembridge International Co, or Sigma-Aldrich (Merck Co). ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD ), NHS ester / maleimide linkers (AMAS, BMPS, GMBS, MBS, SMCC, EMCS, or sulfo-EMCS, SMPB, SMPH, LC-SMCC, sulfo-KMUS, SM(PEG)4, SM(PEG)6, SM(PEG)8, SM(PEG)12, SM(PEG)24); NHS ester / pyridyldithiol (SPDP, LC-SPDP or sulfo-LC-SPDP, SMPT, sulfo-LC-SMPT); NHS ester / haloacetyl (SIA, SBAP, SIAB, or sulfo-SIAB); NHS ester / diazirine (SDA or sulfo-SDA, LC-SDA or sulfo-LC-SDA, SDAD or sulfo-SDAD); maleimide / hydrazine (BMPH, EMCH, MPBH, K MUH); pyridyldithiol / hydrazide (PDPH); isocyanate / maleimide (PMPI) was purchased from Thermo Fisher Scientific Co. SPDB and SPP conjugates were prepared according to the literature (Cumber, A. et al, Bioconjugate Chem., 1992, 3, 397 - 401), and Roche's trastuzumab was purchased from a pharmacy in China. The Trop-2 antibody, a biosimilar of sacituzumab, was prepared in-house, and nimotuzumab, an EGFR antibody was purchased from a pharmacy in China. PEG and PEG derivative compounds were obtained from Bio matrik Inc, (Jiaxing City, Zhejiang Provi nce, China). Topotecan and its derivatives or main components were purchased from several commercial suppliers such as Chengdu Tianyuan Natural Products Co., Ltd. (Chengdu, China), Brightgene Biomedical C o. (Suzhou, China), etc. Experimental animals were purchased from the National Resource Center of Model Mice through GemPh armatech.Co. (Nanjing, China) and SLAC Laboratory Anim al Co., Ltd., (Shanghai, China). Roche's T-DM1 was purchased from a pharmacy in Hong Kong, China. All other reagents and solvents were purchased as the highest grade and used without further purification. ED C (EDCI), PFP, HATU, TATU, PyBrOP, DIPEA, TEA, P PTS, DMAP, BrOP, p-TSA, DTT, EDTA, TCEP, NHS, TF A, Ellman's reagent, trout reagent (2-iminothiolane), γ-thiobutyrolactone, and PTS, DMAP, BrOP, p-TSA, DTT, EDTA, TCEP, NHS, TF A, Ellman's reagent, trout reagent (2-iminothiolane), γ-thiobutyrolactone, and and all other chemical substances were commercially obtained from Sigma-Aldrich International (Merck) or Aladdin Chemical (Shanghai) Ltd. All anhydrous solvents were commercially available products and stored in nitrogen-filled sealed bottles. Separation by preparative HPLC was performed using a Varain PreStar HPLC. The NMR spectra were detected using a Bruker 500 MHz instrument. Chemical shifts ( Δ) were in parts per million (ppm) units, with tetramethylsilane as the standard at 0.00, and coupling constants (J) were in Hz units. Mass spectrometry data were obtained by Waters Xevo Q TOF mass spectrometry equipped with a Waters Acquity UPLC separator and an Acquity TUV detector.

[0194] Example 1; Synthesis of (S)-tert-butyl (1-((4-ethyl-4,9-dihydroxy- 3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’: 6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperidin-4- yl)carbamate (2) [Chemical formula]

[0195] To an acetic acid solution (10 mL) of 10-hydroxycamptothecin (2 g, 5.49 mmol) was added 4-tert-butoxycarbonylaminopiperidine (4.4 g, 21.9 mmol ) and an acetic acid solution (15 mL) of 37% formaldehyde (1.8 g, 21.9 mmol). The reaction mixture was heated to about 60 °C, stirred for 2 hours, and then acetic acid was distilled off. Me Recrystallization with OH (10 mL) gave Compound 2 as a yellow powdery solid (2 .1 g, yield 68%). ESI-MS m / z: [M + H] + Calculated value for C 31 H 36 N4O7: 577.26; experimental value 577. 26.

[0196] Example 2; Synthesis of (S)-10-((4-aminopiperidin-1-yl)methyl)-4-ethyl -4,9-dihydroxy-1H-pyrano[3’,4’:6,7]indolizino[1,2- b]quinoline-3,14(4H,12H)-dione (3)

Chemical Structure

[0197] Compound 2 (150 mg, 0.26 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid ( 2 mL / 6 mL), and stirred at room temperature for 1 hour. Then the mixture was concentrated and dried under vacuum pump to give Compound 3 as a yellow solid (120 mg, yield 100%) . ESI-MS m / z: [M + H] + Calculated value for C 26 H 28 N4O5: 477.21; experimental value 477.21.

[0198] Example 3; Synthesis of Compound (S)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol -1-yl)-N-(1-((4-ethyl-4,9-dihydroxy-3,14-dioxo -3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indoliz ino[1,2-b]quinolin-10-yl)methyl)piperidin-4-yl)butanamide (5)

Chemical Structure

[0199] Compound 3 (62 mg, 0.13 mmol) and perfluorophenyl 4-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoate (Compound 4, 5 6 mg, 0.16 mmol) were dissolved in DMF (5 mL), cooled to about 0 °C, and then N, N-diisopropylethylamine (45 μL, 0.16 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to give Compound 5 (44 mg, yield 54%). ESI-MS m / z: [M+H] + Calculated for C 34 H 35 N5O8: 642.25; found 642.25.

[0200] Example 4; Synthesis of (S)-perfluorophenyl 30-(4-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)butanamide)-27,31-dioxo-2,5 ,8,11,14,17,20,23-octaoxa-26,32-diazahexatriaconta-36-oate (7) Compound 6 (100 mg, 0.13 mmol) dissolved in dichloromethane (5 mL) was

Chemical Structure

[0201] treated with pentafluorophenol (48 mg, 0.26 mmol) and 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol). The reaction mixture was stirred at room temperature, diluted with dichloromethane (50 mL), and washed with water (2×10 mL) added. The reaction mixture was stirred at room temperature, diluted with dichloromethane (50 mL), and washed with water (2×10 mL) and then with water (2×10 mL). Washed with (L), dried over sodium sulfate, filtered, and concentrated to obtain Compound 7 (120 mg, Yield 100%). ESI-MS m / z: [M + H] + Calculated for C 40 H 57 F5N4O 15 : 929.37; Found 92 9.37.

[0202] Example 5; (S)-2-(4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol -1-yl)butanamide)-N1-(4-((1-(((S)-4-Ethyl-4,9- Dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3’,4’:6,7]Indolizino[1,2-b]quinolin-10-yl)methyl)pi peridin-4-yl)amino)-4-oxobutyl)-N5-(2,5,8,11,14 ,17,20,23-Octaoxapentacosane-25-yl)penta diamide (8) Synthesis

Chemical Structure

[0203] Compound 3 (60 mg, 0.126 mmol) and Compound 7 (97 mg, 0.105 mmo l) were dissolved in DMF (5 mL), cooled to about 0 °C, and then N,N-diisopropyleth lamine (37 μL, 0.21 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 8 (50 mg, Yield 39%). ESI-MS m / z: [M + H]+ Calculated for C 60 H 84 N8O 19 : 1221.59 ; Found 1221.59.

[0204] Example 6; tert-Butyl 3-(2-(2-(4-(2,5-dioxo-2,5-di hydro-1H-pyrrol-1-yl)butanamido)ethoxy)ethoxy)propano ate (10) Synthesis

Chemical Structure

[0205] Compound 9 (1.32 g, 5.7 mmol) was dissolved in DMF (10 mL), and 4 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid (1. 04 g, 5.7 mmol) was added, followed by HATU (2.6 g, 6.8 mmol) and tri ethylamine (0.96 mL, 6.8 mmol) were sequentially added, and the reaction mixture was stirred at room temperature for 1 hour, diluted with dichloromethane (100 mL), washed with water (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain Compound 10 (1.8 g, yield 80%). ESI-MS m / z : [M + H] Calculated for C H N2O7: 399.21; Found 399.21. + Calculated value C 19 H 30 N2O7: 399.21; Experimental value 399.21.

[0206] Example 7; 3-(2-(2-(4-(2,5-dioxo-2,5-dihydro-1H-pyr -ol-1-yl)butanamido)ethoxy)ethoxy)propanoic acid (11) Synthesis

Chemical Structure

[0207] Compound 10 (0.40 g, 1.0 mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroacetic acid ( 12 mL / 4 mL), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated , co-evaporated twice with dichloromethane, and dried with a vacuum pump to obtain Compound 11 as a yellow solid (0.34 g, yield 100%). ESI-MS m / z: [M+H] + Calculated for C 15 H 22 N2O7: 34 3.14; found 343.14.

[0208] Example 8; Synthesis of Perfluorophenyl 3-(2-(4-(2,5-dioxo-2,5-dihydro -1H-pyrrol-1-yl)butanamido)ethoxy)ethoxy)propanoate (12)

Chemical Structure

[0209] A solution of Compound 11 (0.34 g, 1.0 mmol) dissolved in dichloromethane (30 mL) was treated with pentafluorophenol (0.46 g, 2.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.57 g, 3.0 mmol) . The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (50 mL), washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated to obtain Compound 12 (0.51 g, yield 100%). ESI-MS m / z: [M + H] Calculated for C + H 21 F5N2O7: 509. 22 13; found 509.13.

[0210] ​Example 9; Synthesis of N,N-dimethylpiperidin-4-amine (13) [Chemical formula]

[0211] Dissolve N-Boc piperidone (10 g, 0.05 mol) in MeOH (100 mL), add aqueous dimethylamine solution (25 mL, 0.22 mol) and 10% palladium-carbon (1 g), evacuate the reaction flask and refill with hydrogen, and stir at room temperature overnight. After filtration , concentrate the filtrate, co-evaporate with dichloromethane three times (3×80 mL), and dry with a vacuum pump to remove all dimethylamine. Add HCl / MeOH (4M, 50 mL) to the residue and stir at room temperature for 30 minutes. A large amount of white solid precipitates, and the mixture is filtered to obtain white solid 1 3 (9 g, yield 90%). ESI-MS m / z: [M + H] + Calculated value for C7H 16 N2, 129.13; experimental value 129.13.

[0212] Example 10; Synthesis of (9H-fluoren-9-yl)methyl 4-(dimethylamino)piperidine -1-carboxylate (14) [Chemical formula]

[0213] Dissolve compound 13 (2.0 g, 9.9 mmol) in a mixed solution of 1,4-dioxane and water (30 mL / 5 0 mL), add sodium bicarbonate (2.5 g, 29.8 mmol), cool the mixture to 0 °C. Add a solution of 9-fluorenylmethoxycarbonyl chloride (3.1 g, 11.9 mmol) in 1,4-dioxane (10 mL) dropwise while adding Then. After the addition, the temperature was gradually raised to room temperature and the reactants were stirred for 1 hour. 1M HCl (10 0 mL) was added, the mixture was washed with ethyl acetate (3 × 50 mL), and the aqueous phase was adjusted to pH ~ 10 with sodium carbonate and extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with water (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (MeOH / dichloromethane) to obtain Compound 14 (2.75 g, 79%). ESI-MS m / z: [M + H] + Calculated for C 22 H 26 N2O2, 351.20; found 351.20.

[0214] Example 11; Synthesis of (S)-tert-butyl (1-((4-(hydroxymethyl)phenyl) amino)-1-oxopropan-2-yl)carbamate (15)

Chemical Structure

[0215] p-Aminobenzyl alcohol (5.0 g, 0.04 mol) and Boc-L-alanine (8.0 g, 0.042 mol) were dissolved in anhydrous THF (100 mL), and 2-ethoxy -1-ethoxycarbonyl-1,2-dihydroquinoline (11 g, 0.044 mol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (300 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with water (100 mL), dried over sodium sulfate and filtered, and concentrated. The crude product was triturated with ethyl acetate / petroleum ether (1:3) and filtered to obtain Compound 15 as a white solid (9.8 g, yield 84%). ES I-MS m / z: [M + H]+ Calculated value C 15 H 22 N2O4: 295.16; Experimental value 295.16.

[0216] Example 12; Synthesis of (S)-tert-butyl (1-((4-(bromomethyl)phenyl)amino)-1-oxopropan-2-yl)carbamate (16)

Chemical Structure

[0217] Compound 3 (3.5 g, 11.9 mmol) and carbon tetrabromide (5.9 g, 17.8 mmol) were dissolved in dichloromethane (80 mL), cooled to about 0 °C, and triphenylphosphine (4.7 g, 17.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 30 minutes, then 20 g of silica gel was added, mixed, dried on a rotary evaporator, and placed on a silica gel column (100 g of silica gel) and eluted with petroleum ether / ethyl acetate to obtain Compound 16 (2.6 g, 62%). ESI-MS m / z: [M + H]+ Calculated value C H BrN2O3: 35 7.07; Experimental value 357.07. 15 H 21 BrN2O3: 35 7.07; Experimental value 357.07.

[0218] Example 13; Synthesis of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(4-(2-(tert-butoxycarbonyl)amino)propanamide)benzyl)-N,N-dimethylpiperidin-4-aminium bromide (17)

Chemical Structure

[0219] ​​​Compound 16 (2.3 g, 6.4 mmol) and compound 14 (2.7 g, 7.7 mmol ) were dissolved in anhydrous THF (50 mL) and stirred at room temperature overnight. Most of the THF was removed by a rotary evaporator, and then ethyl acetate (50 mL) was added to the residue. The resulting slurry was filtered to obtain a white solid (4.5 g, yield 100%). ESI-MS m / z: M + calculated value C 37 H 47 N4O5: 627.35; experimental value 627.35.

[0220] Example 14; (S)-N-(4-(2-((tert-butoxycarbonyl)amino)prop anamido)benzyl)-N,N-dimethylpiperidin-4-aminium bromide (18 ) synthesis

Chemical Structure

[0221] Compound 17 (1.0 g, 1.41 mmol) was dissolved in DMF (5 mL), and piperidine (1 mL) was added. After stirring at room temperature for 30 minutes, ethyl acetate (30 mL) was added and stirred for 10 minutes. The mixture was filtered to obtain a white powdery solid (550 mg, yield 80%). ESI- MS m / z: M + calculated value C 22 H 37 N4O3: 405.29; experimental value 405.29.

[0222] Example 15; N-(4-((S)-2-((tert-butoxycarbonyl)amino)prop anamide)benzyl)-1-(((S)-4-ethyl-4,9-dihydroxy-3, 14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6, 7] Indolizino[1,2-b]quinolin-10-yl)methyl)-N,N-dimethylpi Synthesis of peridin-4-aminium bromide (19)

Chemical Structure

[0223] To an acetic acid solution (5 mL ) of 10-hydroxycamptothecin (375 mg, 1.03 mmol), a solution of compound 18 (550 mg, 1.13 mmol) and 37% formaldehyde (92 mg, 1.13 mmol) in acetic acid solution (5 mL) was added. The mixture was heated to about 65 °C , stirred for 1 hour, concentrated, and co-evaporated with dry MeOH. Recrystallization from dichloromethane and a small amount of MeOH gave compound 19 (0.5 g, 63% yield) as a yellow powder ESI-MS m / z: M + Calculated for C 43 H 53 N6O8: 781.39; Found 781.39.

[0224] Example 16; N-(4-((S)-2-aminopropanamide)benzyl)-1-((( S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinol in-10-yl)methyl)-N,N-dimethylpiperidin-4-aminium bromide (2 0) Synthesis

Chemical Structure

[0225] Compound 19 (50 mg, 0.058 mmol) was dissolved in dichloromethane and trifluoroacetic acid Dissolved in a mixed solvent of acid (2 mL / 6 mL) and stirred at room temperature for 30 minutes. Then, the mixture was concentrated and dried with a vacuum pump to obtain Compound 20 as a yellow solid (44 mg, yield 1 00%). ESI-MS m / z: M + Calculated for C 38 H 45 N6O6: 681.34; Found 681.34.

[0226] Example 17; N-(4-((S)-2-(4-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)butanamide)propanamide)benzyl)-1-(((S )-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetra hydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline -10-yl)methyl)-N,N-dimethylpiperidin-4-aminium formate (2 1) Synthesis

Chemical Structure

[0227] Compound 20 (88 mg, 0.116 mmol) and Compound 4 (49 mg, 0.140 m mol) were dissolved in DMF (5 mL), cooled to about 0 °C, and then N,N-diisoprop ylethylamine (40 μL, 0.232 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 21 (66 mg, yield 68%). ESI-MS m / z: M + Calculated for C 46 H 52 N7O9: 846.38; Found 846.38.

[0228] Example 18; N-(4-((9S,17S)-9-(4-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)butanamide)-17-methyl-6,10,15 -trioXo-2-oxa-5,11,16-triazaoctadecanamide)benzyl) -1-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4, 12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2 -b]quinolin-10-yl)methyl)-N,N-dimethylpiperidin-4-aminium formate (22) synthesis

Chemical formula

[0229] Compound 20 (44 mg, 0.058 mmol) and compound 7 (60 mg, 0.065 m mol) were dissolved in DMF (5 mL), cooled to about 0 °C, and then N,N-diisoprop ylethylamine (20 μL, 0.116 mmol) was added. The reaction was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 22 (51 mg, yield 58%). ESI-MS m / z: M + Calculated value C 72 H 101 N 10 O 20 : 142 5.72; Experimental value 1425.72.

[0230] Example 19; 1-(2-amino-4-fluoro-5-methoxyphenyl)-2-chloroeth tanone (24d) synthesis

Chemical formula

[0231] 3-Fluoro-4-methoxyaniline (5 g, 35.4 mmol) was dissolved in dichloromethane ( 20 mL), and the solution was added dropwise to a solution of boron trichloride (1 M in dichloromethane, 3 8.9 mL) cooled in ice water. After stirring for 10 minutes, chloroacetonitrile ( 3.2 g, 42.5 mmol) and aluminum trichloride (5.2 g, 38.9 mmol) were added. After the addition was complete, the reaction mixture was warmed to room temperature and then refluxed overnight. The reaction mixture was cooled to about 0 °C, quenched with 2 M HCl (80 mL), and stirred at room temperature for 2 hours. The layers were separated, and the aqueous phase was extracted with dichloromethane (3 × 80 mL). The combined organic phases were washed with water (10 0 mL), dried over sodium sulfate, filtered, concentrated, and purified by elution with petroleum ether / ethyl acetate on a silica gel column to obtain Compound 24d as a yellow solid (2 g , yield 26%). ESI-MS m / z: [M + H] Calculated for C9H9ClFNO2: 218.03; Found 218.03. + Example 20; Synthesis of (S)-11-(chloromethyl)-4-ethyl-8-fluoro-4-hydroxy

[0232] -9-methoxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b] quinoline-3,14(4H,12H)-dione (26d)

Chemical Structure

[0233] Compound 24d (0.50 g, 2.29 mmol) and Compound 25 (0.57 g, 2.1 9 mmol) were dissolved in anhydrous toluene (40 mL), and p-toluenesulfonic acid (42 m ​g, 0.219 mmol) was added. The suspension was heated under reflux for 2 days and cooled to room temperature After removing about 2 / 3 of the toluene, the residue was filtered, and the filter cake was washed with dichloromethane and air-dried to obtain Compound 26d as a gray powdery solid (0.7 g, yield 72%) . ESI-MS m / z: [M + H] + Calculated for C 22 H 18 ClFN2O5: 445.09; Found 445.09.

[0234] Example 21; Synthesis of N-(4-((S)-2-((tert-butoxycarbonyl)amino)propyl)amide)benzyl)-1-(((S)-4-ethyl-8-fluoro-4-hydroxy -9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl )-N,N-dimethylpiperidin-4-aminium chloride (27) A mixture of Compound 26d (218 mg, 0.49 mmol) and Compound 18 ( 200 mg, 0.49 mmol) in DMF (5 mL) was stirred at 0 °C for 30 minutes, then triethylamine [Chemical formula]

[0235] (63 μL, 0.45 mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 10 as a yellow solid (240 mg, yield 59%). ESI-MS m / z: M (63 μL, 0.45 mmol) was added and stirring was continued for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 10 as a yellow solid (240 mg, yield 59%). ESI-MS m / z: M (240 mg, yield 59%). ESI-MS m / z: M + Calculated for C 44 H 54 FN6O8: 813.40; Found 813.40.

[0236] Example 22; N-(4-((S)-2-aminopropanamide)benzyl)-1-((( (S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo -3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino (1,2-b)quinolin-11-yl)methyl)-N,N-dimethylpiperidin-4- ammonium (28) synthesis

Chemical formula

[0237] Compound 27 (50 mg, 0.06 mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroacetic acid (2 mL / 6 mL) and stirred at room temperature for 30 minutes. Then, the mixture was concentrated and dried under a vacuum pump to obtain compound 28 as a yellow solid (42 mg, yield 100 %). ESI-MS m / z: M + Calculated value for C 39 H 46 FN6O6: 713.35; Experimental value 713.35.

[0238] Example 23; N-(4-((30S,38S)-30-(4-(2,5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl)butanamide)-38-methyl-27,31 ,36-trioxo-2,5,8,11,14,17,20,23-octaoxa-26 ,32,37-triazanonatriacontanamide)benzyl)-1-(((S)-4- ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4, 12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2 -b]quinolin-11-yl)methyl)-N,N-dimethylpiperidin-4-ammonium Synthesis of Formate (29)

Chem.

[0239] Compound 28 (47 mg, 0.060 mmol) and Compound 7 (60 mg, 0.066 m mol) were dissolved in DMF (5 mL), cooled to about 0 °C, and N,N-diisopropyleth ylamine (21 μL, 0.12 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (water containing acetonitrile / formic acid) to obtain Compound 29 (23 mg, yield 25%). ESI-MS m / z: M Calculated value for C + H 73 H 102 FN 10 O 20 : 1457.73; Experimental value 1457.73.

[0240] Example 24; Synthesis of (S)-11-(Aminomethyl)-4-ethyl-8-fluoro-4-hydro xy-9-methoxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b] quinoline-3,14(4H,12H)-dione (30)

Chem.

[0241] Compound 26d (80 mg, 0.18 mmol) was dissolved in ethanol (5 mL), hexamethylenetetramine (76 mg, 0.54 mmol) was added, and the mixture was refluxed for 90 minutes and then cooled to room temperature. Concentrated hydrochloric acid (100 μL) was added and the mixture was stirred for 30 minutes. After concentration, an off-white solid was obtained, which was purified by preparative HPLC (water containing acetonitrile / formic acid). Prepared to obtain Compound 30 (40 mg, yield 52%). ESI-MS m / z: [M + H] + Calculated value for C 22 H 20 FN3O5: 426.14; experimental value 426.14.

[0242] Example 25; (S)-2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide)-N1-(4-((((S)-4-ethyl-8-fluoro -4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro -1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-10 -yl)methyl)amino)-4-oxobutyl)-N5-(2,5,8,11,14,1 7,20,23-octaoxapentacosan-25-yl)penta diamide (31) synthesis

Chemical Structure

[0243]

[0243] Compound 30 (40 mg, 0.094 mmol) and Compound 7 (120 mg, 0.13 m mol) were dissolved in DMF (5 mL), cooled to about 0 °C, and then N,N-diisoprop ylethylamine (33 μL, 0.188 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 31 (55 mg, yield 50%). ESI-MS m / z: [M + H] + Calculated value for C 56 H 76 FN7O 19 : 1170.52; experimental value 1170.52.

[0244] Example 26; Synthesis of tert-butyl (1-methylpiperidin-4-yl) carbamate (32 ) [Chemical formula]

[0245] 4-(tert-Butoxycarbonylamino)piperidine (2 g, 10 mmol) was dissolved in M eOH (30 mL), and 37% formaldehyde (1.6 g, 20 mmol) and 10% palladium-carbon (0.2 g) were added. The reaction mixture was stirred overnight under 1 atm of hydrogen , and then filtered. The filtrate was concentrated to obtain Compound 32 (2.1 g, yield 100%). ESI-MS m / z : [M + H] + Calculated for C 11 H 22 N2O2: 215.17; Found 215.17.

[0246] Example 27; Synthesis of (S)-4-((tert-butoxycarbonyl)amino)-1-((4- ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4, 12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2 -b]quinolin-11-yl)methyl)-1-methylpiperidin-1-ium chloride (33) [Chemical formula]

[0247] A DMF solution (3 mL) of Compound 26d (50 mg, 0.112 mmol) and Compound 32 (26 mg, 0.12 3 mmol) was stirred at room temperature for 2 h. The reaction solution was purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 6 (33 mg, yield 47%) 。ESI-MS m / z: [M] + Calculated value C 33 H 40 FN4O7: 623.29; Experimental value 623.29.

[0248] Example 28; (S)-4-Amino-1-((4-ethyl-8-fluoro-4-hydroxy -9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H)-pyr ano[3’,4’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl )-1-methylpiperidin-1-ium (34) synthesis

Chemical Structure

[0249] Compound 33 (30 mg, 0.053 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid (3 mL / 1 mL) and stirred at room temperature for 30 minutes. Then the mixture was concentrated and dried under a vacuum pump to obtain Compound 34 (33 mg, yield 100%). ESI-MS m / z : [M] + Calculated value C 28 H 32 N4O5: 477.21; Experimental value 477.21.

[0250] Example 29; 4-((S)-30-(4-(2,5-dioxo-2,5-dihydro-1H -pyrrol-1-yl)butanamide)-27,31-dioxo-2,5,8,11,1 4,17,20,23-octaoxa-26,32-diazahexatriacontanamide )-1-(((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3, 14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6, 7] (Indolizin[1,2-b]quinolin-11-yl)methyl)-1-methylpiperidin Synthesis of -1-ium formate (35) [Chemical formula]

[0251] Compound 34 (30 mg, 0.053 mmol) and compound 7 (60 mg, 0.079 m mol) were dissolved in DMF (5 mL), cooled to about 0 °C, and then N,N-diisoprop ylethylamine (18 μL, 0.106 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 35 (15 mg, yield 21%). ESI-MS m / z: [M]+ calculated value C 62 H 88 FN8O 19 : 1267 .61; experimental value 1267.61.

[0252] Example 30; Synthesis of (9H-fluoren-9-yl)methyl 4-methylpiperazine-1-car boxylate (36) [Chemical formula]

[0253] 1-Methylpiperazine (5.0 g, 50.0 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (60 mL / 100 mL), sodium hydrogen carbonate (12.6 g, 1 50 mmol) was added, and the mixture was cooled to 0 °C. A solution of 9-fluorenylmethoxycarbonyl chloride (15.5 g, 60.0 mmol) in 1,4-dioxane (20 mL) was added dropwise . After the addition, the temperature was gradually raised to room temperature, and the reaction mixture was stirred for 3 hours. 300 mL of 1 M HCl was added, and the mixture was washed with ethyl acetate (2 × 100 mL), and the aqueous phase was adjusted to pH ~ 10 with sodium carbonate and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with water (250 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH / dichloromethane) to obtain Compound 2 (6.5 g, yield 40%). ESI-MS m / z: [M + H] + Calculated for C 20 H 22 N2O2, 323.17; found 323.19 .

[0254] Example 31; (S)-4-(((9H-Fluoren-9-yl)methoxy)carbonyl) -1-(4-(2-((tert-Butoxycarbonyl)amino)propanamide)ben zyl)-1-methylpiperazin-1-ium bromide (37) Synthesis

Chemical Structure

[0255] Compound 16 (2.3 g, 6.4 mmol) and Compound 36 (2.1 g, 6.4 mmol ) were dissolved in anhydrous THF (100 mL) and stirred at room temperature overnight. Most of the THF was removed by rotary evaporator, and then ethyl acetate (200 mL) was added to the residue. The resulting slurry was filtered to obtain a white solid (3.8 g, yield 87%). ESI-MS m / z: M + Calculated for C 35 H 43 N4O5: 599.32; found 599.32.

[0256] Example 32; (S)-1-(4-(2-((tert-Butoxycarbonyl)amino)pro Synthesis of (3-((S)-2-((tert-Butoxycarbonyl)amino)propanamido)benzyl)-1-methylpiperazin-1-ium bromide (38) Synthesis

Chemical formula

[0257] Compound 37 (3.12 g, 4.6 mmol) was dissolved in DMF (25 mL), and piperidine (3 mL) was added. After stirring at room temperature for 2 hours, 200 mL of ethyl acetate was added and stirred for 10 minutes. The mixture was filtered to obtain a white solid (1.54 g, yield 77%). ESI-MS m / z : M Calculated for C + H 20 N4O3: 377.26; Found 377.26. 33

[0258] Example 33; Synthesis of 1-(4-((S)-2-((tert-Butoxycarbonyl)amino)propanamido)benzyl)-4-(((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-1-methylpiperazin-1-ium (39) )-1-methylpiperazin-1-ium (39)

Chemical formula

[0259] A DMF solution (10 mL) of a mixture of compound 38 (0.30 g, 0.66 mmol) and compound 26d (0.25 g, 0.5 6 mmol) was stirred at 0 °C for 30 minutes, N,N-diisopropylethylamine (49 μL, 0.28 mmol) was added, and the reaction mixture was warmed to room temperature. ​​​​​Dissolve it, stir overnight, concentrate, and purify by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 39 (0.40 g, yield 80%). ESI-MS m / z: M + Calculated for C 42 H 50 FN6O8: 7 85.37; found 785.37.

[0260] Example 34; 1-(4-((S)-2-aminopropanamido)benzyl)-4-((( S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo -3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indoliz ino[1,2-b]quinolin-11-yl)methyl)-1-methylpiperazin-1-ium (40) Synthesis

Chemical Structure

[0261] Dissolve Compound 39 (0.30 g, 0.35 mmol) in a mixture of dichloromethane and trifluoroacetic acid (3 mL / 3 mL), and stir at room temperature for 30 minutes. Then, concentrate the mixture and dry it under a vacuum pump to obtain Compound 40 (0.27 g, yield 100%) as a yellow solid ESI-MS m / z: M + Calculated for C 37 H 42 FN6O6: 477.21; found 477.21.

[0262] Example 35; 1-(4-((S)-2-(4-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)butanamido)propanamido)benzyl)-4-(((S )-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo- 3,4,12,14-Tetrahydro-1H-pyrano[3’,4’:6,7]indolizino [1,2-b]quinolin-11-yl)methyl)-1-methylpiperazin-1-ium Synthesis of formate (41)

Chemical Structure

[0263] Compound 40 (50 mg, 0.065 mmol) and compound 4 (30 mg, 0.098 m mol) were dissolved in DMF (3 mL), and N,N-diisopropylethylamine (45 μ L, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, concentrated, and then purified by preparative C- 18 HPLC (acetonitrile / water containing formic acid) to obtain compound 41 (37 m g, yield 61%). ESI-MS m / z: M + Calculated for C 45 H 49 FN7O9: 850.36; found 850.36.

[0264] Example 36; 1-(4-((30S,38S)-30-(4-(2,5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl)butanamide)-38-methyl)-27,3 1,36-trioxo-2,5,8,11,14,17,20,23-octaoxa-2 6,32,37-triazanonatriacontanamide)benzyl)-4-(((S)-4 -ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4 ,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1, 2-b]quinolin-11-yl)methyl)-1-methylpiperazin-1-ium formate (42) Synthesis

Chemical Structure

[0265] Compound 40 (70 mg, 0.092 mmol) was dissolved in DMF (2 mL), and compound 7 (70 mg, 0.092 mmol) in DMF (2 mL) was added. Subsequently, HATU (5 2 mg, 0.138 mmol) and triethylamine (52 μL, 0.368 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. After concentration, the residue was purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 43 (50.9 mg, yield 37%). ESI-MS m / z: [M+] / z: [M+] + Calculated value C 71 H 98 FN 10 O 20 : 1429.69; experimental value 1429.69.

[0266] Example 37; Synthesis of 1-(4-((S)-17-(2,5-dioxo-2,5-dihydro-1H -pyrrol-1-yl)-2-methyl-4,14-dioxo-7,10-dioxa-3, 13-diazaheptadecanamide)benzyl)-4-(((S)-4-ethyl-8-fluoro -4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin- 11-yl)methyl)-1-methylpiperazin-1-ium formate (43) 11-yl)methyl)-1-methylpiperazin-1-ium formate (43)

Chemical Structure

[0267] Compound 40 (0.10 g, 0.13 mmol) in DMF (1 mL) and DMF (2 m Compound 12 (66 mg, 0.13 mmol) in (L) was mixed, and then N,N - diisoprop ylethylamine (90 μL, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and after concentration, it was purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 4 3 (50.9 mg, yield 39%). ESI - MS m / z: calculated value for M+ C 52 H 62 N8O 12 : 1009.45 ; experimental value 1009.45.

[0268] Example 38; Synthesis of (S) - 3 - ((tert - butoxycarbonyl)amino) - 2 - (2,5 -dioxo - 2,5 - dihydro - 1H - pyrrol - 1 - yl)propanoic acid (44)

Chemical Structure

[0269] In an ice - water bath, methyl 2,5 - dioxo - 2,5 - dihydro - 1H - pyrrole - 1 - carboxylate (1.52 g, 9.8 0 mmol) was added to a saturated NaHCO3 solution (20 mL) of 2 - amino - 3 - ((tert - butoxycarbonyl)amino)propanoic acid (1 g, 4.90 mmol). The reaction mixture was stirred for 30 minutes, then poured into a separatory funnel containing 100 mL of ethyl acetate, and the organic phase was separated, washed with 50 mL of water and 50 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 4 (1.39 g, yield 72%)

[0270] .

[0270] Example 39; (S) - Perfluorophenyl 3 - ((tert - butoxycarbonyl)a mino) - 2 - (2,5 - dioxo - 2,5 - dihydro - 1H - pyrrol - 1 - yl)pro Synthesis of Panoate (45) [Chemical formula]

[0271] A solution prepared by dissolving Compound 44 (0.10 g, 0.35 mmol) in dichloromethane (30 mL) was added with pentafluorophenol (97 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.7 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (50 mL), washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated to obtain Compound 45 (0.16 g, yield 100%). ESI-MS m / z: [M + H] + Calculated value for C 18 H 15 F5N2O6: 45 1.09; Experimental value 451.09.

[0272] Example 40; Synthesis of Compound 46 [Chemical formula]

[0273] Compound 40 (0.05 g, 0.065 mmol) and Compound 45 (45 mg, 0.10 mmol) were dissolved in DMF (3 mL), and then N,N-diisopropylethylamine (45 μL, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, concentrated, and then purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 46 (35 mg, yield 52%). ESI-MS m / z: M + Calculated value for C 49 H 56 FN8O 11 : 951.41; Experimental value 951.41.​​​​​

[0274] Example 41; 1-(4-((S)-2-((S)-3-amino-2-(2,5-dioxo -2,5-dihydro-1H-pyrrol-1-yl))propanamide)propanamide) benzyl)-4-(((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy -3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4 ’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-1-methyl piperazin-1-ium(47) synthesis

Chemical formula

[0275] Compound 46 (35 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (1 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated and co-evaporated twice with dichloromethane and dried under a vacuum pump to obtain compound 47 (30.4 mg, yield 96%). ESI-MS m / z: M+ calculated for C H 44 H 48 FN8O9: 851.35; found 851.35.

[0276] Example 42; (S)-tert-butyl (1-((4-ethyl-8-fluoro-4-hydroxy -9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H -pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl)piperidin-4-yl)carbamate (48) synthesis

Chemical formula

Chemical formula

[0277] Compound 26d (50 mg, 0.11 mmol) was dissolved in DMF (3 mL), and tert-butyl piperidin-4-ylcarbamate (25 mg, 0.12 mmol) was added and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated and purified by preparative HPLC (acetonitrile / water containing formic acid) to give compound 48 (30 mg, yield 45%). ESI-MS m / z: [M + H] + Calculated for C 32 H 37 FN4O7: 609.26; Found 609.26.

[0278] Example 43; (S)-11-((4-aminopiperidin-1-yl)methyl)-4-ethyl -8-fluoro-4-hydroxy-9-methoxy-1H-pyrano[3’,4’:6,7 indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (49) Synthesis

Chemical Structure

[0279] Compound 48 (30 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (2 mL). After stirring at room temperature for 1 hour, the mixture was concentrated and co-evaporated twice with dichloromethane and dried under vacuum pump to give compound 49 (25.4 mg, yield 100%). ESI-MS m / z: [M + H] Calculated for C + H 27 FN 30 : 509.21; Found 509.21 45 . .

[0280] Example 44; (S)-2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrro (1-Ethylbutanamide)-N1-(4-((1-(((S)-4-Ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl)piperidin-4-yl)amino)-4-oxobutyl)-N5-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)penta diamide (50) Synthesis luoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetra hydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline -11-yl)methyl)piperidin-4-yl)amino)-4-oxobutyl)-N5- (2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl )pentanediamide (50) Synthesis [Chemical Structure]

[0281] Compound 49 (25.4 mg, 0.05 mmol) was dissolved in DMF (2 mL), and compound 7 (38.1 mg, 0.05 mmol) was added thereto. Subsequently, HATU (28.5 mg , 0.08 mmol) and triethylamine (14 μL, 0.1 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 50 (14.4 mg, yield 23%). ESI-MS m / z: [M + H] , 0.08 mmol) and triethylamine (14 μL, 0.1 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour, concentrated, and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 50 (14.4 mg, yield 23%). ESI-MS m / z: [M + H] and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 50 (14.4 mg, yield 23%). ESI-MS m / z: [M + H] to obtain compound 50 (14.4 mg, yield 23%). ESI-MS m / z: [M + H] + Calculated value C 61 H 85 FN8O 19 : 1253.59; Observed value 1253.59.

[0282] Example 45; tert-Butyl bis(2-(2,2,2-trifluoroacetamide)ethyl)carbamate (51) Synthesis tert-Butyl bis(2-(2,2,2-trifluoroacetamide)ethyl)carbamate (51) Synthesis [Chemical Structure]

[0283] At 0 °C, a dichloromethane solution of diethylenetriamine (6.18 g, 60 mmol) (120 mL) was added dropwise with a dichloromethane solution of ethyl trifluoroacetate (18.75 g, 132 mmol) (60 mL). The mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour. At room temperature, a dichloromethane solution of di-tert-butyl dicarbonate (28.78 g, 132 mmol) and triethylamine (13.33 g, 132 mmol) (60 mL) was added dropwise and stirred overnight. The reaction mixture was washed with saturated sodium carbonate (2 × 200 mL), water (2 × 200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and + concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate) to obtain a white solid (17.4 g, yield 73.3%). 13 ESI-MS m / z: [M + H] 19 Calculated for C

[0284] Example 46; Synthesis of tert-butyl bis(2-aminoethyl)carbamate (52) [Chemical formula]

[0285] Compound 51 (4.28 g, 10.8 mmol) was dissolved in MeOH (50 mL) and stirred at room temperature for 3 hours with an aqueous solution of sodium hydroxide (5.42 g, 135 mmol) (50 mL). The reaction mixture was concentrated, extracted with dichloromethane (3 × 100 mL), and the organic phase was washed with brine (100 mL), dried over sodium+ Calculated value C9H 21 N3O2204.28; Experimental value 204.12.

[0286] Example 47; 4,4'-((((tert-Butoxycarbonyl)azanediyl)bis( ethane-2,1-diyl))bis(azanediyl))bis(4-oxobutanoic acid)(53 ) synthesis

Chemical Structure

[0287] Compound 52 (1.8 g, 8.8 mmol) was dissolved in dichloromethane (150 mL), and succinic anhydride (2.2 g, 22.1 mmol) was added thereto. After stirring overnight at room temperature, the reaction mixture was concentrated and purified by eluting with dichloromethane / MeOH on a silica gel column, to obtain compound 53 (2.99 g, yield 84%). ESI-MS m / z: [M + H] + Calculated value C 17 H 29 N3O 8: 404.43; Experimental value 404.11.

[0288] Example 48; Bis((S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4 ,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1, 2-b]quinolin-9-yl)4,4'-((((tert-butoxycarbonyl)aza nediyl)bis(ethane-2,1-diyl))bis(azanediyl))bis(4-oxo butanoate)(54) synthesis

Chemical Structure

[0289] Compound 53 (853 mg, 2.1 mmol) and a DMF solution (100 mL) of Compound 5 (1.71 g, 4.7 mmol) were successively added with triethylamine (948 mg, 9.4 mmol) and HATU (1.79 g, 4.7 mmol). The resulting mixture was stirred overnight and then concentrated and purified by silica gel column (dichloromethane / MeOH) to obtain Compound 54 (2.84 g, yield 100%). ESI-MS m / z: [M + H] + Calculated value for C 57 H 57 N7O 16 : 1097.10; Experimental value 1097.65.

[0290] Example 49; Synthesis of bis((S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4 ,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1, 2-b]quinolin-9-yl)4,4’-((azanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(4-oxobutanoate) (55)

Chemical Structure

[0291] Compound 54 (2.84 g, 2.1 mmol) was dissolved in dichloromethane (40 mL) and trifluoroacetic acid (20 mL) was added. After stirring the reaction mixture at room temperature for 1 hour, it was concentrated to obtain Compound 55 (3.3 g, yield 100%). ESI-MS m / z: [M + H] + Calculated value for C 52 H 49 N7 O 14 : 996.98; Experimental value 996.60.

[0292] Example 50; (S)-(S)-4-Ethyl-4-hydroxy-3,14-dioxo-3, 4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1 ,2-b]quinolin-9-yl 30-(4-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)butanamide)-37-(2-(4-(((S)-4-eth yl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H- pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-9-yl)oxy ))-4-oxobutanamide)ethyl)-27,31,36,41-tetraoxo-2, 5,8,11,14,17,20,23-octaoxa-26,32,37,40-tetra aza-tetratetracontane-44-oate (56) Synthesis

Chemical Structure

[0293] To a DMF solution (20 mL) of Compound 55 (614 mg, 0.60 mmol) and Compound 53 (470 mg, 0.60 mmol), triethylamine (249 mg, 2.5 mmol) and HATU (234 mg, 0.60 mmol) were sequentially added. The resulting mixture was stirred for 40 minutes, concentrated, and purified by silica gel column (MeOH / dichloromethane) to obtain Compound 56 (46 mg, yield 5%). ESI-MS m / z: [M + H] Calculated value for C H + N1 86 H 105 N1 1O 28 : 17410.81; Experimental value 1742.01.

[0294] Example 51; (S)-4-Ethyl-4-hydroxy-9-methoxy-1H-pyrano[3’ ,4’:6,7]Indolizino[1,2-b]quinoline-3,14(4H,12H)-dione Synthesis of (57)

Chemical formula

[0295] 10-Hydroxycamptothecin (2.5 g, 6.86 mmol) was dissolved in DMF (150 mL ), potassium carbonate (1.90 g, 13.72 mmol) and methyl iodide (1 .17 g, 8.23 mmol) were added, and the mixture was stirred overnight at room temperature. Petroleum ether (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture and stirred. A yellow solid was precipitated, which was collected by filtration and dispersed in water (20 mL). 1N hydrochloric acid was added dropwise until pH 7, and the mixture was filtered again to obtain compound 57 (1.0 g, yield 38%). ES I-MS m / z: [M + H] + Calculated for C 21 H 18 N2O5 379.38; Found 379.05.

[0296] Example 52; Synthesis of bis((S)-4-ethyl-9-methoxy-3,14-dioxo-3,4, 12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2 -b]quinolin-4-yl)(((tert-butoxycarbonyl)azanediyl)bis (ethane-2,1-diyl))dicarbamate (59)

Chemical formula

[0297] Compound 57 (350 mg, 0.9 mmol), 4-dimethylaminopyridine (339 m g, 2.8 mmol), and triphosgene (93 mg, 0.34 mmol) were pulverized and uniformly mixed under N 2. Then anhydrous dichloromethane (8 mL) was added dropwise and stirred for 10 minutes . Compound 52 (64 mg, 0.34 mmo l) dissolved in anhydrous dichloromethane (4 mL) was added, and then triethylamine (93 mg, 0.9 mmol) was added. After stirring for 15 minutes , the solution was concentrated and purified by silica gel column (MeOH / dichloromethane) to obtain compound 59 (200 mg, yield 22%). ESI-MS m / z: [M + H] + Calculated value for C 53 H 53 N7 O 14 : 1013.03; Experimental value 1013.26.

[0298] Example 53; Synthesis of bis((S)-4-ethyl-9-methoxy-3,14-dioxo-3,4, 12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2 -b]quinolin-4-yl)(azanediylbis(ethane-2,1-diyl))dicarbonate (60)

Chemical Structure

[0299] Compound 59 (200 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (5 mL) for 4 hours. By concentrating the reaction mixture, compound 60 was obtained (0.43 g, yield 100%). ESI-MS m / z: [M + H] + Calculated value for C 48 H 45 N7 O 12 : 912.91; Experimental value 912.62.

[0300] ​ Example 54; Bis((S)-4-ethyl-9-methoxy-3,14-dioxo-3,4, 12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2 -b]quinolin-4-yl)(((4-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)butanoyl)azanediyl)bis(ethane-2,1-diyl))di carbamate (61) synthesis

Chemical Structure

[0301] To a dichloromethane solution (10 mL) of Compound 59 (249 mg, 0.27 mmol) and Compound 7 (60 mg, 0.32 mmol) were added triethylamine (112 μL, 0.81 mmol) and HATU (104 mg, 0.27 mmol). The reaction mixture was stirred for 40 minutes and washed with water (20 mL). The organic phase was concentrated and purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain Compound 61 (50 mg). ESI-MS m / z: [M + H] calculated value C H + N8O 56 H 52 N8O 15 1078.06; experimental value 1078.77.

[0302] Example 55; (S)-N,N’-(((((2S,20S)-11-(tert-butoxy carbonyl)-2,20-dimethyl-4,7,15,18-tetraoxo-3,8,1 1,14,19-pentaazapentacosane-1,21-diyl)bis(azanediyl)) bis(4,1-phenylene))bis(methylene))bis(1-(((S)-4-ethyl- 8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,1 4-Tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]qui nolin-11-yl)methyl)-N,N-dimethylpiperidin-4-aminium)(62 ) synthesis

Chemical formula

[0303] Compound 40 (96 mg, 0.132 mmol) and compound 53 (26 mg, 0.066 mmol) were dissolved in DMF (3 mL) and cooled to 0 °C. HATU (50 mg, 0. 132 mmol)) and N,N-diisopropylethylamine (46 μL, 0.264 m mol) were added. After the addition was complete, the mixture was stirred at 0 °C for 30 minutes. The crude reaction mixture was directly purified by preparative H PLC (acetonitrile / water containing formic acid) (acetonitrile / water containing 0.1% formic acid) to obtain compound 62 (80 mg, yield 67%). ESI-MS m / z: [M] Calculated value C 2+ H 91 F 109 2N O 15 : 868.90; Experimental value 868.90. 18 Example 56; (S)-N,N’-(((((2S,20S)-2,20-Dimethyl-4,

[0304] 7,15,18-Tetraoxo-3,8,11,14,19-pentaazapentacosan-1 7,15,18-Tetraoxo-3,8,11,14,19-pentaazapentacosan-1 ,21-dioyl)bis(azanediyl))bis(4,1-phenylene))bis(methyle ne))bis(1-(((S)-4-Ethyl-8-fluoro-4-hydroxy-9-methoxy syl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4 ’:6,7)indolizino[1,2-b]quinolin-11-yl)methyl)-N,N-di Synthesis of (Methylpiperidin-4-aminium)(63) [Chemical formula]

[0305] Compound 62 (80 mg, 0.043 mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroacetic acid (3 mL / 1 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain Compound 63 (yield 100%). ESI-MS m / z: [M] 2+ Calculated value for C 86 H1 01 F2N 15 O 16 : 818.87; Experimental value 818.87.

[0306] Example 57; (S)-N,N'-(((((2S,20S)-11-((S)-30-( 4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide )-27,31-Dioxo-2,5,8,11,14,17,20,23-octaoxa -26,32-Diazahexatriacontan-36-oil)-2,20-dimethyl-4 ,7,15,18-Tetraoxo-3,8,11,14,19-pentaazhenicosane -1,21-Dioyl)bis(azanediyl))bis(4,1-phenylene))bis(meth ylene))bis(1-(((S)-4-Ethyl-8-fluoro-4-hydroxy-9-meth oxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’ ,4’:6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-N,N -dimethylpiperidin-4-aminium)(64) Synthesis [Chemical formula]

[0307] At 0 °C, to a DMF solution (3 mL) of compound 63 (74 mg, 0.043 mmol) and compound 7 (39 mg, 0. 0516 mmol), N,N - diisopropylethylamine ( 15 μL, 0.086 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours. After concentration, the residue was purified by preparative HPLC (acetonitrile / water containing formic acid) to obtain compound 64 (1 2 mg). ESI - MS m / z: [M+] Calculated for C 2+ H 120 F2N 157 O 19 : 1191.06; found 1191. 30 06. 06.

[0308] Example 58; Synthesis of (S) - 4 - ethyl - 8 - fluoro - 4,9 - dihydroxy - 11 - methyl -1H - pyrano[3’,4’:6,7]indolizino[1,2 - b]quinoline - 3,14 (4H,12H) - dione (103)

Chemical Structure

[0309] 1 - (2 - amino - 4 - fluoro - 5 - hydroxyphenyl)ethanone (0.41 g, 2.5 mmol) and compound 25 (0.62 g, 2.5 mmol) were dissolved in anhydrous toluene (40 mL), and p - toluenesulfonic acid (46 mg, 0.25 mmol) was added. The suspension was heated to reflux for 3 days and then cooled to room temperature. After removing the solvent, the residue was purified by column chromatography to obtain compound 103 as a gray powder - like solid (0.69 g, yield 73%) . ESI - MS m / z: [M + H] +Calculated value C 21 H 17 FN2O5: 397.11; Experimental value 397.16.

[0310] Example 59; (S)-9-(2-Bromoethoxy)-4-ethyl-8-fluoro-4-hydroxy-11-methyl-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione 1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione b] Synthesis of quinoline-3,14(4H,12H)-dione (104)

Chemical formula

[0311] A mixture of compound 103 (0.69 g, 1.74 mmol), anhydrous 1,2-dibromoethane (6.4 g, 34.8 mmol), and anhydrous K2CO3 (1.2 g, 8.7 mmol) in anhydrous DMF (10 mL) was mechanically stirred at 80 °C for 16 hours. The reaction mixture was filtered through a pad of Celite, and the filtered residue was washed well with DMF. The filtrate and the washings were combined and evaporated to dryness in vacuo to give a dark residue. The residue was purified by column chromatography (0 - 5% MeOH / dichloromethane) to give compound 104 (0.74 g, 85%). ESI-MS m / z: [M + H] ,2-dibromoethane (6.4 g, 34.8 mmol), and anhydrous K2CO3 (1.2 g ,8.7 mmol) was mechanically stirred at 80 °C for 16 hours. The reaction mixture was filtered through a pad of Celite, and the filtered residue was washed well with DMF. The filtrate and the washings were combined and evaporated to dryness in vacuo to give a dark residue. The residue was purified by column chromatography (0 - 5% MeOH / dichloromethane) to give compound 104 (0.74 g, 85 %)。ESI-MS m / z: [M + H] %)。ESI-MS m / z: [M + H] + Calculated value C 23 H 20 BrFN2O5: 503.05; Experimental value 503.05.

[0312] Example 60; (S)-9-(2-Bromoethoxy)-4-ethyl-8-fluoro-4-hydroxy-11-methyl-10-nitro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione 1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione b] Synthesis of quinoline-3,14(4H,12H)-dione (105)

Chemical formula

[0313] At 0 °C, to the stirred concentrated H2SO4 (1 mL) was slowly added compound 104 (0.74 g, 1.47 m mol), and the resulting clear solution was cooled to -10 °C. A mixture of concentrated H2SO4 (0 .5 mL) and fuming HNO3 (0.5 mL) was pre-cooled to -10 °C and added dropwise to the reaction mixture cooled at -10 °C. The reaction mixture was warmed to 0 °C and stirred for an additional 1 hour, and then slowly poured onto an ice chip. The yellow precipitate was filtered and washed with H2O, col...

Claims

1. A cell surface-binding molecule-camptothecin analog conjugate represented by the following formula (I), or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or an isotope, optical isomer, racemate, diastereomer, or enantiomer thereof: Wherein, T is a cell-binding agent / molecule; L is a releasable linker; is a bond; n is from 1 to 30, and m is from 1 to 10; 【Chemical 1】 The inside of the parentheses is an effective camptothecin analog, wherein, , alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), [Chemical Formula 2] independently to L and R in parentheses １ , R ２ , R ３ , or R ５ connections that are independently connected to the atoms of , aminoalkyl, oxyalkyl, aminoalkylamino, oxyalkylamino, a , minoalkyloxy, oxyalkyloxy, alkylcarboxylic acid, or carbonyl group; R １ and R ２ are independently H; straight-chain or branched C １ ~C ６ alkyl, alkyl alcohol , chloroalkyl, heteroalkylcycloalkyl, alkylcarbonyl, aminoalkylcar , bonyl, oxyalkylcarbonyl, alkyl ether, alkyl ester, alkyl , there is; C ２ to C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, aminosi , alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), , cycloalkyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl Amide, oxyalkylamide, aminoalkylamide, oxime; NH ２ , or OH , X is NH or O; R ３ is, independently, H, C(O)NH, C(O)O, SO ２ R ６ 、SO ３ R ６ 、PR ６ R ６’ , POR ６ R ６’ , CH ２ OP(O)(OR ６ ) ２ , C(O)OP(O)(OR ６ ) ２ , PO(OR ６ )(OR ６’ ), P(O)(OR ６ )OP(O)(OR ６’ ) ２ , C (O)R ６ 、C(O)NHR ６ ; linear or branched C １ ~C ６ alkyl, alkyl alcohol , alkyl alcohol, alkylamine (including primary, secondary, tertiary amine, or quaternary or an alkyl carboxylic acid; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, hetero , ammonium), teroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycloalkyl , alkyl ether, alkyl ester, alkyl amide, oxime; C ５ ~C １２ gly Koshido, NH ２ or OH; R ４ is a halo (F, Cl, Br, or I), CN, NO ２ , SO ３ H, OR ６ , SR ６ , S(O ２ )R ６ , NHR ６ , N(R ６ )(R ６’ ), C(O)XR ６ , N ＋ (R ６ )( R ６’ )(R ６’’ ) is; , heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl e R ５ is H, C(O)O, C(O)NH, R ６ C(O), linear or branched C １ ~C ６ alky , ster, alkylamide, or amino acid; (including ammonium), alkyl carboxylic acid; C ２ ~C ６ carbonate, carbamide, he , alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium) , cycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbo , nyl, alkyl ether, alkyl ester, alkylamide, or amino acid; or a medicinal R ６ 、R ６’ 、and R ６’’ are independently H, C １ ~C ６ alkyl, alkyl alcohol , salt; , or an alkyl carboxylic acid; C ２ -C ６ heteroalkyl, alkyl cycloalkyl, complex , cycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbo , nyl, alkyl ether, alkyl ester, alkylamide, or amino acid; or a medicinal , salt; Furthermore, R １ , R ２ , R ３ , and R ６ cannot exist independently, R ２ , R ３ , X , C-10, and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle; The cell surface-binding agent / molecule T is an antibody, single-chain antibody; an antibody fragment that binds to a target cell ; monoclonal antibody; single-chain monoclonal antibody; monoclonal antibody fragment that binds to a target cell ; chimeric antibody; chimeric antibody fragment that binds to a target cell; domain antibody; domain antibody fragment that binds to a target cell; an adnectin that mimics an antibody; D ​ AR pins; lymphokines; hormones; vitamins; growth factors; colony stimulating factors; nutrients Transport molecules (transferrin); and / or albumin, polymers, dendrimers, lipo somes, nanoparticles, vesicles, or small molecules attached to (viral) capsids, cell-binding peptides, or proteins selected from the group consisting of; L is: 【Chemical Formula 3】 having the formula, wherein -W- is an extension unit; w is 0 or 1; each -Aa- is inde pendently an amino acid unit; r is independently an integer in the range of 0 to 12; -V- is a spacer unit; and v is 0, 1, or 2; When the extension unit (-W-) is present, the targeting binding molecule unit (T) is linked to the amino acid unit (-Aa-), or when Aa is absent, it is linked to V; W linked to T has any of the following structures: R' and R [Chemical Formula 4] 【Chem.】 wherein, R ２０ and R ２１ are C １ to C ８ alkyl, -C １ to C ７ carbocyclic ring, -O-(C １ ~C ８ alkyl)-, -arylene, -C １ ~C ８ alkylene-arylene, -aryle -C １ -C ８ alkylene, -C １ -C ８ alkylene-(C １ -C ８ carbocyclic ring)-, -( C ３ -C ７ carbon ring)-C １ -C ９ alkylene-. -C ３ -C ８ heterocyclo-,-C １ - C ８ alkylene-(C ３ ~C ８ heterocyclo)-,-(C ３ ~C ８ heterocyclo)-C １ ~C ９ alkylene-, -(CH ２ CH ２ O) ｋ -, -(CH(CH ３ )CH ２ O) ｋ -, and -(CH ２ CH ２ O) ｋ -CH ２ -; k is an integer from 1 to 20; -(Aa)r- is a natural or non-natural amino acid, or a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, ’’ is independently H or CH ３ ; heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide, or dodecapeptide unit having the same or different amino acid sequences, and r is an integer from 0 to 12; The spacer unit (-V-) is a self-destructive unit or a non-self-destructive unit, and the self-destructive unit is a para-aminobenzyl-carbamoyl (PAB) group, 2-aminoimidazole-5-methanol derivative, heterocyclic PAB analog, β-glucuronide, and ortho or para-aminobenzyl acetal; or contains any one of the following structures: , heterocyclic alkyl, heteroalkyl group, alkylcarbonyl; or a drug cation salt; v is an integer from 1 to 20; The non-self-destructive spacer linker unit (-V-) is or an L- or D-natural or non-natural peptide containing 1 to 20 identical or different amino acids; wherein, "*" and are additional spacers or releasable linkers, camptothecin analogs, and / or linkages, heterocyclic alkyl; 【Chemical Formula 5】 wherein, ( ＊ ) atoms are additional spacers or releasable linker units, amino acids (A a) ｒ is a binding point with a camptothecin analog and / or a binding molecule (T); X, Y, and Z ３ is independently NH, O, or S; Z ２ is independently H, NH, O, or S is; v is 0 or 1; Q is independently H, OH, C １ -C ６ alkyl, (OCH ２ CH ２ ) ｎ 、 F, Cl, Br, I, OR １７ 、 or SR １７ 、 NR １７ R １８ 、 N=N R １７ 、N = R １７ 、NR １７ R １８ 、NO ２ 、SOR １７ R １８ 、SO ２ R １７ 、SO ３ R １７ 、OSO ３ R １７ 、PR １７ R １８ 、POR １７ R １８ 、PO ２ R １７ R １８ 、 OPO (OR １７ ), (OR １８ ), or OCH ２ PO (OR １７ (OR １８ ), and this Here, R １７ and R １８ are independently H, C １ to C ８ alkyl; C ２ to C ８ alkenyl group, Alkynyl, heteroalkyl; C ３ ~C ８ aryl group, heterocycle, carbocycle, cycloalkyl alkyl, heteroalkyl cycloalkyl group, alkylcarbonyl group, heteroaryl; linkages, heterocycles, carbocycles, cycloalkyls, heteroalkyl cycloalkyls, alkylcarbonyls, heteroaryls; or an ester, ether, or amide having 1 to 8 carbon atoms; or formula ( (p is an integer from 0 to about 1000); [Chemical Formula 6] [Chemical] 【Chem.】 【Chem.】 [Chemical] ​ ​ 【Chemical Formula 7】 ​ is a binding point with the combined molecule; m is from 1 to 10; n is from 1 to 20; X ２ , X ３ , X ４ , X ５ , or X ６ is independently NH; NHNH; N(R １２ ); N(R １２ ), N(R １２ ’ ); O; S; C １ ~C ６ Alkyl; C ２ ~C ６ Heteroalkyl, alkylcycloalkyl ​ ； C ３ -C ８ aryl, Ar-alkyl, heterocyclic ring, carbocyclic ring, cyclo ​ CH ２ OR １２ 、CH ２ SR １２ 、CH ２ NHR １２ 、or 1 to 8 amino acids; Here, R １２ and R １２’ are independently H, C １ ~C ８ alkyl; C ２ ~C ８ hetero a Lukyl, alkylcycloalkyl, heterocyclic alkyl; C ３ ~C ８ Aryl, Ar-alky ​ ​ OCH ２ CH ２ ) ｐ Or (OCH ２ CH(CH ３ )) ｐ of polyethylene oxide units ​ L may have any one of the following structures: -(CR １５ R １６ ) ｍ (Aa) ｒ (CR １７ R １８ ) ｎ (OCH ２ CH ２ ) ｔ -, - (CR １５ R １６ ) ｍ (CR １７ R １８ ) ｎ (Aa) ｒ (OCH ２ CH ２ ) ｔ -, -(A a) ｒ -(CR １５ R １６ ) ｍ (CR １７ R １８ ) ｎ (OCH ２ CH ２ ) ｔ -, -(CR １５ R １６ ) ｍ (CR １７ R １８ ) ｎ (OCH ２ CH ２ ) ｒ (Aa) ｔ -, -(CR １５ R １６ ) ｍ (CR １７ =R １８ )(CR １９ R ２０ ) ｎ (Aa) ｔ (OCH ２ CH ２ ) ｒ -, -(CR １５ R １６ ) ｍ (NR １１ CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -(CR １５ R １６ ) ｍ (Aa) ｔ (NR ２１ CO)(CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -,-(CR １５ R １６ ) ｍ (OCO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -(CR １５ R １６ ) ｍ (OCNR １７ )(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -(CR １５ R １６ ) ｍ (CO)(A a) ｔ -(CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -(CR １５ R １６ ) ｍ (NR ２１ CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -(CR １５ R １ ６ ) ｍ (OCO)(Aa) ｔ (CR １９ R ２０ ) ｎ -(OCH ２ CH ２ ) ｒ -,-(CR １５ R １６ ) ｍ (O C N R １７ )(A a) ｔ (C R １９ R ２０ ) ｎ (O C H ２ C H ２ ) ｒ -, -(CR １５ R １６ ) ｍ (CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -,-(CR １５ R １６ ) ｍ -phenyl-(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, -(CR １５ R １６ ) ｍ -frill-(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, - (CR １５ R １６ ) ｍ -oxazolyl-(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, - (CR １５ R １６ ) ｍ -thiazolyl-(CO)(Aa) ｔ (CCR １７ R １８ ) ｎ -, - (CR １５ R １６ ) ｔ -thienyl-(CO)(CR １７ R １８ ) ｎ -, -(CR １５ R １ ６ ) ｔ -imidazolyl-(CO)(CR １７ R １８ ) ｎ -,-(CR １５ R １６ ) ｔ -mo Rholino-(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -,-(CR １５ R １６ ) ｔ -pipe Radino-(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, -(CR １５ R １６ ) ｔ -N-me Chilupiperazine-(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, -(CR １５ R １６ ) ｍ -(Aa) ｔ phenyl-, -(CR １５ R １６ ) ｍ -(Aa) ｔ furyl-, -(CR １５ R １６ ) ｍ -oxazolyl (Aa) ｔ -, -(CR １５ R １６ ) ｍ -thiazolyl (Aa) ｔ -, -(CR １５ R １６ ) ｍ -thienyl (Aa) ｔ -, -(CR １５ R １６ ) ｍ -imi Dazolyl (Aa) ｔ -, -(CR １５ R １６ ) ｍ -morpholino-(Aa) ｔ -, -(CR １５ R １６ ) ｍ -piperazino-(Aa) ｔ -, -(CR １５ R １６ ) ｍ -N-methylpiper Radino-(Aa) ｔ -, -K(CR １５ R １６ ) ｍ (Aa) ｒ (CR １７ R １８ ) ｎ (O CH ２ CH ２ ) ｔ -, -K(CR １５ R １６ ) ｍ (CR １７ R １８ ) ｎ (Aa) ｒ (OC H ２ CH ２ ) ｔ -, -K(Aa) ｒ (CR １５ R １６ ) ｍ (CR １７ R １８ ) ｎ (OCH ２ CH ２ ) ｔ -, -K(CR １５ R １６ ) ｍ (CR １７ R １８ ) ｎ (OCH ２ CH ２ ) ｒ (Aa) ｔ -,-K(CR １５ R １６ ) ｍ (CR １７ =R １８ )(CR １９ R ２０ ) ｎ ( Aa) ｔ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (NR １１ CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR ５ R ６ ) ｍ (Aa) ｔ (N R ２１ CO)(CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (OCO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (O C N R １７ )(A a) ｔ (C R １９ R ２０ ) ｎ (O C H ２ C H ２ ) ｒ -, - K(CR １５ R １６ ) ｍ (CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (NR ２１ CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OC H ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (OCO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (OCNR １７ )(Aa) ｔ (C R １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ (CO)(Aa) ｔ (CR １９ R ２０ ) ｎ (OCH ２ CH ２ ) ｒ -, -K(CR １５ R １６ ) ｍ - phenyl -(CO)(Aa) ｔ (CR １７ R １８ ) ｎ -,-K(CR １５ R １６ ) ｍ -furyl-( CO)(Aa) ｔ (CR １７ R １８ ) ｎ -,-K(CR １５ R １６ ) ｍ -oxazolyl- (CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, -K(CR １５ R １６ ) ｍ -thiazolyl- (CO)(Aa) ｔ (CR １７ R １８ ) ｎ -, -K(CR １５ R １６ ) ｔ -thienyl-( CO)(CR １７ R １８ ) ｎ -, -K(CR １５ R １６ ) ｔ -imidazolyl-(CO)( CR １７ R １８ ) ｎ -, -K(CR １５ R １６ ) ｔ -morpholino-(CO)(Aa) ｔ ( CR １７ R １８ ) ｎ -, -K(CR １５ R １６ ) ｔ -piperazino-(CO)(Aa) ｔ ( CR １７ R １８ ) ｎ -,-K(CR １５ R １６ ) ｔ -N-methylpiperazine-(CO)( Aa) ｔ (CR １７ R １８ ) ｎ —, —K(CR １５ R １６ ) ｍ —(Aa) ｔ phenyl—, -K(CR １５ R １６ ). ｍ -(Aa) ｔ frill -, -K(CR １５ R １６ ). ｍ -oxazo Ril (Aa) ｔ -, -K(CR １５ R １６ ) ｍ -Thiazolyl (Aa) ｔ -, -K(CR １ ５ R １６ ) ｍ -thienyl (Aa) ｔ -,-K(CR １５ R １６ ) ｍ -imidazolyl (Aa ) ｔ -,-K(CR １５ R １６ ) ｍ - morpholino-(Aa) ｔ -,-K(CR １５ R １６ ) ｍ -piperazino-(Aa) ｔ G-, -K(CR １５ R １６ ) ｍ -N-methylpiperazino -(Aa) ｔ -; wherein the definitions of Aa, m, and n are as described above; t and r are independently 0 is from 0 to 100; R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are independently H; halide; C １ - C ８ Alkyl; C ２ ~C ８ Aryl, alkenyl, alkynyl, ether, ester, amine , or amide, C ３ ~C ８ is aryl, or one or more halides, CN, NR １２ R １２’ 、CF ３ 、OR １２ 、aryl, heterocyclic ring, S(O)R １２ 、SO ２ R １２ 、 -CO ２ H, -SO ３ H, -OR １２ , -CO ２ R １２ , -CONR １２ , -PO ２ R １ ２ R １２ 、 -PO ３ H, or P(O)R １２ R １２’ R １３ optionally substituted with selected from; K is NH, NR １２ , -SS-, -C(=O)-, -C(=O)NH- , -C(=O)O-, -C=NH-O-, -C=N-NH-, -C(=O)NH-NH- , O, S, Se, B, Het (C ３ ~C １２ heterocyclic ring or heteroaromatic ring), or 1 to 20 It is a peptide containing the same or different amino acids.

2. The conjugate of the camptothecin analog described in Claim 1 having the structure of formula (II), or its pharmaceutically acceptable salts, hydrates, or hydrates salts; or polymorphic crystal structures of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantio thiomers; 【Chemical Formula 8】 In the formula, T is a targeting or binding ligand; L is a releasable linker; n is from 1 to 30 and m is from 1 to 10; The inside of the parentheses is an effective camptothecin analog, in the formula, R １ is a straight-chain or branched C １ -C ６ alkyl, alkyloxy, alkylamino (primary primary, secondary, tertiary amino, or quaternary ammonium), oxylcarbonyl, a minocarbonyl, aminoalkyl, oxylalkyl, aminoalkylamino, oxyl alkylamino, aminoalkyloxyl, oxyalkyloxyl, or alkylcarb Xy; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, oxylcycloalkyl, aminocycloalkyl, heteroalkylcycloalkyl, al kylcarbonyl, aminoalkylcarbonyl, oxylalkylcarbonyl, alkyl e ther, alkyl ester, alkylamide, oxylalkylamide, aminoalkyl amide, oxime; NH, or O; R ２ is H, linear or branched C １ ~C ６ alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium), aminoalkyl a lcohol, aminoalkylamine, oxyalkylalcohol, oxyalkylamine, Aminoalkyl, oxyalkyl, alkyl carboxylic acid; C ２ ~C ６ Heteroalkyl, a lalkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alky lcarbonyl, alkyl ether, alkyl ester, alkyl am D, oxime; NH ２ , or OH; R ３ is independently H, R ６ NHCO, R ６ OCO, SO ２ R ６ , SO ３ R ６ , PR ６ R ６’ 、POR ６ R ６’ 、CH ２ OP(O)(OR ６ ) ２ 、C(O)OP(O)( OR ６ ) ２ , PO(OR ６ )(OR ６’ ), P(O)(OR ６ )OP(O)(OR ６’ ) ２ , R ６ C(O), C(O)NR ６ R ６’ ; linear or branched C １ ~C ６ alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium including), or an alkyl carboxylic acid; C ２ -C ６ heteroalkyl, alkyl cycloalkyl l, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alky LUCARBONYL, ALKYL ETHER, ALKYL ESTER, ALKYL AMIDE, OXIME; C ５ ~C １２ which is a glycoside; R ４ is halo (F, Cl, Br, or I), CN, NO ２ , SO ３ H, OR ６ , SR ６ , S(O ２ )R ６ , NHR ６ , N(R ６ )(R ６’ ), C(O)XR ６ , N ＋ (R ６ )( R ６’ )(R ６’’ ) is; X is NH or O; R ５ is H, C(O)OR ６ C(O)NHR ６ R ６ C(O), linear or branched C １ to C ６ alkyl, alkyl alcohol, alkylamine (primary, secondary, tertiary amine, or a quaternary ammonium), an alkyl carboxylic acid; C ２ ~C ６ carbonate, cal bamide, heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl alkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, al kyl ester, alkylamide, or amino acid; R ６ 、R ６’ 、and R ６’’ are independently H, C １ ~C ６ alkyl, alkyl alcohol l, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium) , or an alkyl carboxylic acid; C ２ -C ６ heteroalkyl, alkylcycloalkyl, complex cycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl Nil, alkyl ether, alkyl ester, alkyl amide, or amino acid; or a pharmaceutically acceptable salt; Furthermore, R １ does not exist, and C-7 and L can be directly connected, and R ２ , R ３ , X, C-10 and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle; **Claim 3** A conjugate of a camptothecin analog according to claim 1 having the structure of formula (III), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; or a polymorphic crystalline structure of these compounds; or an isotope, optical isomer, racemate, diastereomer, or enan tiomer thereof; Wherein, 【Chemical Formula 9】 T is a targeting or binding ligand; L is a releasable linker; n is from 1 to 30 and m is from 1 to 10; The inside of the parentheses is an effective camptothecin analog, wherein, primary, secondary, tertiary amino, or quaternary ammonium), oxycarbonyl, am R １ is a linear or branched C １ -C ６ alkyl, alkyloxy, alkylamino (primary inocarbonyl, aminoalkyl, oxyalkyl, aminoalkylamino, oxyalkylamino, aminoalkyloxy, oxyalkyloxy, or alkylcarb oxycycloalkyl, aminocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, aminoalkylcarbonyl, oxyalkylcarbonyl, alkyl e ther, alkyl ester, alkyl amide, oxyalkyl ether, aminoalkyl ether, oxyalkyl ester, aminoalkyl ester, oxyalkyl am Xy; C ２ - C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, ide, aminoalkyl amide, oxime; NH, or O; alkyl alcohol, alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), aminoalkyl alcohol, aminoalkylamine, oxyalkyl alcohol, oxyalkylamine, aminoalkyl, oxyalkyl, alkylcarbocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl e ther, alkyl ester, alkyl amide, oxime; oxyalkyl ether, aminoalkyl ether, oxyalkyl ester, oxyalkyl amide, aminoalkyl am ide; R ２ is NH, NR ６ N ＋ R ６ R ６’ O, S, straight-chain or branched C １ ~C ６ alkyl, alkyl alcohol, alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), aminoalkyl alcohol, aminoalkylamine, oxyalkyl alcohol, oxyalkylamine, aminoalkyl, oxyalkyl, alkylcarbocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl e ther, alkyl ester, alkyl amide, oxime; oxyalkyl ether, aminoalkyl ether, oxyalkyl ester, oxyalkyl amide, aminoalkyl am phosphoric acid; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, ide; alcohol, alkylamine (including primary, secondary, tertiary amine, or quaternary ammonium), heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkyl amide, heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkyl X is NH or O; R ３ is independently H, R ６ NHC(O), R ６ OC(O), SO ２ R ６ , SO ３ R ６ , PR ６ R ６’ 、POR ６ R ６’ 、CH ２ OP(O)(OR ６ ) ２ 、C(O)OP(O)( OR ６ ) ２ , PO(OR ６ )(OR ６’ ), P(O)(OR ６ )OP(O)(OR ６’ ) ２ , R ６ C(O), C(O)NR ６ R ６’ ; linear or branched C １ ~C ６ alkyl, alkyl amide, heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkyl including), or an alkyl carboxylic acid; C ２ ~ C ６ heteroalkyl, alkyl cycloalkyl **END** LUCARBONYL, ALKYL ETHER, ALKYL ESTER, ALKYL AMIDE, OXIME; C ５ ~C １２ which is a glycoside; R ４ is halo (F, Cl, Br, or I), CN, NO ２ , SO ３ H, OR ６ , SR ６ , S(O ２ )R ６ , NHR ６ , N(R ６ )(R ６’ ), C(O)XR ６ , N ＋ (R ６ )( R ６’ )(R ６’’ ) is; amide, heteroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkyl R ５ is H, C(O)OR ６ C(O)NHR ６ R ６ C(O), linear or branched C １ to C ６ alkyl, alkyl alcohol, alkylamine (primary, secondary, tertiary amine, or a quaternary ammonium), an alkyl carboxylic acid; C ２ ~ C ６ carbonate, car ​ Rukil, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, al kyl ester, alkylamide, or amino acid; R ６ 、 R ６’ 、 and R ６’’ are independently H, C １ ~C ６ alkyl, alkyl alcohol L, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium) , or an alkyl carboxylic acid; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, complex Cycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl Nil, alkyl ether, alkyl ester, alkylamide, or amino acid; or a pharmaceutically acceptable Salt; Furthermore, R ２ does not exist, and C-9 and L can be directly connected, and R ２ , R ３ , X, C-10 and C-9 can together form a 5-membered, 6-membered, or 7-membered heterocycle; Yes;

4. A conjugate of a camptothecin analog according to claim 1 having the structure of formula (IV), or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or an isotope, optical isomer, racemate, diastereomer, or enantiomer thereof; Wherein, T is a targeting or binding ligand; L is a releasable linker; n is 1 to 30 , m is 1 to 10; 【Chemical Formula 10】 The inside of the parentheses is an effective camptothecin analog, wherein, , tertiary amino, or quaternary ammonium), oxalylcarbonyl, aminocarbonyl Nil, aminoalkyl, oxyalkyl, aminoalkylamino, oxyalkylamino Chloroalkyl, aminocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl R １ and R ２ are independently H, NR ６ R ６’ , -N ＋ R ６ R ６’ R ６’’ , OH, SH , linear or branched C １ ~C ６ alkyl, alkyloxy, alkylamino (primary, secondary Nil, aminoalkylcarbonyl, oxyalkylcarbonyl, alkyl ether, a Lkyl ester, alkylamide, oxyalkyl ether, aminoalkyl ether Mino, aminoalkyloxyl, oxyalkyloxy, or alkylcarboxy; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, oxysilyl , oxyalkyl ester, aminoalkyl ester, oxyalkylamide, ami Primary, secondary, tertiary amines, or quaternary ammonium), or alkylcarbonyl Cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether X is NH or O; Noalkylamide, oxime; NH ２ , or OH; R ３ is independently, -NHC(O)-, -C(O)-, SO ２ -, SO ２ NH-, R ６ N HC(O), R ６ OC(O), SO ２ R ６ , SO ３ R ６ , PR ６ R ６’ , POR ６ R ６’ , CH ２ OP(O)(OR ６ ) ２ , C(O)OP(O)(OR ６ ) ２ , PO(OR ６ )( OR ６’ ), P(O)(OR ６ ), OP(O)(OR ６’ ) ２ , R ６ C(O), C(O)N R ６ R ６’ ; linear or branched C １ ~C ６ alkyl, alkyl alcohol, alkylamine ( Bamide, heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, cycloalkyl phosphoric acid; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, L, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, al Ru, alkyl ester, alkyl amide, oxime; C ５ ~C １２ which is a glycoside; R ４ is a halo (F, Cl, Br, or I), CN, NO ２ , SO ３ H, OR ６ , SR ６ , S(O ２ )R ６ , NHR ６ , N(R ６ )(R ６’ ), C(O)XR ６ , N ＋ (R ６ )( R ６’ )(R ６’’ ) is; Kyl ester, alkylamide, or amino acid; R ５ is H, C(O)OR ６ C(O)NHR ６ R ６ C(O), linear or branched C １ to C ６ alkyl, alkyl alcohol, alkylamine (primary, secondary, tertiary amine, or a quaternary ammonium), an alkyl carboxylic acid; C ２ ~ C ６ carbonate, cal L, alkylamine (including primary, secondary, tertiary amines, or quaternary ammonium) Cycloalkyl, heterocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl Nil, alkyl ether, alkyl ester, alkylamide, or amino acid; or a pharmaceutically acceptable R ６ 、R ６’ 、and R ６’’ are independently H, C １ ~C ６ alkyl, alkyl alcohol ​ , or an alkyl carboxylic acid; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, complex ​ ​ is a salt; Furthermore, R ３ does not exist, and X and L of C-10 can be directly connected, and R ２ , R ３ , X, C-10, and C-9 together form a 5-membered, 6-membered, or 7-membered heterocyclic ring; can be;

5. A conjugate of a camptothecin analog according to claim 1 having the structure of formula (V), or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or an isotope, optical isomer, racemate, diastereomer, or enantiomer thereof; wherein, T is a targeting or binding ligand; L is a releasable linker; n is 1 to 30; and m is 1 to 10; 【Chemical 11】 The inside of the parentheses is an effective camptothecin analog, wherein, , a tertiary amino, or a quaternary ammonium), oxalylcarbonyl, aminocarbonyl, aminoalkyl, oxyalkyl, aminoalkylamino, oxyalkylaminoalkyl, aminoalkylchloroalkyl, aminocycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, aminoalkylcarbonyl, oxyalkylcarbonyl, alkyl ether, alkyl ester, alkylamide, oxyalkyl ether, aminoalkyl ether, oxyalkyl ester, aminoalkyl ester, oxyalkylamide, aminoalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocyclic ring, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl ester, alkylamide, or oxime; alkyl, alkylcycloalkyl, heterocyclic alkyl, heterocyclic ring, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl ester, alkylamide, or amino acid; X is NH or O; R １ and R ２ each independently represents H, NR ６ R ６’ , -N ＋ R ６ R ６’ R ６’’ , OH, SH , linear or branched C １ ~C ６ alkyl, alkyloxy, alkylamino (primary, secondary , alkyl alcohol, alkylamine (primary, secondary, tertiary amine, or quaternary ammonium), alkylchloroalkyl, alkylcycloalkyl, heterocyclic alkyl, heterocyclic ring, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl ester, alkylamide, or amino acid; alkyl, alkylamine (primary, secondary, tertiary amine, or quaternary ammonium), cycloalkyl, heterocyclic ring, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, alkyl ether, alkyl ester, alkylamide, or amino acid; or a medicinal salt; Mino, aminoalkyloxyl, oxyalkyloxy, or alkylcarboxy; C ２ ~C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, oxysilyl , X, C-10, and C-9 together can form a 5-membered, 6-membered, or 7-membered heterocyclic ring.

6. The camptothecin analog linked to the linker L is II-1 to II-61, II shown below; ​ Noalkylamide, oxime; NH ２ , or OH; R ３ is independently R ６ NHCO−, R ６ CO−, R ６ SO ２ −SO ２ NHR ６ , R ６ OC(O), R ６’ SO ２ R ６ -, SO ３ R ６ , PR ６ R ６’ , POR ６ R ６’ , CH ２ OP(O)(OR ６ ) ２ , C(O)OP(O)(OR ６ ) ２ , PO(OR ６ )( OR ６’ ), P(O)(OR ６ ), OP(O)(OR ６’ ) ２ , R ６ C(O), C(O)N R ６ R ６’ ; linear or branched C １ ~C ６ alkyl, alkyl alcohol, alkylamine ( including primary, secondary, and tertiary amines), or an alkyl carboxylic acid; C ２ -C ６ hetero A ​ ​ ​ R ４ is a halo (F, Cl, Br, or I), CN, NO ２ , SO ３ H, OR ６ , SR ６ , S(O ２ )R ６ , NH(R ６ )S(O ２ )R ６’ , N(R ６ )(R ６’ ), C(O)X R ６ 、N ＋ (R ６ )(R ６’ )(R ６’’ ) is; ​ R ５ is C(O)O, C(O)NH, R ６ C(O), straight-chain or branched C １ ~C ６ alkyl ​ ammonium), alkyl carboxylic acid; C ２ ~C ６ carbonate, carbamide, hete ​ ​ ​ R ６ 、 R ６’ 、 and R ６’’ are independently H, C １ ~C ６ alkyl, alkyl alcohol ​ , or an alkyl carboxylic acid; C ２ ~C ６ heteroalkyl, alkyl cycloalkyl, complex ​ ​ ​ Furthermore, R ５ does not exist, and the O of C-20 and L can be directly connected, and R ２ , R ３ ​ ​ ​ ​ Having the structures of I-1 to III-52, IV-1 to IV-47, and V-1 to V-61, The conjugate of a camptothecin analog according to any one of claims 2 to 5, or a pharmaceutically acceptable salt, hydrate, or hydrate salt thereof; or a polymorphic crystal structure of these compounds; or their isotopes, optical isomers, racemates, diastereomers, or enantiomers; 【Chemical Formula 12】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 Wherein, 【Chemical 13】 Is the binding site with the linker L; R ６ and R ６ ’ independently represent H, C １ ~C ６ alkyl, alkyl alcohol, alkyl An amine (including primary, secondary, tertiary amines, or quaternary ammonium), or an alkyl Lukarboxylic acid; C ２ ~C ６ Heteroalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycle, cycloalkyl, heterocycloalkyl, alkylcarbonyl, alkyl ether yl, alkyl ester, alkylamide, or amino acid; or a medicinal salt.

7. The linker L preferably contains an amino group, sulfonamide, phosphamide, or amino acid group The side chain of formula (I-q) can be bonded through the above groups, where the amino acid in the linker L is preferably selected from aspartic acid, glutamic acid, lysine, ornithine, or tyro cine, wherein one or two of these amino groups, carboxyl groups, or functional groups of the phenoxy group are linked to the long side chain of formula (I-q), according to any one of claims 1 to 5 1 conjugate of the camptothecin analog described in item; 【Chemical 14】 Wherein, 【Chemical 25】 Is the binding site with the sulfonyl group, phosphate ester group, amino group, or carbonyl group in the linker; ; G １ is NH, NHNH, C(=O), NHNH C(O), C(=O)NH, C(=N H) NH, CH ２ , CH ２ C(O), C(O)O, NH C(O) NH, or (Aa) ｒ , (r = 1 to 12); G ２ is NH, NHNH, C(=O), NHNHCO, C(=O)NH, C(=N H), NH, CH ２ , C(O)O, NHCO NH, O, S, B, P(O)(OH), N HP(O)(OH), NHP(O)(OH)NH, CH ２ P(O)(OH)NH, OP( O)(OH)O, CH ２ P(O)(OH)O, NHS(O) ２ , NHS(O) ２ NH, C H ２ S(O) ２ NH, OS(O) ２ O, CH ２ S(O) ２ O, Ar, ArCH ２ , ArO , ArNH, ArS, ArNR １ , (Aa) ｒ , (r = 1 to 12); X １ and X ２ are independently O, CH ２ , S, NH, N(R １２ ), ＋ NH(R １２ ), ＋ N(R １２ )(R １３ ), C(O), OC(O), OC(O)O, NHSO ２ NH, N HP(O)(NH) ２ 、SO ２ NH、P(O)(NH) ２ 、NHSO NH、NHP( O)(OH)(NH), OC(O)NH, NHC(O)NH; Y ２ is O, NH, NR １ , CH ２ , S, Ar; G ３ is OH, SH, OR １ , SR １ , OC(O)R １ , NHC(O)R １２ , C(O ), R １２ , CH ３ , NH ２ , NR １２ , ＋ NH(R １２ ), ＋ N(R １２ )(R １３ ), C(O)OH, C(O)NH ２ , NH C(O)NH ２ , BH ２ , BR １２ R １３ , P(O )(OH) ２ , NHP(O)(OH) ２ , NHP(O)(NH ２ ) ２ , S(O) ２ (OH ), (CH ２ ) ｑ１ C(O)OH, (CH ２ ) ｑ１ P(O)(OH) ２ , C(O)(CH ２ ) ｑ１ C(O)OH, OC(O)(CH ２ ) ｑ１ C(O)OH, NHC(O)(CH ２ ) ｑ１ C(O)OH, CO(CH ２ ) ｑ１ P(O)(OH) ２ , NHC(O)O(CH ２ ) ｑ１ -C(O)OH, OC(O)NH-(CH ２ ) ｑ１ C(O)OH, NHCO(CH ２ ) ｑ１ P(O)(OH) ２ , NHC(O)(NH)(CH ２ ) ｑ１ C(O)OH, CO NH(CH ２ ) ｑ１ -P(O)(OH) ２ 、NHS(O) ２ (CH ２ ) ｑ１ C(O)OH , CO(CH ２ ) ｑ１ S(O) ２ (OH), NHS(O) ２ NH-(CH ２ ) ｑ１ C(O ), OH, OS(O) ２ NH(CH ２ ) ｑ１ C(O)OH, NHCO(CH ２ ) ｑ１ S(O ) ２ (OH), NHP(O)(OH)(NH)-(CH ２ ) ｑ１ C(O)OH, CONH (CH ２ ) ｑ１ S(O)(OH), OP(O)(OH) ２ (CH ２ ) ｑ１ P(O)(N H) ２ , NHS(O) ２ (OH), NHS(O) ２ NH ２ 、CH ２ S(O) ２ NH ２ 、O S(O) ２ OH, OS(O) ２ OR １ 、CH ２ S(O) ２ OR １ 、Ar、ArR １２ 、A rOH, ArNH ２ , ArSH, ArNHR １２ , or (Aa) ｑ１ ; p １ 、 p ２ 、 and p ３ are independently from 0 to 30, but not 0 at the same time; q １ and q ２ are each independently from 0 to 24; Preferably, G ３ is a linear or branched C ２ -C ５０ polycarboxylic acid or C ２ -C ５ ０ Polyalkylamine; C ６ ~C ５０ Oligosaccharide or polysaccharide; C ６ ~C ５０ Zwitterionic betaine A zwitterionic poly(sulfo betaine)) (PSB) containing a quaternary ammonium cation and a sulfonate anion; (poly(lactic acid / glycolic acid) (PLGA), poly(acry late), chitosan, copolymer of N-(2-hydroxypropyl)methacrylamide, poly[2-(methacryloyloxy)ethyl phosphorylcholine)] (PMPC), poly- L-glutamic acid, poly(lactide-co-glycolide) (PLG), poly(lactide-co -glycolide), poly(ethylene glycol) (PEG), poly(propylene glycol ) (PPG), poly(lactide-co-glycolide), poly(ethylene glycol)-modified peptide tide, poly(ethylene glycol) containing an amino acid or peptide, poly(ethylene glycol)-modified lipid, poly(ethylene glycol)-modified alkyl carboxylic acid, poly(ethylene glycol); Poly(ethylene glycol)-modified alkylamine, poly(lactide-co-glycolide), hyaluronic acid ( HA) (glycosaminoglycan), heparin / heparan sulfate (HSGAG), chondro itin sulfate / dermatan sulfate (CSGAG), poly(ethylene glycol)-modified alkyl sulfate, poly(ethylene glycol)-modified alkyl phosphate, or poly(ethylene glycol)-modified alkyl quaternary ammonium; It is a biodegradable polymer composed of:

8. The side chain linker of formula (I-q) according to claim 7 is selected from the following: 【Chemical Formula 15】 where G １ , p １ , p ２ , p ３ , Aa, r, X ２ , q １ , and m １ are defined in claim 7 Is the same as.

9. A conjugate of a camptothecin analog according to any one of claims 1 to 5, produced by the easy binding reaction of a cell-binding molecule T with a compound of formula (VI), (VII), (VIII), (IX), and ( X) respectively: In the formula, Lv is a reactive group capable of reacting with a thiol, amine, carboxylic acid, selenol, phenol, 【Chemical 16】 or hydroxyl group on the cell-binding molecule; the reactive group is a halide (fluoride, R １ 、 R ２ 、 R ３ 、 R ４ 、 R ５ 、 L, X, and m have the same definitions as in the above formula (I); chloride, bromide, iodide), maleimide, methanesulfonyl (mesyl), toluenesulfonyl tosyl), trifluoromethylsulfonyl (triflate), trifluoromethyl sulfonate, nitrophenoxy, N-succinimidyl dioxy (NHS), phenoxy xyl; dinitrophenoxyl, pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluorophenoxyl pentafluorophenoxyl, 1H-imidazol-1-yl, chlorophenoxyl, di chlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(ben zotriazol-yl)oxyl, 2-ethyl-5-phenylisoxazolium-3'- sulfonyl, phenyloxadiazole-sulfonyl (-sulfonate-ODA), oxa diazol-yl, unsaturated carbon (double or triple bond between carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphorus, sulfur-nitrogen, phosphorus-nitrogen, oxygen-nitrogen, or carbon-oxygen), or a molecule selected from intermediates generated by a condensation reagent for the Mitsunobu reaction; examples of the condensation reagent include EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide ​ ​ ​ ​ Mid), DCC (dicyclohexyl - carbodiimide), N,N'-diisopropylcarb odiimide (DIC), N-cyclohexyl-N'-(2-morpholinoethyl)carbodi imide meso-p-toluenesulfonate (CMC, or CME - CDI), 1,1'-carb onyldiimidazole (CDI), TBTU (O-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate), N,N,N ',N'-tetramethyl - O-(1H-benzotriazol-1-yl)uronium hexa fluorophosphate (HBTU), (benzotriazol-1-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotri azol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate ( PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N' -tetramethylformamidinium hexafluorophosphate, 1 - [bis(dimethyl amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3- oxide hexafluorophosphate (HATU), 1 - [(dimethylamino)(morph olino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3-oxide hexafluorophosphate (HDMA), 2-chloro-1,3-dime thylimidazolidinium hexafluorophosphate (CIP), chlorotripyrrolidino phosphonium hexafluorophosphate (PyCloP), fluoro-N,N,N', N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTF FH), N,N,N',N'-tetramethyl - S-(1-oxide-2-pyridyl)thiou ronium hexafluorophosphate, O-(2-oxo-1(2H)pyridyl)-N, N,N',N'-tetramethylthiuronium tetrafluoroborate (TPTU), S- (1-oxide-2-pyridyl)-N,N,N',N'-tetramethylthiuronium tet rafluoroborate, O - [(ethoxycarbonyl)cyanomethyleneamino]-N,N, N',N'-tetramethyluronium hexafluorophosphate (HOTU), (1- cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpho lino - N - carbonyldiimidazole hexafluorophosphate (COMU), O - (benzotriazol - 1 - yl) - N,N,N',N' - bis(tetramethylene)uronium hexafluoride phosphate (HBPyU), N - benzyl - N' - cyclohexylcarbodiimide (with or without conjugate bond), dipyrrolidino(N - succinimidyloxy) - carbo nium hexafluorophosphate (HSPyU), chlorodipyrrolidinocarbonium hexafluorophosphate (PyCIU), 2 - chloro - 1,3 - dimethylimidazolium tetrafluoroborate (CIB), (benzotriazol - 1 - yloxy)dipiperidinocarbonium hexafluorophosphate (HBPipU), O - (6 - chloro benzotriazol - 1 - yl) - N,N,N',N' - tetramethyluronium tetra fluoroborate (TCTU), bromotris(dimethylamino)phosphonium hexa fluorophosphate (BroP), propylphosphonic anhydride (PPACA, T3P ( registered trademark)), 2 - morpholinoethyl isocyanide (MEI), N,N,N',N' - te tramethyl - O - (N - succinimidyl)uronium hexafluorophosphate (H STU), 2 - bromo - 1 - ethyl - pyridinium tetrafluoroborate (BEP), O - [(ethoxycarbonyl)cyanomethyleneamino] - N,N,N',N' - tetramethyl uronium tetrafluoroborate (TOTU), 4 - (4,6 - dimethoxy - 1, 3,5 - triazin - 2 - yl) - 4 - methylmorpholinium chloride (MMTM, DM TMM), N,N,N',N' - tetramethyl - O - (N - succinimidyl)uronium tetrafluoroborate (TSTU), O - (3,4 - dihydro - 4 - oxo - 1,2 benzotriazin - 3 - yl) - N,N,N',N' - tetramethyluronium tetra fluoroborate (TDBTU), 1,1' - (azodicarbonyl)dipiperidine ( ADD), di - (4 - chlorobenzyl)azodicarboxylate (DCAD), di - tert butylazodicarboxylate (DBAD), diisopropylazodicarboxylate (DIAD), diethylazodicarboxylate (DEAD); furthermore, Lv １ and Lv ２ are formed by the acid itself or by other C １ -C ８ anhydrides formed by anhydrides substances may also be used; More preferably, Lv is a halide (fluoride, chloride, bromide, iodide), ma Lemide, methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoro Methylsulfonyl (triflate), trifluoromethylsulfonate, nitrophenoxy Syl, N-succinimidyl oxy (NHS), phenoxyl; dinitrophenoxy Ru, pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxy Syl, difluorophenoxyl, monofluorophenoxyl, pentachlorophenoxyl , 1H-imidazol-1-yl, chlorophenoxyl, dichlorophenoxyl, tri Rolophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-yl) oxy Syl, 2-ethyl-5-phenylisoxazolium-3'-sulfonyl, phenyloxadia Zol-sulfonyl (-sulfonate-ODA), oxadiazol-yl, unsaturated Carbon (carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphorus, sulfur-nitrogen, phosphorus-nitrogen, acid Double or triple bond between nitrogen, or carbon-oxygen), or selected from one of the following structures Ru; 【Chemical 17】 【Chem.】 In the formula, X １ ' is F, Cl, Br, I, or Lv ３ ; X ２ ' is O, NH, N(R １ ) 、 or CH ２ ; R ３ is H, an aromatic group, a heteroaromatic group, or one or several The H atoms are independently -R １ , -halogen, -OR １ , -SR １ , -NR １ R ２ , -NO ２ , -S(O)R １ , -S(O) ２ R １ , or -COOR １ is an aromatic group substituted therewith wherein R １ and R ２ are as defined above; Lv ３ is F, Cl, Br, I, nitro Rophenol; N-hydroxysuccinimide (NHS); phenol; dinitropheno R, pentafluorophenol, tetrafluorophenol, difluorophenol, Monofluorophenol, pentachlorophenol, triflate, imidazole, dich Rolophenol, tetrachlorophenol, 1-hydroxybenzotriazole, tosyle Rate, mesylate, 2-ethyl-5-phenylisoxazolium-3'-sulfonate, A leaving group selected from those formed by itself or formed together with other anhydrides, such as acetic anhydride or formic anhydride Ru.

10. The conjugate of the camptothecin analog according to any one of claims 1 to 5, represented by the following formulas (IIq-1), (IIq-2), (IIq-3), (IIq-4), ( IIq-5), (IIq-6), (IIq-7), or (IIq-8): In the formula, 【Chemical Formula 18】 【Chem.】 ; m''' is 0 or 1; and mAb is a cell-binding molecule, preferably an antibody; N R’ and R’’ are independently H, Me, Et, ｉ Pr, ｉ Bu, Bz(CH ２ C ６ H ５ ), CH ２ COOH, CH ２ CH ２ COOH, CH ２ CONH ２ , CH ２ CH ２ CONH ２ , CH ２ CH ２ CH ２ CH ２ NH ２ , CH ２ CH ２ SCH ３ , CH ２ OH, CH ２ CH ２ CH ２ NH C(=NH)NH ２ 、CH(OH)CH ３ 、CH ２ C ６ H ４ OH, or C H ２ C ３ N ２ H ３ is; p １ and p ２ are independently 0 to 24; q １ is 1 to 18 is; q ３ is from 0 to 6; q ４ is from 0 to 4; m' and m'' are independently from 0 to 6 H-Drug is the above compounds II-1 to II-61, III-1 to III-52, IV- 1 to IV-47, and V-1 to V-61; and Is the site where it is bound to NH-Drug. 【Chemical Formula 19】

11. ​ The conjugateable compound according to claim 9, represented by the following formula (IIq-9), (IIq-10), (IIq-11), (IIq-12 ), (IIq-13), (IIq-14), (IIq-15), or (IIq-16): In the formula, 【Chemical 20】 【Chem.】 is 0 or 1; NH-Drug is the above compounds II-1 to II-61, III-1 to III R’ and R’’ are independently H, Me, Et, ｉ Pr, ｉ Bu, Bz(CH ２ C ６ H ５ ), CH ２ COOH, CH ２ CH ２ COOH, CH ２ CONH ２ , CH ２ CH ２ CONH ２ , CH ２ CH ２ CH ２ CH ２ NH ２ , CH ２ CH ２ SCH ３ , CH ２ OH, CH ２ CH ２ CH ２ NH C(=NH)NH ２ 、CH(OH)CH ３ 、CH ２ C ６ H ４ OH、CH ２ C ３ N ２ H ３ ; p １ and p ２ are independently 0 to 24; q １ is 1 to 18; q ３ is 0 ~6; q ４ is 0 to 4; m' and m'' are independently 0 to 6; m''' is -51, IV-1 to IV-47, and V-1 to V-61; is the binding site with NH-Drug. 【Chemical Formula 21】

12. C1-005, C1-008, C1-021, C1-022, C1-029 shown below , C1-031, C1-035, C1-041, C1-042, C1-043, C1-0 47, C1-050, C1-056, C1-061, C1-064, C1-070, C1 -075, C1-081, C1-086, C1-088, C1-090, C1-094, C1-099, C1-102, C1-110, C1-102, C1-110, C1-11 3, C1-114, C1-119a, C1-119b, C1-123, C1-127, C 1-131, C1-137a, C1-137b, C1-140, C1-147a, C1- 147b, C1-151, C1-152, C1-156, C1-157, C1-158, C1-159a, C1-159b, C1-165, C1-166, C1-168, C1- 170a, C1-170b, C1-177, C1-188, C1-200, C1-208 , C1-213, C1-226, C1-238, C1-243, C1-247, C1-2 62a, C1-262b, C1-262c, C1-262d, C1-266, C1-28 5a to C1-285z, C1-285a1 to C1-285i1, C1-291a to C1- 291z, C1-291a1 to C1-291i1, C1-297a to C1-297z, C 1-297a1 to C1-297i1, C1-305, C1-306, C1-311, C1 -362, C1-397, C1-402, C1-407, C1-411, C1-414, C1-419, C1-424, C1-428, C1-436, C2-005, C3-00 5, C2-008, C3-008, C2-021, C3-021, C2-022, C3- 022, C2-029, C3-029, C2-031, C3-031, C2-035, C 3-035, C2-041, C3-041, C2-042, C3-042, C2-043 ​ , C3-043, C2-047, C3-047, C2-050, C3-050, C2-0 56, C3-056, C2-061, C3-061, C2-064, C3-064, C2 -070, C3-070, C2-075, C3-075, C2-081, C3-081, C2-086, C3-086, C2-088, C3-088, C2-090, C3-09 0, C2-094, C3-094, C2-099, C3-099, C2-102, C3- 102, C2-110, C3-110, C2-113, C3-113, C2-114, C 3-114, C2-119a, C3-119a, C2-119b, C3-119b, C2 -123, C3-123, C2-127, C3-127, C2-131, C3-131, C2-137a, C3-137a, C2-137b, C3-137b, C2-140, C 3-140, C2-147a, C3-147a, C2-147b, C3-147b, C2 -151, C3-151, C2-152, C3-152, C2-156, C3-156, C2-157, C3-157, C2-158, C3-158, C2-159a, C3-1 59a, C2-159b, C3-159b, C2-165, C3-165, C2-166 , C3-166, C2-168, C3-168, C2-170a, C3-170a, C2 -170b, C3-170b, C2-177, C3-177, C2-188, C3-18 8, C2-200, C3-200, C2-208, C3-208, C2-213, C3- 213, C2-226, C3-226, C2-238, C3-238, C2-243, C 3-243, C2-247, C3-247, C2-262a, C3-262a, C2-2 62b, C3-262b, C2-262c, C3-262c, C2-262d, C3-2 62d, C2-266, C3-266, C2-285a to C2-285z, C3-285 a to C3-285z, C2-285a1 to C2-285i1, C3-285a1 to C3- 285i1, C2-291a to C2-291z, C2-291a1 to C2-291i1, C3-291a to C3-291z, C3-291a1 to C3-291i1, C2-297 a to C2-297z, C2-297a1 to C2-297i1, C3-297a to C3-2 97z, C3-297a1 to C3-297i1, C2-305, C3-305, C2-3 06, C3-306, C2-311, C3-311, C2-362, C3-362, C2 -397, C3-397, C2-402, C3-402, C2-407, C3-407, C2-411, C3-411, C2-414, C3-414, C2-419, C3-41 9, C2-424, C3-424, C2-428, C3-428 having the structure of, claim 1 to 5 of any one of the conjugates of camptothecin analogs: 【Chemical 22】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] Wherein, mAb is an antibody.

13. The following 29, 31, 35, 41, 42, 43, 47, 50, 56, 61, 64, 7 ０、７５、８１、８６、８８、９０、９４、９９、１０２、１１０、１１３、１１４、１ 19a, 119b, 123, 127, 131, 137a, 137b, 140, 147a, 147b, 151, 152, 157, 158, 159a, 159b, 165, 166, 1 68, 170a, 170b, 177, 188, 200, 208, 213, 226, 238 , 243, 247, 262a, 262b, 262c, 262d, 266, 285 (285 a to 285z, 285a １ to 285i １ ), 291, 297, 305, 306, 311, 362, 397, 402, or having the structure of 436, for the production of a CPT conjugate, The compounds of formula (VI), (VII), (VIII), (IX), and (X) according to claim 9:

14. 【Chemical 23】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 The conjugate according to claim 1, 2, 3, 4, 5, 1 0, or 12, wherein the cell-binding molecule (T or mAb) is selected from: (A); antibodies, proteins, pro-bodies, nanobodies, vitamins (including folic acids), peptides, polymeric micelles, liposomes, lipoprotein-based drug carriers, nanoparticle drug carriers, dendrimers, and molecules or particles bound to cell-binding ligands or coated with cell-binding ligands, or combinations of the above; (B); antibody-like proteins, full-length antibodies (polyclonal antibodies, monoclonal antibodies, antibody dimers, antibody multimers), multispecific antibodies (selected from bispecific antibodies, trispecific antibodies, or tetra specific antibodies); single-chain antibodies, antibody fragments that bind to target cells, monoclonal antibodies, single-chain monoclonal antibodies, monoclonal antibody fragments that bind to target cells, chimeric antibodies, chimeric antibody fragments that bind to target cells, domain antibodies, domain antibody fragments that bind to target cells, surface-reconstructed antibodies, single-chain surface-reconstructed antibodies, surface-reconstructed antibodies that bind to target cells, humanized antibodies, surface-reconstructed humanized antibodies, single-chain humanized antibodies, human ​ Humanized antibody fragments, anti-idiotype (anti-Id) antibodies, CDRs, bispecific antibodies, trispecific antibodies, tetra specific antibodies, miniantibodies, probodies, probody fragments, small immunoproteins (SIPs), lymphokines, hormones, vitamins, growth factors, colony-stimulating factors, nutrient transport factors, large molecular weight proteins, fusion proteins, kinase inhibitors, gene targeting agents, nanoparticles, or polymers modified with antibodies or large molecular weight proteins; (C) cell-binding ligands or receptor agonists selected from the following: folic acid derivatives; glutamic acid urea derivatives; somatostatin and its analogs (selected from the group consisting of octreotide (Sandostatin) and lanreotide (Somatuline)).); aromatic sulfonamides; pituitary adenylate cyclase-activating peptide (PACAP) (PAC1); vasoactive intestinal peptide (VIP / PACAP) (VPAC1, VPAC2); melanocyte-stimulating hormone (α-MSH); cholecystokinin (CCK) / gastrin receptor agonists; (selected from the group consisting of gastrin-releasing peptide (GRP)).); neurotensin receptor ligands (NTR1, NTR2, NTR3); substance P (NK1 receptor) ligand; Bombesin (Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 consisting of neuropeptide Y (Y1-Y6); RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimeric and multimeric cyclic RGD peptides (selected from cRGDfV).), TAASGVRSMH and LTLRWLVGLMS (chondroitin sulfate proteoglycan NG2 receptor ligand) and homing peptides containing the F3 peptide; cell-penetrating peptides (CPPs); luteinizing hormone releasing hormone (LHRH) agonists and antagonists, and gonadotropin-releasing hormone (GnRH) agonists selected from the group consisting of, like testosterone production, acting by targeting follicle-stimulating hormone (FSH) and luteinizing hormone (LH), buserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), gonadorelin (Pyr-His-Trp-Ser-Tyr-Glu-AzGly-NH2), histrelin (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NH ​ ​ ​ ​ y-Leu-Arg-Pro-Gly-NH 2 ), goserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro ​ Et), leuprorelin (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), naprelin (Py r-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH 2 ), tryptorelin (Pyr-His-Trp-Ser-Ty r-D-Trp-Leu-Arg-Pro-Gly-NH 2 ), nafarelin, deslorelin, abarelix (Ac-D- 2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropyl-Pro- DAla-NH 2 )), setorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr -D-Cit-Leu-Arg-Pro-D-Ala-NH 2 ) Degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pi lysyl)Ala-Ser-4-amioPhe(L-hydroorotyl)-D-4-amioPhe(carbamoyl)-Leu-isop Lopil Lys-Pro-D-Ala-NH 2 ), and ganirelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pi lysyl)Ala-Ser-Tyr-D-(N9, N10-diethyl)-homoArg-Leu-(N9, N10-diethyl)-homoArg-P ro-D-Ala-NH 2 a peptide hormone selected from the group consisting of); Toll-like receptor (TLR ), a ligand, a C-type lectin, and a Nod-like receptor (NLRs) ligand; a calcitonin receptor agonist; an integrin GRGDSPK, cyclo(RGDFV)(L1) and its derivatives [cyclo(-N(Me) receptors and their receptor subtypes (α Ｖ β １ 、α Ｖ β ３ 、α Ｖ β ５ 、α Ｖ β ６ 、α ６ β ４ 、 α ７ β １ 、 α Ｌ β ２ 、 α ＩＩｂ β ３ is selected from the group consisting of. ) An agonist ( R-GDFV), cyclo(R-Sar-DfV), cyclo(RG-N(Me)D-fV) , cyclo(RGD-N(Me)f-V), cyclo(RGDF-N(Me)V-)(ciliate )]; a nanobody (a derivative of VHH (camel Ig)); a domain antibody (dAb, a derivative of VH or VL domain), a bispecific T cell inducer (Bite, a bispecific antibody); a bispecific affinity targeting (DART, a bispecific antibody); a tetravalent tandem antibody (TandAb , a dimerized bispecific antibody); an anticalin (a derivative of lipocalin); an adnectin (the 10th FN3 (fibronectin)); a designed ankyrin repeat protein (DARPins); an avimer; an EGF receptor and a VEGFR agonist (D): a small molecule of a cell-binding molecule / ligand or a cell receptor agonist selected from the following: LB01 (folic acid) represented by the following structure, LB02 (PSMA ligand), LB03 (PSMA ligand), LB04 (PSMA ligand), LB05 (somatostatin), ； LB06 (somatostatin), LB07 (octreotide, a somatostatin analog), L B08 (lanreotide, a somatostatin analog), LB09 (bapreotide (samba), a somatostatin analog), LB10 (CAIX ligand), LB11 (CAIX ligand d), LB12 (gastrin-releasing peptide receptor (GRPr), MBA), LB13 (yellow ​ ​ ​ Gonadotropin-releasing hormone (LH-RH) ligand and GnRH), LB14 (luteotropic hormone-releasing hormone (LH-RH) and GnRH ligand), LB15 (GnRH ant agonist, abarelix), LB16 (cobalamin, vitamin B12 analog), L B17 (cobalamin, vitamin B12 analog), LB18 (α ｖ β ３ integrin receptor for, cyclic RGD pentapeptide), LB19 (heterobivalent peptide ligand for VEGFR), LB20 (neuromedin B), LB21 (G protein-coupled receptor Bombesin for the body), LB22 (TLR for Toll-like receptor ２ ), LB23 (a LB24 (α for androgen receptor) ｖ Sirencitide for integrin receptor (cilengitide) / cyclo(-RGDfV-), LB23 (fludrocortisone ), LB25 (rifabutin analog), LB26 (rifabutin analog), LB27 ( rifabutin analog), LB28 (fludrocortisone), LB29 (dexamethasone) , LB30 (fluticasone propionate), LB31 (beclomethasone dipropionate) , LB32 (triamcinolone acetonide), LB33 (prednisone), LB34 (p rednisolone), LB35 (methylprednisolone), LB36 (betamethasone), LB 37 (irinotecan analog), LB38 (crizotinib analog), LB39 (bortezomib analog) carfilzomib analog), LB40 (carfilzomib analog), LB41 (carfilzomib analog), LB42 (leuprolide analog), LB43 (trypt relin analog), LB44 (clindamycin), LB45 (liraglutide analog), L B46 (semaglutide analog), LB47 (retapamulin analog), LB48 (indi relin analog), LB49 (vinblastine analog), LB50 (lixisenatide analog) , LB51 (osimertinib analog), LB52 (nucleoside analog), LB53 (e rlotinib analog), or LB54 (lapatinib analog); 【Chemical 24】 [Chemical] [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】

15. The cell-binding molecule is a tumor cell, a virus-infected cell, a microorganism-infected cell, a parasite-infected cell , an autoimmune disease cell, an activated tumor cell, a bone marrow cell, an activated T cell, an affected B cell , a melanocyte, or any cell expressing any one of the following antigens or receptors The conjugate according to any one of claims 1 to 5, 10 or 12, which can be targeted: CD1, CD1 a, CD1b, CD1c, CD1d, CD1e, CD2, CD3, CD3d, CD3e, CD3g, CD4, CD5, CD6, CD7, CD8, CD8a, CD8b, CD9, C D10, CD11a, CD11b, CD11c, CD11d, CD12w, CD13, C D14, CD15, CD16, CD16a, CD16b, CDw17, CD18, CD1 9, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD2 7, CD28, CD29, CD30, CD31, CD32, CD32a, CD32b, C D33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, C D41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD 44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD49c , CD49d, CD49f, CD50, CD51, CD52, CD53, CD54, CD 55, CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, C D65, CD65s, CD66, CD66a, CD66b, CD66c, CD66d, C D66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72 , CD73, CD74, CD75, CD75s, CD76, CD77, CD78, CD7 9, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, C D85, CD85a, CD85b, CD85c, CD85d, CD85e, CD85f, CD85g, CD85i, CD85j, CD85k, CD85m, CD86, CD87, CD88, CD89, CD90, CD91, CD92, CD93, CD94, CD95, CD96, CD97, CD98, CD99, CD100, CD101, CD102, CD 103, CD104, CD105, CD106, CD107, CD107a, CD107 b, CD108, CD109, CD110, CD111, CD112, CD113, CD 114, CD115, CD116, CD117, CD118, CD119, CD120, CD120a, CD120b, CD121, CD121a, CD121b, CD122, CD123, CD123a, CD124, CD125, CD126, CD127, CD1 28, CD129, CD130, CD131, CD132, CD133, CD134, C D135, CD136, CD137, CD138, CD139, CD140, CD140 a, CD140b, CD141, CD142, CD143, CD144, CD145, C Dw145, CD146, CD147, CD148, CD149, CD150, CD15 1, CD152, CD153, CD154, CD155, CD156, CD156a, C D156b, CD156c, CD156d, CD157, CD158, CD158a, C D158b1, CD158b2, CD158c, CD158d, CD158e1, CD1 58e2, CD158f2, CD158g, CD158h, CD158i, CD158j , CD158k, CD159, CD159a, CD159b, CD159c, CD160 , CD161, CD162, CD163, CD164, CD165, CD166, CD1 67, CD167a, CD167b, CD168, CD169, CD170, CD171 , CD172, CD172a, CD172b, CD172g, CD173, CD174, CD175, CD175s, CD176, CD177, CD178, CD179, CD1 79a, CD179b, CD180, CD181, CD182, CD183, CD184 , CD185, CD186, CDw186, CD187, CD188, CD189, CD 190, CD191, CD192, CD193, CD194, CD195, CD196, CD197, CD198, CD199, CDw198, CDw199, CD200, CD 201, CD202, CD202(a, b), CD203, CD203c, CD204, CD205, CD206, CD207, CD208, CD209, CD210, CDw2 10a, CDw210b, CD211, CD212, CD213, CD213a1, CD 213a2, CD214, CD215, CD216, CD217, CD218, CD21 8a, CD218, CD21b9, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD23 0, CD231, CD232, CD233, CD234, CD235, CD235a, C D235b, CD236, CD237, CD238, CD239, CD240, CD24 0ce, CD240d, CD241, CD242, CD243, CD244, CD245 , CD246, CD247, CD248, CD249, CD250, CD251, CD2 52, CD253, CD254, CD255, CD256, CD257, CD258, C D259, CD260, CD261, CD262, CD263, CD264, CD265 , CD266, CD267, CD268, CD269, CD270, CD271, CD2 72, CD273, CD274, CD275, CD276, CD277, CD278, C D279, CD281, CD282, CD283, CD284, CD285, CD286 , CD287, CD288, CD289, CD290, CD291, CD292, CD2 93, CD294, CD295, CD296, CD297, CD298, CD299, C D300, CD300a, CD300b, CD300c, CD301, CD302, CD 303, CD304, CD305, CD306, CD307, CD307a, CD307 b, CD307c, CD307d, CD307e, CD307f, CD308, CD30 9, CD310, CD311, CD312, CD313, CD314, CD315, CD 316, CD317, CD318, CD319, CD320, CD321, CD322, CD323, CD324, CD325, CD326, CD327, CD328, CD32 9, CD330, CD331, CD332, CD333, CD334, CD335, CD 336, CD337, CD338, CD339, CD340, CD341, CD342, CD343, CD344, CD345, CD346, CD347, CD348, CD34 9, CD350, CD351, CD352, CD353, CD354, CD355, CD 356, CD357, CD358, CD359, CD360, CD361, CD362, CD363, CD364, CD365, CD366, CD367, CD368, CD36 9, CD370, CD371, CD372, CD373, CD374, CD375, CD 376, CD377, CD378, CD379, CD381, CD382, CD383, CD384, CD385, CD386, CD387, CD388, CD389, CRIP TOR, CR, CR1, CRGF, CXCR5, LY64, TDGF1, 4-1BB, AP O2, ASLG659, BMPR1B, 5AC, 5T4 (villus glycoprotein, TPBG , 5T4, Wnt activation inhibitor 1 or WAIF1), adenocarcinoma antigen, AGS-5, AGS- 22M6, Activin receptor-like kinase 1, AFP, AKAP-4, ALK, α integrin, αvβ6, Aminopeptidase N, Amyloid β, Androgen receptor, Angiopoietin 2, Angiopoietin 3, Annexin A1, Anthrax toxin protective antigen, Anti-transferrin receptor, AOC3 (VAP-1), B7-H3, Anthrax, BAFF (B-cell activating factor), BCMA, B-lymphocytes, bcr-abl, Bombesin, BORIS, C5, C242 antigen, CA125 (Carbohydrate antigen 125, MUC16), CA-IX (or CAIX, Carbonic anhydrase 9), CALLA, CanAg, Canine IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11 (C-C motif chemokine 11), CCR4 (CC chemokine receptor type 4), CCR5, CD3E (epsilon), CEA (Carcinoembryonic antigen), CEACAM3, CEACAM5 (Carcinoembryonic antigen), CFD (Factor D), Ch4D5, Cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), Clumping factor A, cMet, Cripto, FCSF1R (Colony stimulating factor 1 receptor), CSF2 (Colony stimulating factor 2, Granulocyte macrophage colony stimulating factor (GM-CSF)), CSP4, CTLA4 (Cytotoxic T-lymphocyte associated protein 4), CTAA16.88 tumor antigen, CXCR4, CXCR chemokine receptor type 4, cADP ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL4 (Delta-like ligand 4), DPP4 (Dipeptidyl peptidase 4), DR5 (Death receptor 5), Escherichia coli Shiga toxin type 1, Escherichia coli Shiga toxin type 2, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, Endoglin, Endothelin B receptor, Endotoxin, EpCAM (Epithelial cell adhesion molecule), EphA2, Epithin, ERBB2 (Epidermal growth factor receptor 2), ERBB3, ERG (TMPSRS2ETS fusion gene), Escherichia coli, ET V6-AML, FAP (Fibroblast activation protein α), FCGR1, α-fetoprotein, Fibrin II, β-chain, Fibronectin external domain B, FOLR (Folate receptor), Folate receptor α, Folate hydrolase, Fos-related antigen 1F, F protein of RSV ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Protein, Frizzled receptor, fucosyl GM1, GD2 ganglioside, G-28 (cell surface glycolipid antigen), GD3 idiotype, GloboH, glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor alpha chain, growth differentiation factor 8, GP100, GP NMB (membrane protein NMB), GUCY2C (guanylate cyclase 2C, guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor, heat-stable enterotoxin receptor (hSTAR)), heat shock protein, hemagglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1) HER2, HER2 / neu, HER3 (ERBB-3), IgG4, HGF / SF (stem cell growth factor / cell-dispersing factor), HHGF receptor, HIV-1, histone complex, HLA- DA (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human cell-dispersing factor receptor kinase, HPV E6 / E7, Hsp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idiotype, IGF 1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN-γ, influenza hemagglutinin, IgE, IgE Fc region, IGHE, interleukin (IL- 1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-6R, IL-7, IL -8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL -17, IL-17A, IL-18, IL-19, IL-20, IL-21, IL-22 IL-23, IL-27, or IL-28), IL-31RA, ILGF2 (insulin 1, α6β4, α7β7, αIIβ3, α5β5, αvβ5), interferon γ-induced protein, ITAGA2, ITGB2, KIR2D, LCK, Le, legumain, Lewis -Y antigen, LFA-1 (lymphocyte function-related antigen 1, CD11a), LHRH, LINGO-1, lipoteichoic acid, LIV1A, LM P2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, M AGE-3, MAGEA1, MAGEA3, MAGE4, MART1, MCP-1, MI F (macrophage migration inhibitory factor or glycosylation inhibitory factor (GIF)), MS4A1 ( Factor 2), integrin (α4, α ＩＩＩｂ β ３ 、αvβ3, α ４ β ７ 、α5β ​ ​ ​ ​ ​ ​ ​ Transmembrane 4-Domain Subfamily A Member 1), MSLN (Mesothelin), MUC1 ( Mucin 1, Cell Surface-Associated (MUC1) or Polymorphic Epithelial Mucin (PEM)), MUC1-K LH, MUC16 (CA125), MCP1 (Monocyte Chemoattractant Protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1 (Transmembrane 4-Domain Subfamily A), MYCN, Myelin-Associated Glycoprotein, Myostatin, NA17, NARP-1, NCA-90 (Granulocyte Antigen), Nectin-4 (ASG-22ME), NGF, Neural Apopt osis Regulatory Protease 1, NOGO-A, Notch Receptor, Nucleolin, Neu Oncogene Product, NY-BR-1, NY-ESO-1, OX-40, OxLDL (Oxidized Low-Density Lipoprotein), OY-TES1, P21, p53 Non-Mutant, P97, Page4, PAP, Paratope Against (N-Glycolylneuraminic Acid), PAX3, PAX5, PCS K9, PDCD1 (PD-1, Programmed Cell Death Protein 1), PDGF-Rα (Platelet-Derived Growth Factor Receptor α), PDGFR-β, PDL-1, PLAC1, PLA P-Like Testicular Alkaline Phosphatase, Platelet-Derived Growth Factor Receptor β, Sodium Phosphate Cotrans porter, PMEL17, Polysialic Acid, Proteinase 3 (PR1), Prostate Cancer, PS (Ho sphatidylserine), Prostate Cancer Cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, Rabies V irus Glycoprotein, RHD (Rh Polypeptide 1 (RhPI)), Rhesus Factor (R hesus factor), RANKL, PhoC, Ras Mutant, RG55, ROB O4, RS Virus, RON, Sarcoma Metastasis Breakpoint, SART3, Sclerostin SLAMF7 (SLAM Family Member 7), Selectin P, SDC1 (Syndecan 1), sLe(a), Somatomedin C, SIP (Sphingosine-1-Phosphate) Somatostatin, Sperm Protein 17, SSX2, STEAP1 (Prostate 1 Six-Transmembrane Epithelial Antigen), STEAP2, STn, TAG-22 (Tumor-Associated Glycoprotein 72), Sa rbivin, T-Cell Receptor, T-Cell Transmembrane Protein, TEM1 (Tumor Epithelial Marker 1), TENB2, Tenascin C (TN-C), TGF-α, TGF-β (Transforming Growth Factor β), TGF-β1, TGF-β2 (Transforming Growth Factor β2), Tie(CD202b), Tie2, TIM-1(CDX-014), TN, TNF, T NF-α, TNFRSF8, TNFRSF10B(tumor necrosis factor receptor superfamily member 10B), TNFRSF13B(tumor necrosis factor receptor superfamily member 13B), TPBG(trophoblast glycoprotein), TRAIL-R1(tumor necrosis apoptosis inducing ligand receptor 1), TRAILR2(cell death receptor 5(DR5)), major related calcium signal transducer 2, tumor-specific glycosylation of MUC1, TW AK receptor, TYRP1(glycoprotein 75), TRP-2, tyrosinase, VCAM- 1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR2, or vimentin, WT1, XAGE1, or any insulin growth factor receptor-expressing cell, or any epidermal growth factor receptor.

16. The tumor cells according to claim 15 are selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cell carcinoma cells, small cell lung cancer cells, non-small cell lung cancer cells, testicular cancer cells, malignant cells, or any cells that grow and divide at a rapid pace in a disorderly manner and cause cancer.

17. A pharmaceutical composition for the treatment or prevention of cancer, an autoimmune disease, or an infectious disease, comprising a therapeutically effective amount of the conjugate compound according to claims 1 to 5, 10 or 12, and a pharmaceutically acceptable salt, carrier, diluent, or excipient, or a combination of the conjugates.

18. The conjugate according to claims 1 to 5, 10, or 12, having cell killing activity in vitro (in vitro), in vivo (in vivo), or ex vivo (e x vivo).

19. A chemotherapeutic agent, radiotherapy, immunotherapeutic agent, autoimmune disease drug, anti-infective agent, or synergistically 。 administered simultaneously with another conjugate for treating or preventing cancer, an autoimmune disease, or an infectious disease, the pharmaceutical composition according to claim 17.

20. The chemotherapeutic agent according to claim 19 is selected from any one or more of the following: (1) a) An alkylating agent selected from the following: nitrogen mustard: chloramb sil, chloronaphazine, cyclophosphamide, dacarbazine, estramustine, ifos ​ ​ ​ Sphamid, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobu ronitol, melphalan, mitolactol, pipobroman, nobenbitin, fenestin rine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1 065 and synthetic analogs of adozelesin, carzelesin and bizelesin; duocarmy cin and its synthetic analogs KW-2189 and CBI-TMI; benzodiazepine dimers or pyrrolobenzodiazepine (PBD) dimers, tomatimycin dimers, indri nobenzodiazepine dimers, imidazobenzothiadiazepine dimers, or oxazolidino benzodiazepine dimers; nitrosourea compounds including carmustine, lomustine, chlorozotocin, fotemustine , nimustine, ranimustine; alkyl sulfonates including busulfan, treosulfan , improsulfan, and piposulfan; triazene or dacarbazine; platinum-containing compounds including carboplatin, cisplatin, and oxaliplatin; aziridines, benzodopa, carboquone, meturedopa, and uredopa; ethyl lenimines, and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide , triethylenethiophosphoramide, trimethylolomelamine; b) Plant alkaloids selected from the group consisting of: vinca alkaloids including vincristine, vinblastine, vindesine, vinorelbine, navelbine; taxoids including paclitaxel and docetaxel and their analogs; maytansinoids including DM1, DM2, DM 3, DM4, DM5, DM6, DM7, maytansine, ansamitocin and their analogs; cryptophycins including the group of cryptophycin 1 and cryptophycin 8; epothilones, erythrobins, discodermolides, briostatin s, drostatins, auristatins, tubulysins, cephalostatins; pancratistatin; sarcodictyin; spongistatin; c) DNA topoisomerase inhibitors selected from: 9-aminocamptothecin camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, ​ ​ ​ ​ ​ ​ ​ Irinotecan, mitoxantrone, novantrone, retinoic acid (retinols), teni poside, topotecan, 9-nitrocamptothecin or epipodophyllins containing RFS 2000; and mitomycins, and their analogs; d) Antimetabolites: {[Antifolates: (DHFR inhibitors: methotrexate, trimethoprim, denopterin, pteropterin, aminopterin (4-aminopteroic acid), or other folate analogs.); IMP dehydrogenase inhibitors (including mycophenolic acid, thiazofurin, ribavirin, EICAR).); Ribonucleotide reductase inhibitors (including hydroxyurea, deferoxamine).]; [Pyrimidine analogs: Uracil analogs (including ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, raltitrexed).); Cytosine analogs: (including cytarabine, cytosine arabinoside, fludarabine).); Purine analogs: (including azathioprine, fludarabine, mercaptopurine, thiampurine, thioguanine).]; Folic acid supplements, folinic acid} selected from the group consisting of; e) Hormone therapy agents: Receptor antagonists: [Antiestrogens: (including megestrol, laroxifene, tamoxifen); LHRH agonists: (including goserelin, leuprolide acetate); Antiandrogens: (including bicalutamide, flutamide, calusterone, drostanolone propionate, epitestanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, trilostane, and other similar androgen inhibitors).]; Retinoids / Triangle muscle: [Vitamin D3 analogs: (including CB1093, EB1089, KH1060, cholecalciferol, ergocalciferol); Photodynamic therapy agents: (including verteporfin, phthalocyanine, photosensitizer Pc4, demethoxyporphyrin A); Cytokines: (including interferon alpha, interferon gamma, tumor necrosis factor (TNF), TNF domain-containing human proteins)]} selected from; f) Kinase inhibitors: BIBW2992 (anti-EGFR / Erb2), imatinib, ge ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Fitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, bismodegib, iniparib, luxitinib, CYT387, axitinib, tiboxanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinesib, selected from the group consisting of; g) Olaparib, niraparib, iniparib, talazoparib, veliparib, CEP9722 (Cephalon), E7016 (Astellas), BGB-290 (BeiGene), or 3 -aminobenzamide, a poly(ADP-ribose) polymerase (PARP) inhibitor selected from the group consisting of; h) Enediyne antibiotics (calicheamicins, calicheamicin γ1, δ1, α1, or β1; dynemicin A and dynemicin including deoxydynemicin; esperamicin, kedarcidin, C-1027, mazlopeptin, or neocarzinostatin chromophore and related pigment protein enediyne antibiotic chromophores selected from), aclarubicin, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, carabicin, calminomycin, cardifilin; chromomycins, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, eribulin, esorubicin, idarubicin, marcellomycin, mitomycins (nitomycins), mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, queramycin, rhodomycin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin, an antibiotic selected from; i) Polyketides (acetogenins), bratasin and bratasinone; gemcitabine, j) k) l) m) n) o) p) q) r) s) t) u) v) w) x) y) z) aa) Epoxomicins and carfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zibotentan, PLX4032, STA-909 0, Stimuvax, alovectin-7, zygeba, probenecid, elbow, isoprenylation inhibitors and lovastatin, dopaminergic neurotoxins and 1-meth yl-4-phenylpyridinium ion, cell cycle inhibitors (including staurosporine), a ctinomycins (including actinomycin D, dactinomycin), amanitins, bleomycins (including bleomycin A2, bleomycin B2, peplomycin ), anthracyclines (including daunorubicin, doxorubicin (adriamycin), i darubicin, epirubicin, pirarubicin, zorubicin), mitoxantrone, MDR inhibitor or verapamil, Ca ２＋ ATP inhibitor or thapsigargin, histone dea histone deacetylase inhibitors (including vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat (MGCD0103), belinostat, PCI-24781, entinostat, SB939, resminostat, givinostat, AR-42, CUDC- 101, sulforaphane, trichostatin A); thapsigargin, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A, adrenolytic agents (selected from the group consisting of aminoglutethimide, mitotane, trilostane), aceglutamide; aldophosphamide cricoside; aminolevulinic acid; amsacrine (a msacrine); arabinoside, bestrabucil; bisantrene; edatrexate ; defofamine; dexamethasone; diazicon; difluoromethylornithine (DFMO), difluoro romethylornithine; elliptinium acetate; etoposide; gallium nitrate, gastrocine, hydroxy urea; ibandronate, lentinan; lonidamine; mitoguazone; mopidamol; nit ralactin; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethyl hydrazide; procarbazine; PSK (registered trademark); razoxane; lysroxine; schizofi ran; spirigermanium; tenuazonic acid; triazicon; 2,2’,2’’-trich lorotriethylamine; trichothecenes (including T2 toxin, verrucarin A, roridin A, and anguidine); urethane, siRNA, antisense pharmaceuticals; 2) Anti-autoimmune disease drugs: Cyclosporine, Cyclosporine A, Aminocaproic acid, Aza thioguanine, Bromocriptine, Chlorambucil, Chloroquine, Cyclophosphamide, Cor ticosteroids (Amcinonide, Betamethasone, Budesonide, Hydrocortisone, Fluniso lide, Fluticasone Propionate, Fluocortolone Danazol), Dexamethasone, Triamcinolone Acetonide, Di betamethasone Valerate).), DHEA, Etanercept, Hydroxychloro quine, Infliximab, Meloxicam, Methotrexate, Mofetil, Mycophenolate mofetil, Prednisone, Sirolimus, Tacrolimus; 3) Anti-infective drugs: a) Aminoglycosides: Amikacin, Astromicin, Gentamicin (Netilmicin, Sisomicin, Isepamicin), Hygromycin B, Kanamycin (Am ikacin, Albekacin, Bekanamycin, Dibekacin, Tobramycin), Neomycin (Framycetin, Paromomycin, Ribostamycin), Netilmicin, Spectinomycin , Streptomycin, Tobramycin, Verdamicin; b) Amphenicols: Azidamfenicol, Chloramphenicol, Florfenicol, Thiamphenicol; c) Ansamycins: Geldanamycin, Herbimycin; d) Carbapenems: Biapenem, Doripenem, Ertapenem, Imipenem, Sila statin, Meropenem, Panipenem; e) Cephems: Carbacefem (Loracarbef), Cefacetrile, Cefaclor , Cefradine, Cefadroxil, Cefalonium, Cefaloridine, Cefalothin or Cefalothin, Cefalexin, Cefaloglycin, Cefamandole, Cefapyrin, Cefatriaxone, Cefazafur, Cefazedone, Cefazolin, Cefbuperazone, Cefca pen, Cefdaloxime, Cefepime, Cefminox, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren , Cefepime, Cefetamet, Cefmenoxime, Cefodizime, Cefonicid, Cefopera zone, Ceforanide, Cefotaxime, Cefothiam, Cefozopran, Cefalexi n, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cef fepime, Cefotetan, Cefmenoxime, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefothiam, Cefozopran, Cefalexin, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cef fepime, Cefotetan, Cefmenoxime, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefothiam, Cefozopran, Cefalexin, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cef fepime, Cefotetan, Cefmenoxime, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefothiam, Cefozopran, Cefalexin, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cef Quinome, cefuroxime, ceftazidime, cefotiam, cefixime, cefpodoxime, cef tizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefzonam, cefama cin (including cefoxitin, cefotetan, cefmetazole); e) Oxacephems: flomoxef, latamoxef; f) Glycopeptides: bleomycin, vancomycin (including oritavancin, telavancin), teicoplanin (dalbavancin), ramoplanin; g) Glycylcyclines: tigecycline; h) β-Lactamase inhibitors: penams (sulbactam, tazobactam), clavams ( clavulanic acid); i) Lincomycins: clindamycin, lincomycin; j) Lipopeptides: daptomycin, A54145, calcium-dependent antibiotics ( CDA); k) Macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolides (telithromycin, cethromycin), midecamycin, miocamycin, oleandomycin, rifamycin (rifampicin, rifampin, rifabutin, rifapentine), roxithromycin, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), troleandomycin, telithromycin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: linezolid; n) Penicillins: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, azidocillin, azlocillin, ben zylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, chromocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mesilinam (pivmesilinam), mezlocillin, methicillin, nafcillin, oxacillin, penamesilin, penicillin, phenethicillin, phenoxymethylpenicillin, piperacillin, pro picillin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, ​ Ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxacin, galenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, canofloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin; q) Streptogramins: pristinamycin, quinupristin / dalfopristin; r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole); s) Steroid antibacterial agents: selected from fusidic acid; t) Tetracyclines: doxycycline, chlortetracycline, chromocycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, glycylcycline (including tigecycline); u) Other antibiotics: annonacin, arsphenamine, bacteriophage inhibitor (bacitracin), DADA / LAR inhibitor (cycloserine), dactinomycin, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laurimarid, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitor (fosfomycin), nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampicin (rifampin), tazobactam tinidazole, uvaricin; (4) Antiviral drugs: a) Entry / fusion inhibitors: apravirine, maraviroc, vicriviroc, gp41 (enfuvirtide), PRO140, CD4 (ibalizumab); b) Integrase inhibitors: raltegravir, elvitegravir, globoidnan A c) Maturation inhibitors: bevirimat, vicafor; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ； ​ d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides and nucleotides: abacavir, acyclovir, adefovir, amdoxovir, apricitabine, brequinar, cidofovir, clevudine, dexelburcitabine, didanosine (DDI), erbucitabine, emtricitabine (FTC), entecavir, famciclovir, fluorouracil (5-FU), 3'-fluoro-substituted 2',3'-dideoxynucleoside analogs (consisting of 3'-fluoro-2',3'-dideoxythymidine (FLT) and 3'-fluoro-2',3'-dideoxyguanosine (FLG).) homibursen, ganciclovir, idoxuridine, lamivudine (3TC), L-nucleosides (including the group consisting of β-L-thymidine and β-L-2'-deoxycytidine.) penciclovir, lasivir, ribavirin, stampidine, stavudine set (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluridine, valacyclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT f) Non-nucleosides: amantadine, ataviridine, capravirine, diarylpyrimidine (etravirine, rilpivirine), delavirdine, docosanol, emivirine, efavirenz, foscarnet (phosphonoformic acid), imiquimod, interferon α, loviride, rodenosine, methylthiazone, nevirapine, NOV-205, pegylated interferon α, podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848), tromantadine; g) Protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, preclinavir, ritonavir, saquinavir, telaprevir (VX-950), tipranavir; h) Other types of antiviral drugs: abzyme, arbidol, calanolide a, celgosivir, cyanovirin-n, diarylpyrimidine, epigallocatechin gallate (EGCG), foscarnet, griffithsin, taribavirin (viramidine), hydroxycarbamide, KP-1461, miltefosine, preclinavir, portmanteau inhibitors, ribavirin, sericlib; (5) Pharmaceutically acceptable salts, acids, derivatives, hydrates or solvates of any of the above drugs ​ ​ ​ ）； ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ salt; or crystal structure; or optical isomer, racemic compound, diastereomer or enantio mer.

21. The synergist according to claim 19 is selected from one or more of the following drugs: abatacept , abemaciclib, abiraterone acetate, abraxane, acetaminophen / hydrocod one, acalabrutinib, aducanumab, adalimumab, ADXS31-142, ADX S-HER2, afatinib dimaleate, aldesleukin, alectinib, alemtuz umab, alitretinoin, ado-trastuzumab emtansine, amphetamine / dex stroamphetamine, anastrozole, aripiprazole, anthracycline, a ripiprazole, atazanavir, atezolizumab, atorvastatin, avelumab, Ax icabtagene ciloleucel, axitinib, belinostat, live BCG , bevacizumab, bexarotene, blinatumomab, bortezomib, bosutinib, brentux imab vedotin, brigatinib, budesonide, budesonide / formoterol, bupreno lufin, cabazitaxel, cabozantinib, capmatinib, capecitabine, calcifedi molib, T cells engineered with chimeric antigen receptor (CAR-T), celecoxib, ceritinib , cetuximab, kidamide, cyclosporine, cinacalcet, crizotinib, cobimet inib, cosentyx, crizotinib, tisagenlecleucel, CT L019, dabigatran, dabrafenib, dacarbazine, daclizumab, dacomitinib , daptomycin, daratumumab, darbepoetin alpha, darunavir, dasatinib, deniro kinji fucosidotoxin, denosumab, depakote (Depakote), dexlansopra zole, dexmethylphenidate, dexamethasone, DigniCap Cooling g System, dinutuximab, doxcycline, duloxetine, duvelisib , durvalumab, elotuzumab, emtricitabine / rilpivirine / tenofovir, fumar ate disoproxil, emtricitabine / tenofovir / efavirenz, enoxaparin, ensartinib, enzalutamide, epoetin alpha, erlotinib, esomeprazole, e szopiclone, etanercept, everolimus, exemestane, everolimus, exi Naciti ER, Ezetimibe, Ezetimibe / Simvastatin, Fenofibrate, Filgrastim Fingolimod, Fluticasone Propionate, Fluticasone / Salmeterol , Fulvestrant, Gazyva, Gefitinib, Glatiramer, Goserelin Acetate , Icotinib, Imatinib, Ibritumomab Tiuxetan, Ibrutinib, Idelalisib , Ifosfamide, Infliximab, Imiquimod, ImmuCyst, ImmunoBCG , Iniparib, Insulin Aspart, Insulin Detemir, Insulin Glargine , Insulin Lispro, Interferon α, Interferon α-1b, Inter , Interferon α-2a, Interferon α-2b, Interferon β, Interfer , Interferon β1a, Interferon β1b, Interferon γ-1a, Lapatinib, Ipil , Ipilimumab, Ipratropium Bromide / Salbutamol, Ixazomib, Kanuma , Lanreotide Acetate, Lenalidomide, Lenaridomide, Lenvatinib Mesylate, Retrozole , Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lis , Dexamfetamine, LN-144, Lorlatinib, Memantine, Methylphenidate , Metoprolol, Mekinist, Mericitabine / Rilpivirine / Tenofovir, Modafinil , Mometasone, Mycida c-C, Necitumumab, Neratinib, Nilotinib, Niraparib , Nivolumab, Ofatumumab, Obinutuzumab, Olaparib, Olmesartan, Ol , Olmesartan / Hydrochlorothiazide, Omalizumab, ω3 Fatty Acid Ethyl Ester, Onco , Lin, Oseltamivir, Osimertinib, Oxycodone, Palbociclib, Parvizumab , Panitumumab, Panobinostat, Pazopanib, Pembrolizumab, PD-1 Antibody, P , PD-L1 Antibody, Pemetrexed, Pertuzumab, Pneumococcal Conjugate Vaccine, Pomalidomide , Pregabalin, ProscaVax, Propranolol, Quetiapine, Rabeprazole , Radium 223 Chloride, Raloxifene, Raltegravir, Ramucirumab, Ranibizumab , Regorafenib, Ribociclib, Rituximab, Rivaroxaban, Romidepsin, Ro , Svastatin, Luxolitinib Phosphate, Salbutamol, Sabolitinib, Semaglutide , Sevamer, Sildenafil, Siltuximab, Sipuleucel-T, Sitagliptin Sitagliptin / Metformin, Solifenacin, Solanesumab, Sonidegib, Sorafenib, Sunitinib, Tacrolimus, Tacrolimus, Tadalafil, Tamoxifen, Tafinlar, Talimogene laherparepvec, Talazoparib, Telaprevir, Talazoparib, Temozolomide, Temsirolimus, Tenofovir / Emtricitabine, Disoproxil Fumarate Tenofovir, Testosterone Gel, Thalidomide, TICE BCG, Tiotropium Bromide, Tisagenlecleucel, Toremifene, Trametinib, Trastuzumab, Trabectedin (ecteinascidin 743), Trametinib, Tremelimumab, Trifluridine / Tipiracil, Uro-BCG, Ustekinumab, Valsartan, Verubecestat, Vandetanib, Bemorafenib, Venetoclax, Bortezomib, DIB-Aflibercept, and Zostavax, and analogs, derivatives, pharmaceutically acceptable salts, carriers, diluents or excipients therefor, or combinations thereof. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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